The incidence of transfusion-related acute lung injury using active surveillance: A systematic review and meta-analysis.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a leading cause of transfusion-related mortality. A concern with passive surveillance to detect transfusion reactions is underreporting. Our aim was to obtain evidence-based estimates of TRALI incidence using meta-analysis of active surveillance studies and to compare these estimates with passive surveillance. STUDY DESIGN AND METHODS: We performed a systematic review and meta-analysis of studies reporting TRALI rates. A search of Medline and Embase by a research librarian identified studies published between January 1, 1991 and January 20, 2023. Prospective and retrospective observational studies reporting TRALI by blood component (red blood cells [RBCs], platelets, or plasma) were identified and all inpatient and outpatient settings were eligible. Adult and pediatric, as well as general and specific clinical populations, were included. Platelets and plasma must have used at least one modern TRALI donor risk mitigation strategy. A random effects model estimated TRALI incidence by blood component for active and passive surveillance studies and heterogeneity was examined using meta-regression. RESULTS: Eighty studies were included with approximately 176-million blood components transfused. RBCs had the highest number of studies (n = 66) included, followed by platelets (n = 35) and plasma (n = 34). Pooled TRALI estimates for active surveillance studies were 0.17/10,000 (95% confidence intervals [CI]: 0.03-0.43; I2 = 79%) for RBCs, 0.31/10,000 (95% CI: 0.22-0.42; I2 = <1%) for platelets, and 3.19/10,000 (95% CI: 0.09-10.66; I2 = 86%) for plasma. Studies using passive surveillance ranged from 0.02 to 0.10/10,000 among the various blood components. DISCUSSION: In summary, these estimates may improve a quantitative understanding of TRALI risk, which is important for clinical decision-making weighing the risks and benefits of transfusion.

All-cause, premature, and cardiovascular death attributable to socioeconomic and ethnic disparities among New Zealanders with type 1 diabetes 1994-2019: a multi-linked population-based cohort study.

BACKGROUND: New Zealand (NZ) research into type 1 diabetes mellitus (T1DM) mortality can inform policy and future research. In this study we aimed to quantify the magnitude to which ethnicity and socioeconomic disparities influenced mortality at the population level among people with Type 1 diabetes (T1DM) in Auckland, New Zealand (NZ). METHODS: The cohort data were derived from the primary care diabetes audit program the Diabetes Care Support Service (DCSS), and linked with national primary care, pharmaceutical claims, hospitalisation, and death registration databases. People with T1DM enrolled in DCSS between 1994-2018 were included. All-cause, premature, and cardiovascular mortalities were estimated by Poisson regression models with adjustment for population-level confounders. The mortality rates ratio (MRR) was standardized against the DCSS type 2 diabetes population. Mortality rates were compared by ethnic group (NZ European (NZE) and non-NZE) and socioeconomic deprivation quintile. The population attributable fraction (PAF) was estimated for ethnic and socioeconomic disparities by Cox regression adjusting for demographic, lifestyle, and clinical covariates. The adjusted slope index inequality (SII) and relative index of inequality (RII) were used to measure the socioeconomic disparity in mortalities. RESULTS: Overall, 2395 people with T1DM (median age 34.6 years; 45% female; 69% NZE) were enrolled, among whom the all-cause, premature and CVD mortalities were 6.69 (95% confidence interval: 5.93-7.53), 3.30 (2.77-3.90) and 1.77 (1.39-2.23) per 1,000 person-years over 25 years. The overall MRR was 0.39 (0.34-0.45), 0.65 (0.52-0.80), and 0.31 (0.24-0.41) for all-cause, premature and CVD mortality, respectively. PAF attributable to ethnicity disparity was not significantly different for mortality. The adjusted PAF indicated that 25.74 (0.84-44.39)% of all-cause mortality, 25.88 (0.69-44.69)% of premature mortality, 55.89 (1.20-80.31)% of CVD mortality could be attributed to socioeconomic inequality. The SII was 8.04 (6.30-9.78), 4.81 (3.60-6.02), 2.70 (1.82-3.59) per 1,000 person-years and RII was 2.20 (1.94-2.46), 2.46 (2.09-2.82), and 2.53 (2.03-3.03) for all-cause, premature and CVD mortality, respectively. CONCLUSIONS: Our results suggest that socioeconomic disparities were responsible for a substantial proportion of all-cause, premature and CVD mortality in people with T1DM in Auckland, NZ. Reducing socioeconomic barriers to management and self-management would likely improve clinical outcomes.

Long-term impact of type 2 diabetes onset on dementia incidence rate among New Zealanders with impaired glucose tolerance: A tapered-matched landmark analysis over 25 years.

INTRODUCTION: We aimed to investigate the association between the onset of type 2 diabetes (T2D) and dementia incidence rates (IR) in the population with impaired glucose tolerance (IGT) identified in primary care in New Zealand (NZ) over 25 years. METHODS: Tapered matching and landmark analysis (accounting for immortal bias) were used to control for potential effects of known confounders. The association between T2D onset and 5- and 10-year IR of dementia was estimated by weighted Cox models. RESULTS: The onset of T2D was significantly associated with the 10-year IR of dementia, especially in the socioeconomically deprived, those of non-NZ European ethnicity, those currently smoking, and patients with higher metabolic measures. DISCUSSION: Our findings suggest that the onset of T2D is a significant risk factor for dementia in individuals with IGT. Dementia screening and structured diabetes prevention are vital in the population with IGT, particularly those from deprived or ethnic minority backgrounds. HIGHLIGHTS: Increased dementia incidence rate links with T2D onset in people with IGT. Significant incidence varied by ethnicity, socioeconomic status, and health factors. Results emphasize the diabetes manage and socioeconomic factors on dementia risk. Secondary analysis highlights the key role of vascular health in dementia prevention.

Effect of onset of type 2 diabetes on risks of cardiovascular disease and heart failure among new Zealanders with impaired glucose tolerance over 25 years: tapered-matched landmark analysis.

BACKGROUND: This study aimed to examine the association between the incident onset of T2DM and 5- and 10-year risks of CVD and HF in people with IGT identified in primary care in South and West Auckland, New Zealand (NZ) between 1994 and 2019. METHODS: We compared CVD and HF risks in patients with IGT and with/without T2D newly diagnosed within the exposure window (1-5 years). Tapered matching and landmark analysis (to account for immortal bias) were used to control for potential effects of known confounders. RESULTS: Among 26,794 patients enrolled with IGT, 845 had T2D newly diagnosed within 5 years from enrolment (landmark date) and 15,452 did not have T2D diagnosed. Patients progressing to T2D (vs. those not progressing) had a similar 5-year risk for CVD (hazard ratio 1.19; 95% CI 0.61-2.32) but significantly higher 10-year risk of CVD (2.45(1.40-4.29)), 5-year risk of HF (1.94(1.20-3.12)) and 10-year risk of HF (2.84(1.83-4.39). The association between the onset of T2D and risk of 10-year risk of CVD, 5-year and 10-year risk of HF was more likely among men, the socioeconomically deprived, those currently smoking, patients with higher metabolic measures and/or those with lower renal function. Patients of NZ European ethnicity had a lower 10-year risk of CVD. CONCLUSIONS: The study suggests that the diagnosis of T2D mediates the risk of CVD and HF in people with IGT. The development of risk scores to identify and better manage individuals with IGT at high risk of T2D is warranted.

Meta-analysis of bacterial growth characteristics in platelet components: Refining the inputs of a simulation analysis comparing the relative safety of testing strategies.

BACKGROUND: The relative safety of bacterial risk control strategies for platelets that include culture with or without rapid testing has been compared using simulation analysis. A wide range of bacterial lag and doubling times were included. However, published data on growth rates are available and these data have not been synthesized. We conducted a systematic review and meta-analysis to estimate growth rates and used these estimates to refine a comparative safety analysis of bacterial risk control strategies in the FDA guidance STUDY DESIGN AND METHODS: Data were extracted from published studies on bacterial growth rates in platelet components during storage. These data were used to estimate the practical range of growth rates. This refined the inputs for a simulation model comparing the safety of the testing strategies. RESULTS: In total, 108 growth curves for 11 different aerobic organisms were obtained. Doubling times ranged from 0.8 to 12 h, but the lower 90% range was approximately 1-5 h. The revised comparative safety simulation using the narrower 1-5-h range showed similar rankings to the prior simulation, with 48-h large-volume delayed sampling with 7-day expiration (48C-7) demonstrating the lowest-ranking relative performance at the 103 and 105 colony forming unit (CFU)/mL exposure thresholds. DISCUSSION: This was a two-step study. First, meta-analysis of published data on aerobic bacterial growth rates in stored platelets showed the vast majority of doubling times were 1-5 h. Next, an updated comparative safety simulation yielded similar results to a prior study, with 48C-7 showing the least favorable relative safety performance.

The epidemiology of transfusion-related acute lung injury: A scoping review and analysis.

BACKGROUND: The purpose of this scoping review was to identify available sources of evidence on the epidemiology of transfusion-related acute lung injury (TRALI) and whether meta-analysis on the incidence of TRALI is feasible. TRALI is a serious complication and the second leading cause of death related to blood transfusion. Estimates of the incidence of TRALI would provide a useful benchmark for research to reduce TRALI. STUDY DESIGN AND METHODS: We searched the Medline, EMBASE, and PubMed databases for publications related to the incidence of TRALI and hemovigilance. We included all studies irrespective of language or country. Both full-text articles and conference abstracts were included. Participants of the studies must all have received a blood transfusion. Reviews and case studies were excluded. RESULTS: We identified 427 articles or abstracts to include for review. More than half were abstracts, and the majority were published after 2010. Reported TRALI definitions varied, but only 27.2% of studies reported any definition for TRALI. TRALI rates were reported using different denominators, such as per blood unit (54.1%), patient (34.4%), and transfusion episode (14.8%). Study populations and contexts were mostly general (75.6% and 80.3%, respectively). There was also variation in study design with most being observational (90.6%) and only 13.1% of all studies used modern donor restriction policies. DISCUSSION: There was substantial variation in reporting in studies on TRALI incidence. Meta-analysis of TRALI rates may be feasible in specific circumstances where reporting is clear. Future studies should clearly report key items, such as a TRALI definition.

Bacterial culture time to detection in platelet components: An evidence synthesis and estimation of detection failures.

BACKGROUND: Non-pathogen reduction platelet bacterial risk control strategies in the US FDA guidance include at least one culture. Almost all of these strategies have a culture hold time of ≥12 h. Studies have reported time to detection (TTD) of bacterial cultures inoculated with bacteria from contaminated platelets, but these data and estimates of risk associated with detection failures have not been synthesized. METHODS: We performed a literature search to identify studies reporting TTD for samples obtained from spiked platelet components. Using extracted data, regression analysis was used to estimate TTD for culture bottles at different inoculum sizes. Detection failures were defined as events in which contaminated components are transfused to a patient. We then used published data on time of transfusion (ToT) to estimate the risk of detection failures in practice. RESULTS: The search identified 1427 studies, of which 16 were included for analysis. TTD data were available for 16 different organisms, including 14 in aerobic cultures and 11 in anaerobic cultures. For inocula of 1 colony forming unit (CFU), the average TTD for aerobic organisms was 19.2 h while it was 24.9 h in anaerobic organisms, but there was substantial overall variation. A hold time of 12 versus 24 h had minimal effect for most organisms. CONCLUSION: TTD variation occurs between bacterial species and within a particular species. Under typical inventory management, the relative contribution of culture detection failures is much smaller than the residual risk from sampling failures. Increasing the hold period beyond 12 h has limited value.

Precision quality control: a dynamic model for risk-based analysis of analytical quality.

OBJECTIVES: There is continuing pressure to improve the cost effectiveness of quality control (QC) for clinical laboratory testing. Risk-based approaches are promising but recent research has uncovered problems in some common methods. There is a need for improvements in risk-based methods for quality control. METHODS: We provide an overview of a dynamic model for assay behavior. We demonstrate the practical application of the model using simulation and compare the performance of simple Shewhart QC monitoring against Westgard rules. We also demonstrate the utility of trade-off curves for analysis of QC performance. RESULTS: Westgard rules outperform simple Shewhart control over a narrow range of the trade-off curve of false-positive and false negative risk. The risk trade-off can be visualized in terms of risk, risk vs. cost, or in terms of cost. Risk trade-off curves can be "smoothed" by log transformation. CONCLUSIONS: Dynamic risk-models may provide advantages relative to static models for risk-based QC analysis.

Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates.

Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs. In reprogramming, the same factors are often used to reprogram many different donor cell types. As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors, it remains unclear how identical combinations of transcription factors can silence so many different donor programs. Distinct lineage repressors would have to be induced in different donor cell types. Here, by studying the reprogramming of mouse fibroblasts to neurons, we found that the pan neuron-specific transcription factor Myt1-like (Myt1l) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. In agreement with its repressive function, the genomic binding sites of Myt1l are similar in neurons and fibroblasts and are preferentially in an open chromatin configuration. The Notch signalling pathway is repressed by Myt1l through silencing of several members, including Hes1. Acute knockdown of Myt1l in the developing mouse brain mimicked a Notch gain-of-function phenotype, suggesting that Myt1l allows newborn neurons to escape Notch activation during normal development. Depletion of Myt1l in primary postmitotic neurons de-repressed non-neuronal programs and impaired neuronal gene expression and function, indicating that many somatic lineage programs are actively and persistently repressed by Myt1l to maintain neuronal identity. It is now tempting to speculate that similar 'many-but-one' lineage repressors exist for other cell fates; such repressors, in combination with lineage-specific activators, would be prime candidates for use in reprogramming additional cell types.

Cardiovascular risk prediction in type 2 diabetes before and after widespread screening: a derivation and validation study.

BACKGROUND: Until recently, most patients with diabetes worldwide have been diagnosed when symptomatic and have high cardiovascular risk, meaning most should be prescribed cardiovascular preventive medications. However, in New Zealand, a world-first national programme led to approximately 90% of eligible adults being screened for diabetes by 2016, up from 50% in 2012, identifying many asymptomatic patients with recent-onset diabetes. We hypothesised that cardiovascular risk prediction equations derived before widespread screening would now significantly overestimate risk in screen-detected patients. METHODS: New Zealanders aged 30-74 years with type 2 diabetes and without known cardiovascular disease, heart failure, or substantial renal impairment were identified from the 400 000-person PREDICT primary care cohort study between Oct 27, 2004, and Dec 30, 2016, covering the period before and after widespread screening. Sex-specific equations estimating 5-year risk of cardiovascular disease were developed using Cox regression models, with 18 prespecified predictors, including diabetes-related and renal function measures. Equation performance was compared with an equivalent equation derived in the New Zealand Diabetes Cohort Study (NZDCS), which recruited between 2000 and 2006, before widespread screening. FINDINGS: 46 652 participants were included in the PREDICT-1° Diabetes subcohort, of whom 4114 experienced first cardiovascular events during follow-up (median 5·2 years, IQR 3·3-7·4). 14 829 (31·8%) were not taking oral hypoglycaemic medications or insulin at baseline. Median 5-year cardiovascular risk estimated by the new equations was 4·0% (IQR 2·3-6·8) in women and 7·1% (4·5-11·2) in men. The older NZDCS equation overestimated median cardiovascular risk by three times in women (median 14·2% [9·7-20·0]) and two times in men (17·1% [4·5-20·0]). Model and discrimination performance measures for PREDICT-1° Diabetse equations were also significantly better than for the NZDCS equation (eg, for women: R2=32% [95% CI 29-34], Harrell's C=0·73 [0·72-0·74], Royston's D=1·410 [1·330-1·490] vs R2=24% [21-26], C=0·69 [0·67-0·70], and D=1·147 [1·107-1·187]). INTERPRETATION: International treatment guidelines still consider most people with diabetes to be at high cardiovascular risk; however, we show that recent widespread diabetes screening has radically changed the cardiovascular risk profile of people with diabetes in New Zealand. Many of these patients have normal renal function, are not dispensed glucose-lowering medications, and have low cardiovascular risk. These findings have clear international implications as increased diabetes screening is inevitable due to increasing obesity, simpler screening tests, and the introduction of new-generation glucose-lowering medications that prevent cardiovascular events. Cardiovascular risk prediction equations derived from contemporary diabetes populations, with multiple diabetes-related and renal function predictors, will be required to better differentiate between low-risk and high-risk patients in this increasingly heterogeneous population and to inform appropriate non-pharmacological management and cost-effective targeting of expensive new medications. FUNDING: Health Research Council of New Zealand, Heart Foundation of New Zealand, and Healthier Lives National Science Challenge.

Automation of AMOEBA polarizable force field for small molecules: Poltype 2.

A next-generation protocol (Poltype 2) has been developed which automatically generates AMOEBA polarizable force field parameters for small molecules. Both features and computational efficiency have been drastically improved. Notable advances include improved database transferability using SMILES, robust torsion fitting, non-aromatic ring torsion parameterization, coupled torsion-torsion parameterization, Van der Waals parameter refinement using ab initio dimer data and an intelligent fragmentation scheme that produces parameters with dramatically reduced ab initio computational cost. Additional improvements include better local frame assignment for atomic multipoles, automated formal charge assignment, Zwitterion detection, smart memory resource defaults, parallelized fragment job submission, incorporation of Psi4 quantum package, ab initio error handling, ionization state enumeration, hydration free energy prediction and binding free energy prediction. For validation, we have applied Poltype 2 to ~1000 FDA approved drug molecules from DrugBank. The ab initio molecular dipole moments and electrostatic potential values were compared with Poltype 2 derived AMOEBA counterparts. Parameters were further substantiated by calculating hydration free energy (HFE) on 40 small organic molecules and were compared with experimental data, resulting in an RMSE error of 0.59 kcal/mol. The torsion database has expanded to include 3543 fragments derived from FDA approved drugs. Poltype 2 provides a convenient utility for applications including binding free energy prediction for computational drug discovery. Further improvement will focus on automated parameter refinement by experimental liquid properties, expansion of the Van der Waals parameter database and automated parametrization of modified bio-fragments such as amino and nucleic acids.

An Efficient Approach to Large-Scale Ab Initio Conformational Energy Profiles of Small Molecules.

Accurate conformational energetics of molecules are of great significance to understand maby chemical properties. They are also fundamental for high-quality parameterization of force fields. Traditionally, accurate conformational profiles are obtained with density functional theory (DFT) methods. However, obtaining a reliable energy profile can be time-consuming when the molecular sizes are relatively large or when there are many molecules of interest. Furthermore, incorporation of data-driven deep learning methods into force field development has great requirements for high-quality geometry and energy data. To this end, we compared several possible alternatives to the traditional DFT methods for conformational scans, including the semi-empirical method GFN2-xTB and the neural network potential ANI-2x. It was found that a sequential protocol of geometry optimization with the semi-empirical method and single-point energy calculation with high-level DFT methods can provide satisfactory conformational energy profiles hundreds of times faster in terms of optimization.

The incremental benefit of anaerobic culture for controlling bacterial risk in platelets: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Septic transfusion reactions are a principal cause of transfusion-related mortality. The frequency of detectable bacterial contamination is greater in platelets compared to other blood components because platelets are stored at room temperature. Most strategies outlined in the September 2019 FDA guidance require both aerobic culture (AC) and anaerobic culture (AnC) testing. We performed a systematic review and meta-analysis in an effort to provide the best available estimate of the effectiveness of AnC. MATERIALS AND METHODS: Our analysis was performed according to published guidelines. Broad and context-specific meta-analyses of bacterial detection rates in platelets by AnC were performed to assess the practical effectiveness of AnC as a risk control measure. RESULTS: Seven studies with a total of 1 767 014 tested platelet components were included for analysis. With exclusion of positives due to Cutibacterium/Propionibacterium species and redundancy due to AC results, AnC detected 0·06 contamination events per thousand (EPT) components tested, twofold lower than the AC (0·12 EPT). CONCLUSION: Excluding Cutibacterium/Propionibacterium species, AnC detects occasional bacterial contamination events that are not detected by AC (~1 in 17 000 platelet components).

E2EDNA: Simulation Protocol for DNA Aptamers with Ligands.

We present E2EDNA, a simulation protocol and accompanying code for the molecular biophysics and materials science communities. This protocol is both easy to use and sufficiently efficient to simulate single-stranded (ss)DNA and small analyte systems that are important to cellular processes and nanotechnologies such as DNA aptamer-based sensors. Existing computational tools used for aptamer design focus on cost-effective secondary structure prediction and motif analysis in the large data sets produced by SELEX experiments. As a rule, they do not offer flexibility with respect to the choice of the theoretical engine or direct access to the simulation platform. Practical aptamer optimization often requires higher accuracy predictions for only a small subset of sequences suggested, e.g., by SELEX experiments, but in the absence of a streamlined procedure, this task is extremely time and expertise intensive. We address this gap by introducing E2EDNA, a computational framework that accepts a DNA sequence in the FASTA format and the structures of the desired ligands and performs approximate folding followed by a refining step, analyte complexation, and molecular dynamics sampling at the desired level of accuracy. As a case study, we simulate a DNA-UTP (uridine triphosphate) complex in water using the state-of-the-art AMOEBA polarizable force field. The code is available at https://github.com/InfluenceFunctional/E2EDNA.

Open Source Remote Monitoring of Research Lasers.

An open source remote monitoring system is designed and built to address the needs of researchers to provide basic illuminated visual indication of laser operation for university research laboratories that are equipped with multiple types of high-powered lasers and have limited financial resources. The 3D printed remote monitoring system selectively monitors either the total current running through a laser or a TTL shutter signal to wirelessly indicate at the laboratory entrances that a laser is in use. Several lasers can be monitored in a single room and each room entrance can have its own wireless laser activity indicator. The wireless feature eliminates the expense of in-wall wiring for the system. An emergency shut off switch is included as an optional attachment. This article describes the design of the readily deployed open source laser monitoring system, including how it was built and tested for integration into a microscopy research laboratory.

Residual bacterial detection rates after primary culture as determined by secondary culture and rapid testing in platelet components: A systematic review and meta-analysis.

BACKGROUND: Primary culture alone was a bacterial risk control strategy intended to facilitate interdiction of contaminated platelets (PLTs). A September 2019 FDA guidance includes secondary testing options to enhance safety. Our objective was to use meta-analysis to determine residual contamination risk after primary culture using secondary culture and rapid testing. STUDY DESIGN AND METHODS: A December 2019 literature search identified articles on PLT bacterial detection rates using primary culture and a secondary testing method. We used meta-analysis to estimate secondary testing detection rates after a negative primary culture. We evaluated collection method, sample volume, sample time, and study date as potential sources of heterogeneity. RESULTS: The search identified 6102 articles; 16 were included for meta-analysis. Of these, 12 used culture and five used rapid testing as a secondary testing method. Meta-analysis was based on a total of 103 968 components tested by secondary culture and 114 697 by rapid testing. The residual detection rate using secondary culture (DRSC ) was 0.93 (95% CI, 0.24-0.6) per 1000 components, while residual detection rate using rapid testing (DRRT ) was 0.09 (95% CI, 0.01-0.25) per 1000 components. Primary culture detection rate was the only statistically significant source of heterogeneity. CONCLUSION: We evaluated bacterial detection rates after primary culture using rapid testing and secondary culture. These results provide a lower and upper bound on real-world residual clinical risk because these methods are designed to detect high-level exposures or any level of exposure, respectively. Rapid testing may miss some harmful exposures and secondary culture may identify some clinically insignificant exposures.

Bacterial contamination rate of platelet components by primary culture: a systematic review and meta-analysis.

BACKGROUND: Platelets have the highest bacterial contamination risk of all blood components, and septic transfusion reactions remain a problem. A good estimate of contamination rates could provide information about residual risk and inform optimal testing strategies. We performed a systematic review and meta-analysis of platelet contamination rates by primary culture. STUDY DESIGN AND METHODS: A literature search in December 2019 identified articles on platelet contamination rates using primary culture. We used meta-analysis to estimate the overall rate of contamination and meta-regression to identify heterogeneity. We studied the following sources of heterogeneity: collection method, sample volume, positivity criteria, and study date. Contamination rate estimates were obtained for apheresis (AP), platelet rich plasma (PRP), and buffy coat (BC) collection methods. RESULTS: The search identified 6102 studies, and 22 were included for meta-analysis. Among these 22 studies, there were 21 AP cohorts (4,072,022 components), 4 PRP cohorts (138,869 components), and 15 BC cohorts (1,474,679 components). The overall mean contamination rate per 1000 components was 0.51 (95% CI: 0.38-0.67) including AP (0.23, 95% CI: 0.18-0.28), PRP, (0.38, 95% CI: 0.15-0.70), and BC (1.12, 95% CI: 0.51-1.96). There was considerable variability within each collection method. Sample volume, positivity criteria, and publication year were significant sources of heterogeneity. CONCLUSION: The bacterial contamination rate of platelets by primary culture is 1 in 1961. AP and PRP components showed a lower contamination rate than BC components. There is clinically significant between-study variability for each method. Larger sample volumes increased sensitivity, and bacterial contamination rates have decreased over time.

The comparative safety of bacterial risk control strategies for platelet components: a simulation study.

BACKGROUND: Bacterial contamination of platelets is a problem that can lead to harmful septic transfusion reactions. The US Food and Drug Administration published a guidance in September 2019 detailing several permissible risk control strategies. Our objective was to compare the safety of each bacterial testing strategy for apheresis platelets. STUDY DESIGN AND METHODS: We used simulation to compare safety of the nine risk control strategies involving apheresis platelet testing. The primary outcome was the risk of exposure. An exposure event occurred if a patient received platelets exceeding a specific contamination threshold (>0, 103 , and 105 colony-forming units (CFU/mL). We generated a range of bacterial contamination scenarios (inoculum size, doubling time, lag time) and compared risk of exposure for each policy in each contamination scenario. We then computed the average risk difference over all scenarios. RESULTS: At the 0 CFU/mL exposure threshold, two-step policies that used secondary culture ranked best (all top three), while single-step 24-hour culture with 3-day expiration ranked last (ninth). This latter policy performed well (median rank of 1) at both the 103 and 105 CFU/mL thresholds, but 48-hour culture with 7-day expiration performed relatively poorly. At these higher thresholds, median ranks of two-step policies that used secondary culture were again top three. Two-step policies that used rapid testing improved at the higher (105 CFU/mL) harm threshold, with median rankings between 1 and 5. CONCLUSION: Two-step policies that used secondary culture were generally safer than single-step policies. Performance of two-step policies that used rapid testing depended on the CFU per milliter threshold of exposure used.

Accurate description of molecular dipole surface with charge flux implemented for molecular mechanics.

The molecular dipole moment is strongly coupled to molecular geometry among different phases, conformational states, intermolecular interaction energy, and vibrational spectroscopy. Our previous inclusion of geometry dependent charge flux into the atomic multipole-based polarizable AMOEBA+ force field has shown significant improvement of water properties from gaseous to condensed phases [C. Liu et al., J. Phys. Chem. Lett. 11(2), 419-426 (2020)]. In this work, the parameterization of the CF model for a broad range of organic and biomolecular fragments is presented. Atom types are automatically assigned by matching the predefined SMARTS patterns. Comparing to the current AMOEBA+ model without the CF component, it is shown that the AMOEBA+ (CF) model improves the description of molecular dipole moments for the molecules we studied over both equilibrium and distorted geometries. For the equilibrium-geometry structures, AMOEBA+ (CF) reduces the mean square error (MSE) from 6.806 × 10-1 (without CF) to 4.249 × 10-4 D2. For non-equilibrium structures, the MSE is reduced from 5.766 × 10-1 (without CF) to 2.237 × 10-3 D2. Finally, the transferability of the CF model and parameters were validated on two sets of molecules: one includes molecules in the training set but with different geometries, and the other one involves new molecules outside of the training set. A similar improvement on dipole surfaces was obtained on the validation sets. The CF algorithms and parameters derived in this work are general and can be implemented into any existing molecular mechanical force fields.