Commutability and Uncertainty of Blood Hemoglobin A1c Testing Materials.

BACKGROUND: Hemoglobin A1C (HbA1C) is used to evaluate glycemic control over a three-month period. Blood matrix-based HbA1C materials are needed for quality control and evaluation of HbA1C measurements. This study investigated the commutability of blood materials (BMs) and aimed to upgrade BMs for HbA1C testing for use as proficiency test (PT) material. METHODS: We measured BMs from a DM blood donor (n = 1), an in vitro glycation procedure (n = 3), and from commercial sources (n = 2) for HbA1C in parallel with fresh unprocessed BMs (n = 3) and clinical blood samples (n = 25). Two NGSP-certified methods, including a turbidimetric and an enzymatic immunoassay, were used for HbA1C determinations. Commutability as investigated according to CLSI EP14-Ed4 guidelines. RESULTS: The commutable BMs exhibited a mean paired difference of 0% to 9% when compared to reference methods, whereas the non-commutable BMs represented a mean paired difference of 3% to 11%. Fresh, unprocessed BMs with a low HbA1C of 6.0% were more commutable than BMs with a high HbA1C. The values of HbA1C in BMs (mean and uncertainty following ISO Guide 35 for RM production) were applied to upgrade the PT material to be used as a reference material. The relative uncertainty of BM-Ndm-1 and BM-Gcb-3 were 1 and 0.4%, respectively. CONCLUSIONS: The commutability of hemoglobin in BMs is dependent on the preparation process. Blood materials with a high HbA1C content are usually less commutable versus materials with low HbA1C content when prepared by the same process. Our study showed BMs can be successfully used as quality control or PT materials.

Point of care blood glucose devices in the hospital setting.

Dysglycemia is common among hospitalized patients. Accurate point-of-care (POC) glucose monitoring is necessary for the safe administration of insulin. Unfortunately, POC glucose meters are not all created equal. Interfering factors such as abnormal hematocrit, abnormal oxygen tension, and oxidizing/reducing substances can lead to inaccurate glucose measurements and result in inappropriate insulin dosing. The introduction of autocorrecting glucose meters has changed the POC testing landscape. Autocorrecting glucose meters provide more accurate measurements and have been associated with improved glycemic control in hospitalized patients. Continuous glucose monitoring has also created interest in using these platforms in at-risk inpatient populations. Future glucose monitoring technologies such as artificial intelligence/machine learning, wearable smart devices, and closed-loop insulin management systems are poised to transform glycemic management. The goal of this review is to provide an overview of glucose monitoring technology, summarize the clinical impact of glucose monitoring accuracy, and highlight emerging and future POC glucose monitoring technologies.

Machine learning and artificial intelligence for the diagnosis of infectious diseases in immunocompromised patients.

PURPOSE OF REVIEW: Immunocompromised patients are at high risk for infection. During the coronavirus disease (COVID-19) pandemic, immunocompromised patients exhibited increased odds of intensive care unit admission and death. Early pathogen identification is essential to mitigating infection related risk in immunocompromised patients. Artificial intelligence (AI) and machine learning (ML) have tremendous appeal to address unmet diagnostic needs. These AI/ML tools often rely on the wealth of data found in healthcare to enhance our ability to identify clinically significant patterns of disease. To this end, our review provides an overview of the current AI/ML landscape as it applies to infectious disease testing with emphasis on immunocompromised patients. RECENT FINDINGS: Examples include AI/ML for predicting sepsis in high risk burn patients. Likewise, ML is utilized to analyze complex host-response proteomic data to predict respiratory infections including COVID-19. These same approaches have also been applied for pathogen identification of bacteria, viruses, and hard to detect fungal microbes. Future uses of AI/ML may include integration of predictive analytics in point-of-care (POC) testing and data fusion applications. SUMMARY: Immunocompromised patients are at high risk for infections. AI/ML is transforming infectious disease testing and has great potential to address challenges encountered in the immune compromised population.

Evaluation of pharmacist guided intervention using procalcitonin and respiratory virus testing.

INTRODUCTION: Acute respiratory infections make up a sizable percentage of emergency department (ED) visits and many result in antibiotics being prescribed. Procalcitonin (PCT) has been found to reduce antibiotic use in both outpatient and critical care settings, yet remains underused in the ED. This study aimed to evaluate whether point of care molecular influenza and Respiratory Syncytial Virus (RSV) testing, PCT, and a pharmacist driven educational intervention in aggregate optimizes antibiotic and antiviral prescribing in the ED setting. METHODS: A randomized trial of the Cobas Liat Flu/RSV Assay, procalcitonin, and the use of pharmacist-led education in patients 0-50 years of age being seen in the ED for Influenza Like Illness (ILI) or acute respiratory illness. The study enrolled 200 ED patients between March 2018 and April 2022. RESULTS: There was little difference in antibiotic or antiviral prescribing between the intervention and control groups in this study (39%-32% = 7.0%, 95% CI: -6.2, 20.2, P = 0.30). However, a post-hoc analysis of the use of procalcitonin showed results were used as indicated in the ED (P = 0.001). CONCLUSION: PCT can be used in both adult and pediatric populations to help guide the decision of whether to treat with antibiotics in the ED setting. Pharmacist guided education may not be a driving factor.

Hearing outcomes in children with pneumococcal meningitis in the PCV13 era.

INTRODUCTION: Streptococcus pneumoniae, is associated with the highest incidence of post-meningitic SNHL. The exact impact of 13-valent pneumococcal conjugate vaccine (PCV) on pediatric SNHL from pneumococcal meningitis is unknown. We aimed to identify clinical factors associated with post-meningitic SNHL (pmSNHL) from pneumococcal meningitis and describe its rates based on three time periods: pre-PCV, PCV-7 and PCV13 eras. METHODS: A retrospective case-control study was performed for patients 18 years and younger diagnosed with pneumococcal meningitis from January 1, 2010 to December 31, 2020 at Children's Hospital Colorado. Demographic and clinical risk factors between those with or without SNHL were compared. Detailed hearing outcomes of those with resulting SNHL are described. RESULTS: 23 patients with CSF cultures or Meningitis/Encephalitis Panel positive for pneumococcal meningitis were identified. Twenty patients both survived the infection and had audiologic evaluation. Six patients had pmSNHL, with 50 % affected bilaterally. The rate of pmSNHL from S. pneumoniae in the PCV-13 era at our institution was similar to historical rates from the pre-PCV and PCV-7 eras. Similar proportions of patients with pmSNHL completed PCV vaccination (66.7 %) compared to those without (71.4 %). Non-PCV-13 serotypes were responsible 83 % of patients with pmSNHL versus 57 % of patients without pmSNHL. CONCLUSIONS: Despite high rates of PCV-13 uptake in our cohort, pmSNHL was still common, severe, and commonly associated with non-PCV-13 serotypes. Non-PCV-13 serotypes may be contributing to the persistently high rate of post-meningitic SNHL and the severity of SNHL. Newer pneumococcal conjugate vaccines with expanded serotypes may help mitigate the SNHL associated with pneumococcal meningitis.

Structures of regulatory machinery reveal novel molecular mechanisms controlling B. subtilis nitrogen homeostasis.

All cells must sense and adapt to changing nutrient availability. However, detailed molecular mechanisms coordinating such regulatory pathways remain poorly understood. In Bacillus subtilis, nitrogen homeostasis is controlled by a unique circuitry composed of the regulator TnrA, which is deactivated by feedback-inhibited glutamine synthetase (GS) during nitrogen excess and stabilized by GlnK upon nitrogen depletion, and the repressor GlnR. Here we describe a complete molecular dissection of this network. TnrA and GlnR, the global nitrogen homeostatic transcription regulators, are revealed as founders of a new structural family of dimeric DNA-binding proteins with C-terminal, flexible, effector-binding sensors that modulate their dimerization. Remarkably, the TnrA sensor domains insert into GS intersubunit catalytic pores, destabilizing the TnrA dimer and causing an unprecedented GS dodecamer-to-tetradecamer conversion, which concomitantly deactivates GS. In contrast, each subunit of the GlnK trimer "templates" active TnrA dimers. Unlike TnrA, GlnR sensors mediate an autoinhibitory dimer-destabilizing interaction alleviated by GS, which acts as a GlnR chaperone. Thus, these studies unveil heretofore unseen mechanisms by which inducible sensor domains drive metabolic reprograming in the model Gram-positive bacterium B. subtilis.

Intra-abdominal desmoid fibromatosis mimicking tumour recurrence after the operation: A case series.

INTRODUCTION: Desmoid fibromatosis is a multifactorial disorder classified as a category of intermediate, locally aggressive behaviour, which might be associated with CTNNB1 or APC mutations, trauma, surgery, or pregnancy. CASE REPORTS: We present two cases of postoperative intra-abdominal desmoid fibromatosis. The first case occurred 14 months after the resection of a retroperitoneal gastrointestinal stromal tumour. The second case was located in the mesentery, as evidenced on an 18-month followup after a laparoscopy-assisted anterior resection for adenocarcinoma at the rectosigmoid junction. Under the clinical diagnosis of recurrence, tissue excisions were conducted. Microscopically, the tissue was composed of bland spindle cells without cytological atypia, admixed with collagen bundles. Both tumours exhibited nuclear expression of ß-catenin on immunohistochemical staining, which is a desirable criterion for desmoid fibromatosis. DISCUSSION: Although positron emission tomography aids the diagnosis of recurrence, the radiological features of desmoid fibromatosis in computed tomography or magnetic resonance images are nonspecific and preoperative diagnosis of desmoid fibromatosis is difficult. The histological diagnosis of desmoid fibromatosis is difficult, especially when the specimen is small. The histological differential diagnosis of desmoid fibromatosis includes other myofibroblastic or fibroblastic tumours or lesions. Additional studies, such as ß-catenin immunohistochemistry or CTNNB1 mutation analysis, can enable accurate diagnosis of desmoid fibromatosis. A correct diagnosis is essential, because the current therapeutic strategy is a "waitand- watch" approach, which is significantly different from those of the other locally aggressive, intermediate soft tissue neoplasms. We have summarised the clinicopathological, histological and immunohistochemical features of the post-operative desmoid fibromatosis.

The NanDeSyn database for Nannochloropsis systems and synthetic biology.

Nannochloropsis species, unicellular industrial oleaginous microalgae, are model organisms for microalgal systems and synthetic biology. To facilitate community-based annotation and mining of the rapidly accumulating functional genomics resources, we have initiated an international consortium and present a comprehensive multi-omics resource database named Nannochloropsis Design and Synthesis (NanDeSyn; http://nandesyn.single-cell.cn). Via the Tripal toolkit, it features user-friendly interfaces hosting genomic resources with gene annotations and transcriptomic and proteomic data for six Nannochloropsis species, including two updated genomes of Nannochloropsis oceanica IMET1 and Nannochloropsis salina CCMP1776. Toolboxes for search, Blast, synteny view, enrichment analysis, metabolic pathway analysis, a genome browser, etc. are also included. In addition, functional validation of genes is indicated based on phenotypes of mutants and relevant bibliography. Furthermore, epigenomic resources are also incorporated, especially for sequencing of small RNAs including microRNAs and circular RNAs. Such comprehensive and integrated landscapes of Nannochloropsis genomics and epigenomics will promote and accelerate community efforts in systems and synthetic biology of these industrially important microalgae.

Clinical Performance of the Point-of-Care cobas Liat for Detection of SARS-CoV-2 in 20 Minutes: a Multicenter Study.

Highly accurate testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the point of care (POC) is an unmet diagnostic need in emergency care and time-sensitive outpatient care settings. Reverse transcription-PCR (RT-PCR) technology is the gold standard for SARS-CoV-2 diagnostics. We performed a multisite U.S. study comparing the clinical performance of the first U.S. Food and Drug Administration (FDA)-authorized POC RT-PCR for detection of SARS-CoV-2 in 20 min, the cobas Liat SARS-CoV-2 and influenza A/B nucleic acid test, to the most widely used RT-PCR laboratory test, the cobas 68/8800 SARS-CoV-2 test. Clinical nasopharyngeal swab specimens from 444 patients with 357 evaluable specimens at five U.S. clinical laboratories were enrolled from 21 September 2020 to 23 October 2020. The overall agreement between the Liat and 68/8800 systems for SARS-CoV-2 diagnostics was 98.6% (352/357). Using Liat, positive percent agreement for SARS-CoV-2 was 100% (162/162) and the negative percent agreement was 97.4% (190/195). The Liat is an RT-PCR POC test that provides highly accurate SARS-CoV-2 results in 20 min with performance equivalent to that of high-throughput laboratory molecular testing. Rapid RT-PCR testing at the POC can enable more timely infection control and individual care decisions for coronavirus disease 2019.

Evolving Applications of Artificial Intelligence and Machine Learning in Infectious Diseases Testing.

BACKGROUND: Artificial intelligence (AI) and machine learning (ML) are poised to transform infectious disease testing. Uniquely, infectious disease testing is technologically diverse spaces in laboratory medicine, where multiple platforms and approaches may be required to support clinical decision-making. Despite advances in laboratory informatics, the vast array of infectious disease data is constrained by human analytical limitations. Machine learning can exploit multiple data streams, including but not limited to laboratory information and overcome human limitations to provide physicians with predictive and actionable results. As a quickly evolving area of computer science, laboratory professionals should become aware of AI/ML applications for infectious disease testing as more platforms are become commercially available. CONTENT: In this review we: (a) define both AI/ML, (b) provide an overview of common ML approaches used in laboratory medicine, (c) describe the current AI/ML landscape as it relates infectious disease testing, and (d) discuss the future evolution AI/ML for infectious disease testing in both laboratory and point-of-care applications. SUMMARY: The review provides an important educational overview of AI/ML technique in the context of infectious disease testing. This includes supervised ML approaches, which are frequently used in laboratory medicine applications including infectious diseases, such as COVID-19, sepsis, hepatitis, malaria, meningitis, Lyme disease, and tuberculosis. We also apply the concept of "data fusion" describing the future of laboratory testing where multiple data streams are integrated by AI/ML to provide actionable clinical knowledge.

ED syphilis and gonorrhea/chlamydia cotesting practices before and after the implementation of an electronic health record-based alert.

BACKGROUND: The prevalence of syphilis is increasing in many countries, including the USA. The ED is often used by underserved populations, making it an important setting to test and treat patients who are not evaluated in outpatient clinical settings. We aimed to assess the utility of an ED-based syphilis and gonorrhoea/chlamydia cotesting protocol by comparing testing practices before and after its implementation. METHODS: We implemented an electronic health record (EHR) alert that prompted clinicians to order syphilis testing in patients undergoing gonorrhoea/chlamydia testing. We performed a retrospective cohort analysis that compared outcomes between the preimplementation period (January-November 2018) and the postimplementation period (January-November 2019). Patients were tested for Treponema pallidum antibody (TPA) using a multiplex flow immunoassay (MFI), and positive results were confirmed by rapid plasma reagin (RPR). The primary implementation outcome was the number of syphilis tests/month, and the primary clinical outcome was the number of syphilis diagnoses/month (defined as positive TPA MFI and RPR). We performed an interrupted time-series analysis to evaluate the effect of implementing the alert over time. RESULTS: Four-hundred and ninety-four and 1106 unique patients were tested for syphilis in the preimplementation and postimplementation periods, respectively. Syphilis testing increased by 55.6 tests/month (95% CI 45.9 to 65.3, p<0.001) following alert implementation. Patients tested in the postimplementation period who were tested using the alert were much younger (difference: 14 years (95% CI 12 to 15)) and were more likely to be female (difference: 15% (95% CI 8 to 21)) and African-American (difference: 11% (95% CI 5 to 17)) than patients tested by clinician-initiated testing. Presumptive syphilis diagnoses increased from 3.4 diagnoses/month to 7.9 diagnoses/month (difference, 4.5 (95% CI 2.2 to 6.9), p<0.001). CONCLUSIONS: Our study demonstrates that use of a targeted EHR alert testing protocol can increase syphilis testing and diagnosis and may reduce clinician bias in testing.

Investigating Transfusion-related Sepsis Using Culture-Independent Metagenomic Sequencing.

BACKGROUND: Transfusion-related sepsis remains an important hospital infection control challenge. Investigation of septic transfusion events is often restricted by the limitations of bacterial culture in terms of time requirements and low yield in the setting of prior antibiotic administration. METHODS: In 3 gram-negative septic transfusion cases, we performed metagenomic next-generation sequencing (mNGS) of direct clinical blood specimens in addition to standard culture-based approaches utilized for infection control investigations. Pathogen detection leveraged IDSeq, a new open-access microbial bioinformatics portal. Phylogenetic analysis was performed to assess microbial genetic relatedness and understand transmission events. RESULTS: mNGS of direct clinical blood specimens afforded precision detection of pathogens responsible for each case of transfusion-related sepsis and enabled discovery of a novel Acinetobacter species in a platelet product that had become contaminated despite photochemical pathogen reduction. In each case, longitudinal assessment of pathogen burden elucidated the temporal sequence of events associated with each transfusion-transmitted infection. We found that informative data could be obtained from culture-independent mNGS of residual platelet products and leftover blood specimens that were either unsuitable or unavailable for culture or that failed to grow due to prior antibiotic administration. We additionally developed methods to enhance accuracy for detecting transfusion-associated pathogens that share taxonomic similarity to contaminants commonly found in mNGS library preparations. CONCLUSIONS: Culture-independent mNGS of blood products afforded rapid and precise assessment of pathogen identity, abundance, and genetic relatedness. Together, these challenging cases demonstrated the potential for metagenomics to advance existing methods for investigating transfusion-transmitted infections.

Relationship of Cerebrospinal Fluid Vitamin B12 Status Markers With Parkinson's Disease Progression.

BACKGROUND: Using blood specimens from untreated early Parkinson's disease (PD) patients from the DATATOP trial, we found that subjects in the low serum vitamin B12 tertile experienced greater annualized change in ambulatory capacity score, whereas those with moderately elevated (>15 µmol/L) total homocysteine had greater annualized declines in the Mini-Mental State Exam. METHODS: In this this study we sought to determine whether levels of cerebrospinal fluid (CSF) B12 markers were also associated with progression of PD. RESULTS: The annualized change in the UPDRS "walking" item, a component of the ambulatory capacity score, was worse in the low B12 tertile. No association with change in the Mini-Mental State Exam was seen for those 7% with the highest baseline CSF total homocysteine. CONCLUSIONS: In these untreated early-PD subjects, low CSF B12 predicted greater worsening of the UPDRS "walking" item, whereas CSF total homocysteine was not associated with progression of cognitive impairment. These findings extend and partially support our findings in serum. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Pooled cohort risk equation and subclinical cerebrovascular diseases.

BACKGROUND AND PURPOSE: In 2013, the American College of Cardiology/American Heart Association (ACC/AHA) introduced a novel pooled cohort risk (PCR) model for atherosclerotic cardiovascular disease. In this study, we evaluated the relationship between the PCR score and cerebral large- and small-vessel diseases (cLVD and cSVD) in a healthy population, METHODS: We assessed consecutive health check-up volunteers from 2006 to 2013. We calculated the estimated 10-year atherosclerotic cardiovascular disease risk as the PCR score based on the 2013 ACC/AHA guidelines. We evaluated both cSVD/cLVD, including the prevalence of cLVD, lacunes and cerebral microbleed (CMB), and the volume of white matter hyperintensity (WMH). In addition to PCR score, the risk factors that were associated with outcome variables at P < 0.10 in univariate analysis were included for further multivariable linear or regression analyses. RESULTS: A total of 2720 participants were evaluated (mean age, 57 years, male sex, 54%). In multivariable analysis, PCR score was associated with WMH volume [ß = 0.361; 95% confidence interval (CI), 0.320-0.402, P < 0.001], cLVD [adjusted odds ratio (aOR), 1.66; 95% CI, 1.29-2.16, P < 0.001], lacunes (aOR, 1.80; 95% CI, 1.52-2.14, P < 0.001) and CMBs (aOR, 1.75; 95% CI, 1.40-2.19, P < 0.001). Furthermore, PCR score also showed dose-response tendencies according to the burden of cLVD, WMH, lacunes and CMB. CONCLUSIONS: A higher PCR score based on the ACC/AHA guidelines is closely associated with a higher prevalence and burden of cLVD and cSVD.

Molecular basis for a protein-mediated DNA-bridging mechanism that functions in condensation of the E. coli chromosome.

The E. coli chromosome is condensed into insulated regions termed macrodomains (MDs), which are essential for genomic packaging. How chromosomal MDs are specifically organized and compacted is unknown. Here, we report studies revealing the molecular basis for Terminus-containing (Ter) chromosome condensation by the Ter-specific factor MatP. MatP contains a tripartite fold with a four-helix bundle DNA-binding motif, ribbon-helix-helix and C-terminal coiled-coil. Strikingly, MatP-matS structures show that the MatP coiled-coils form bridged tetramers that flexibly link distant matS sites. Atomic force microscopy and electron microscopy studies demonstrate that MatP alone loops DNA. Mutation of key coiled-coil residues destroys looping and causes a loss of Ter condensation in vivo. Thus, these data reveal the molecular basis for a protein-mediated DNA-bridging mechanism that mediates condensation of a large chromosomal domain in enterobacteria.

Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up.

BACKGROUND: Novel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045. PATIENTS AND METHODS: Adult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab [200 mg every 3 weeks (Q3W)] or investigator's choice of paclitaxel (175 mg/m2 Q3W), docetaxel (75 mg/m2 Q3W), or vinflunine (320 mg/m2 Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR. RESULTS: A total of 542 patients were enrolled (pembrolizumab, n = 270; chemotherapy, n = 272). Median follow-up as of 26 October 2017 was 27.7 months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4 months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy. CONCLUSIONS: Long-term results (>2 years' follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02256436.

Left ventricular ejection fraction is associated with small vessel disease in ischaemic stroke patients.

BACKGROUND AND PURPOSE: The purpose was to evaluate the association between the left ventricular ejection fraction (LVEF) and cerebral small vessel disease (cSVD) in ischaemic stroke patients. METHODS: Consecutive first-ever ischaemic stroke patients between 2010 and 2013 were included. White matter hyperintensity (WMH) volumes were rated using both the Fazekas score and quantitative methods on fluid-attenuated inversion recovery images. As spectra of cSVD, lacunes, cerebral microbleeds (CMBs) and enlarged perivascular spaces (EPVSs) were also evaluated. To assess the dose-response relationship between LVEF and cSVD, the burdens of each radiological marker and the total cSVD score were rated. RESULTS: A total of 841 patients were included [median WMH volume 2.98 (1.22-10.50) ml; the frequencies of lacunes, CMBs and moderate to severe EPVSs were 38%, 31% and 35%, respectively]. In the multivariate analysis about predictors of WMH volumes, the LVEF (B = -0.052, P < 0.001) remained significant after adjusting for confounders. LVEF was also a predictor of lacunes [adjusted odds ratio (aOR) 0.978, P = 0.012], CMBs (aOR = 0.96, P < 0.001) and moderate to severe EPVSs (aOR = 0.94, P < 0.001) after adjusting for their confounders. The LVEF values were negatively correlated with the burdens of lacunes (P = 0.026), CMBs (P < 0.001) and EPVSs (P = 0.002). The total cSVD score also showed a negative association with LVEF in a dose-response manner (P < 0.001). CONCLUSIONS: The burden of cSVD is negatively correlated with the LVEF in a dose-response manner. Our results suggest clues for further studies about determining the pathophysiology of cSVD.

Clopidogrel may decrease the risk of post-stroke infection after ischaemic stroke.

BACKGROUND AND PURPOSE: The P2Y12 receptor, a well-known factor in the platelet activation pathway, plays a role in thrombosis as well as systemic inflammation. Clopidogrel, a prototype P2Y12 receptor antagonist, reportedly decreases inflammation and systemic infection. The aim of this study was to evaluate whether clopidogrel use decreases the risk of post-stroke infection following ischaemic stroke. METHODS: A total of 1643 patients with acute ischaemic stroke (within 7 days after onset) were included for analysis between March 2010 and December 2015. Patients were categorized into two groups (clopidogrel users versus clopidogrel non-users), and clinical characteristics and risks of post-stroke infection were compared between the two groups. The inverse probability of treatment weighting using propensity scores for baseline imbalance adjustments was applied. RESULTS: Of the included patients (mean age 67.7 years; men 60.6%), 670 (40.8%) patients were clopidogrel users and 164 (10.0%) patients had post-stroke infection. The proportion of patients with post-stroke infection was significantly lower in clopidogrel users compared to clopidogrel non-users (6.7% vs. 12.2%, P ≤ 0.001). Moreover, clopidogrel users were less likely to be admitted to the intensive care unit (13.3% vs. 35.3%, P = 0.006). A multivariate analysis with inverse probability of treatment weighting revealed that clopidogrel users exhibited a lower risk of post-stroke infection (odds ratio 0.56, 95% confidence interval 0.42-0.75) and intensive care unit admission (odds ratio 0.34, 95% confidence interval 0.22-0.53). CONCLUSIONS: The study suggested that clopidogrel users exhibit a lower risk of infection and develop less severe infections after ischaemic stroke. Further prospective studies are needed.

Favorable impact of non-alcoholic fatty liver disease on the cerebral white matter hyperintensity in a neurologically healthy population.

BACKGROUND AND PURPOSE: Although non-alcoholic fatty liver disease (NAFLD) shares common cardiovascular risk factors with cerebral white matter hyperintensity (WMH), few studies have reported the association between NAFLD and WMH. The association between the presence of NAFLD with its severity and the volume of WMH was investigated. METHODS: This cross-sectional study was conducted for 2460 subjects who voluntarily participated in health screening check-ups including brain magnetic resonance imaging and liver ultrasonography at the Health Promotion Center at Seoul National University Hospital from 2009 to 2013. Ultrasonography was used to detect the presence and severity of NAFLD combined with the NAFLD fibrosis score and the FIB-4 index. The volume of WMH was measured using a semi-automated quantification method by a trained neurologist. RESULTS: The prevalence of NAFLD was 36.5%, and the median volume of WMH in all the subjects was 1.1 ml (interquartile range 0.2-2.7 ml). The presence of NAFLD was associated with a smaller volume of WMH [ß (standard error, SE) -0.051 (0.046); P = 0.012]. Moderate to severe NAFLD was associated with a smaller volume of WMH than was non-NAFLD [ß (SE) -0.067 (0.061); P = 0.002]. The negative correlation observed between NAFLD severity and WMH volume was persistent only in those with low FIB-4 index and low NAFLD fibrosis scores, whereas there was a positive association in those with high FIB-4 index and NAFLD fibrosis scores. CONCLUSIONS: Non-alcoholic fatty liver disease, and its severity, showed a favorable association with WMH volume. However, its causality and mechanism should be evaluated in further relevantly designed studies.

Prospective study of serum and ionized magnesium pharmacokinetics in the treatment of children with severe acute asthma.

PURPOSE: Intravenous (IV) magnesium sulfate (MgSO4) is clinically useful as adjunct therapy in treating acute asthma exacerbations. Despite its clinical utility, the disposition of magnesium in children is poorly described. The purpose of this study is to describe the pharmacokinetics (PK) of ionized and total serum magnesium following IV MgSO4 administration in children with severe acute asthma. METHODS: Thirty-two children receiving 50 mg/kg IV MgSO4 for acute asthma exacerbations at Primary Children's Hospital in Salt Lake City, UT, were prospectively enrolled in the study. Blood samples were collected before, as well as 30 min and 2 h after each child's IV MgSO4 dose, and used to determine total serum and ionized magnesium concentrations. The collected data were analyzed using population PK techniques using NONMEM® software. RESULTS: Total serum magnesium concentrations were used to externally validate our previously published model constructed with retrospective data (median prediction error 10.3%, median absolute prediction error 18.1%). The mean (%CV) observed endogenous ionized magnesium concentration was calculated to be 6.0 mg/L (12%), approximately one third of the same value for endogenous total serum magnesium (17.6 mg/L (22%)) in this dataset. Weight was a significant predictor of both clearance and volume in a population PK model describing ionized magnesium concentrations. No adverse events were observed in this pediatric cohort. CONCLUSIONS: This prospective study supports and extends our previous PK analysis of total serum magnesium concentrations. Ionized and total serum magnesium followed similar PK profiles following IV MgSO4 administration in children. A single bolus infusion of IV MgSO4 was safe in this small sample of children receiving it for acute asthma.