Outcome-based analytical performance specifications: current status and future challenges.

Analytical performance specifications (APS) based on outcomes refer to how 'good' the analytical performance of a test needs to be to do more good than harm to the patient. Analytical performance of a measurand affects its clinical performance. Without first setting clinical performance requirements, it is difficult to define how good analytically the test needs to be to meet medical needs. As testing is indirectly linked to health outcomes through clinical decisions on patient management, often simulation-based studies are used to assess the impact of analytical performance on the probability of clinical outcomes which is then translated to Model 1b APS according to the Milan consensus. This paper discusses the related key definitions, concepts and considerations that should assist in finding the most appropriate methods for deriving Model 1b APS. We review the advantages and limitations of published methods and discuss the criteria for transferability of Model 1b APS to different settings. We consider that the definition of the clinically acceptable misclassification rate is central to Model 1b APS. We provide some examples and guidance on a more systematic approach for first defining the clinical performance requirements for tests and we also highlight a few ideas to tackle the future challenges associated with providing outcome-based APS for laboratory testing.

High clonal diversity of Staphylococcus aureus isolates from children's playgrounds in Hungary.

Staphylococcus aureus is one of the most important human pathogenic bacteria and environmental surfaces play an important role in the spread of the bacterium. Presence of S. aureus on children's playgrounds and on toys was described in international studies, however, little is known about the prevalence and characteristics of S. aureus at playgrounds in Europe. In this study, 355 samples were collected from playgrounds from 16 cities in Hungary. Antibiotic susceptibility of the isolates was tested for nine antibiotics. Presence of virulence factors was detected by PCR. Clonal diversity of the isolates was tested by PFGE and MLST. The overall prevalence of S. aureus was 2.81% (10/355) and no MRSA isolates were found. Presence of spa (10), fnbA (10), fnbB (5), icaA (8), cna (7), sea (2), hla (10), hlb (2) and hlg (6) virulence genes were detected. The isolates had diverse PFGE pulsotypes. With MLST, we have detected isolates belonging to ST8 (CC8), ST22 (CC22), ST944 and ST182 (CC182), ST398 (CC398), ST6609 (CC45), ST3029 and ST2816. We have identified a new sequence type, ST6609 of CC45. S. aureus isolates are present on Hungarian playgrounds, especially on plastic surfaces. The isolates were clonally diverse and showed resistance to commonly used antibiotics. These data reinforce the importance of the outdoor environment in the spread for S. aureus in the community.

Applying the Milan models to setting analytical performance specifications - considering all the information.

Analytical performance specifications (APS) are used for decisions about the required analytical quality of pathology tests to meet clinical needs. The Milan models, based on clinical outcome, biological variation, or state of the art, were developed to provide a framework for setting APS. An approach has been proposed to assign each measurand to one of the models based on a defined clinical use, physiological control, or an absence of quality information about these factors. In this paper we propose that in addition to such assignment, available information from all models should be considered using a risk-based approach that considers the purpose and role of the actual test in a clinical pathway and its impact on medical decisions and clinical outcomes in addition to biological variation and the state-of-the-art. Consideration of APS already in use and the use of results in calculations may also need to be considered to determine the most appropriate APS for use in a specific setting.

World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline update - XII - Recommendations on milk formula supplements with and without probiotics for infants and toddlers with CMA.

Background: Cow's milk allergy (CMA) is the most common food allergy in infants. The replacement with specialized formulas is an established clinical approach to ensure adequate growth and minimize the risk of severe allergic reactions when breastfeeding is not possible. Still, given the availability of multiple options, such as extensively hydrolyzed cow's milk protein formula (eHF-CM), amino acid formula (AAF), hydrolyzed rice formula (HRF) and soy formulas (SF), there is some uncertainty as to the most suitable choice with respect to health outcomes. Furthermore, the addition of probiotics to a formula has been proposed as a potential approach to maximize benefit. Objective: These evidence-based guidelines from the World Allergy Organization (WAO) intend to support patients, clinicians, and others in decisions about the use of milk specialized formulas, with and without probiotics, for individuals with CMA. Methods: WAO formed a multidisciplinary guideline panel balanced to include the views of all stakeholders and to minimize potential biases from competing interests. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to review by stakeholders. Results: After reviewing the summarized evidence and thoroughly discussing the different management options, the WAO guideline panel suggests: a) using an extensively hydrolyzed (cow's milk) formula or a hydrolyzed rice formula as the first option for managing infants with immunoglobulin E (IgE) and non-IgE-mediated CMA who are not being breastfed. An amino-acid formula or a soy formula could be regarded as second and third options respectively; b) using either a formula without a probiotic or a casein-based extensively hydrolyzed formula containing Lacticaseibacillus rhamnosus GG (LGG) for infants with either IgE or non-IgE-mediated CMA.The issued recommendations are labeled as "conditional" following the GRADE approach due to the very low certainty about the health effects based on the available evidence. Conclusions: If breastfeeding is not available, clinicians, patients, and their family members might want to discuss all the potential desirable and undesirable consequences of each formula in infants with CMA, integrating them with the patients' and caregivers' values and preferences, local availability, and cost, before deciding on a treatment option. We also suggest what research is needed to determine with greater certainty which formulas are likely to be the most beneficial, cost-effective, and equitable.

Effect of lactase supplementation on infant colic: Systematic review of randomized controlled trials.

To systematically review evidence on the efficacy and safety of using a lactase supplementation for managing infant colic. The MEDLINE, EMBASE, and Cochrane Library databases were searched (up to September 2023) for randomized controlled trials (RCTs) comparing oral lactase supplementation with placebo or no intervention in infants younger than 6 months old with infant colic. The risk of bias was assessed using the revised version of the Cochrane risk-of-bias tool. Outcomes measured were selected according to a standardized core outcome set. Five RCTs involving a total of 391 infants were identified. Three RCTs reported reduced crying duration, but one showed effect only in a compliant group (40.4%, p = 0.0052). A meta-analysis of two RCTs found no difference in crying duration and fussing time during 1 week of lactase treatment compared with placebo (mean difference [MD] -17.66 min/day, 95% confidence interval [CI], -60.8 to 25.5; I2 = 68% and MD 2.75, 95% CI, -58.2 to 57.2; I2 = 80%, respectively). Other outcomes were assessed only in individual studies or not reported. The risk of bias was low in only one RCT, high in three, and raised some concerns in one. While individual trials have shown some promise, the overall evidence for the efficacy of lactase supplementation in treating infant colic remain inconclusive. Further well-designed RCTs are necessary to determine the effects of lactase on managing infant colic.

Evaluating the impact of lactase supplementation on infant colic: Study protocol for a systematic review of randomized controlled trials.

Infant colic is a common functional gastrointestinal disorder that affects infants during their first months of life. The etiology of this condition remains unclear. However, some studies suggest lactase deficiency may be a contributing factor. Currently, the evidence on dietary treatment and lactase supplementation for management of infant colic is limited. We aim to systematically review evidence on the efficacy and safety of using a lactase supplementation for managing infant colic. The Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), MEDLINE, and EMBASE will be searched to identify randomized controlled trials comparing oral lactase supplementation with placebo or no intervention in infants aged less than 6-month-old with infant colic using any recognized definition. The risk of bias will be assessed using the second version of the Cochrane Collaboration's risk-of-bias tool. The main outcome will be the number of responders in each group after treatment, defined as infants who experienced a decrease in daily crying as reported by the study authors. Additional outcomes will include the duration and frequency of crying episodes, infant sleep duration, parental satisfaction, discomfort of infants, number of hospital admissions, family quality of life, and adverse events during the intervention. The study findings will be published in a peer-reviewed journal and will be submitted to relevant conferences.

Prevalence, serogroup distribution and risk factors of Neisseria meningitidis carriage in high school and university students in Hungary.

Neisseria meningitidis causes life-threatening invasive meningococcal disease (IMD) with high mortality worldwide. Asymptomatic pharyngeal meningococcus colonisation is an important reservoir for the spread of the bacterium. The aim of this study was to determine N. meningitidis colonisation rates in asymptomatic high school and university students and to identify risk factors for carriage. Oropharyngeal swab samples and data from a self-reported questionnaire were obtained from overall 610 students, among them 303 university students and 307 high school students, aged between 15 and 31 years in Budapest, Hungary, between November 2017 and December 2018. Meningococcal carriage and serogroup of N. meningitidis were determined by RT-PCR from DNA extracted directly from the specimen. N. meningitidis was identified in 212 (34.8 %) of the participants. Significantly higher carriage rate was found among high school students (48.9 %) compared to university students (20.5 %). Peak of colonisation rate was among 17-19-year-old students (48.7 %). Most carriage isolates were non-typable (87.3 %). From the 212 meningococcus carriers, 19 were colonised by serogroup B (9 %), 5 by serogroup C (2.4 %), and 1 had serogroup Y (0.5 %). Significantly higher colonisation rate was found among males (42.4 %) than in females (33.1 %). Antibiotic use in the past 2 months has decreased the rate of meningococcal colonisation. Recent respiratory infection, active or passive smoking and attending parties have not influenced meningococcal colonisation rate significantly. In conclusion, we have found high asymptomatic meningococcus carriage rate among high school students and young adults, however, the majority of the colonizing meningococci were non-typable.

Gastrointestinal Comorbidities Associated with Atopic Dermatitis-A Narrative Review.

The current understanding of atopic dermatitis (AD) seems to be extending beyond a skin-confined condition frequently associated with allergic comorbidities, as in a number of epidemiological studies, the prevalence rate of a range of illnesses has been determined to be greater in patients with AD, or inversely. In most cases, the reasons for this are vague. A subset of these conditions are gastrointestinal disorders, including food sensitization (FS) and food allergy (FA), eosinophilic esophagitis (EoE) (it is of mixed background, both IgE-dependent and independent), food protein-induced enterocolitis syndrome (FPIES) (it exemplifies an IgE-independent food allergy), Crohn's disease (CD), colitis ulcerosa (CU), celiac disease, irritable bowel syndrome (IBS), and gastroesophageal reflux disease (GERD). In this review, we performed a comprehensive search of the literature using the PubMed database. We addressed the epidemiology of the increased co-occurrence of these diseases with AD and discussed potential causes for this subject. Multiple gastroenterological comorbidities appear to be more common in patients with AD, according to our review. The mechanisms that underlie this phenomenon are largely unknown, highlighting the need for further study in this field.

Nutritional status and feeding difficulties in children up to 2 years of age with cow's milk allergy.

BACKGROUND/OBJECTIVES: To assess the nutritional status and incidence of feeding difficulties in Polish children up to 2 years of age with cow's milk allergy (CMA) on cow's milk proteins-free diet. METHODS: A cross-sectional, multi-center study included children aged 6 months to 2 years with confirmed or suspected (without oral food challenge) diagnosis of CMA on the elimination diet for at least 1 month. The primary outcomes were an assessment of proportion of children with impaired nutritional status (with the weight for length and body mass index (BMI) z-score > 1 and <-1), and feeding difficulties according to the Montreal Children's Hospital Feeding Scale. Children with confirmed and suspected CMA were assessed separately. RESULTS: A 144 children with confirmed CMA and 88 with suspected CMA were included (57 and 78% with multiple food allergies, respectively). Among children with confirmed CMA, one-third (35.5%) of participants had any nutritional status impairment regardless of definition. Among those, most of children had mild malnutrition (10.4 vs. 9%) and possible risk of overweight (11.1 vs. 9.7%; following respectively BMI for age and weight for length z-scores). Only 16.0% of children had feeding difficulties. Feeding difficulties was identified to be a risk factor for moderate malnutrition compared to children without feeding difficulties (odds ratio 10, 95% confidence interval: 4-27). CONCLUSIONS: Mild malnutrition and possible risk of overweight are concern in children up to 2 years of age on cow's milk proteins-free diet. Feeding difficulties are less common, however, may affect the nutritional status.

Direct-to-consumer tests advertised online in Australia and their implications for medical overuse: systematic online review and a typology of clinical utility.

OBJECTIVES: The objective of this study is to map the range and variety of direct-to-consumer (DTC) tests advertised online in Australia and analyse their potential clinical utility and implications for medical overuse. DESIGN: Systematic online search of DTC test products in Google and Google Shopping. DTC test advertisements data were collected and analysed to develop a typology of potential clinical utility of the tests at population level, assessing their potential benefits and harms using available evidence, informed by concepts of medical overuse. RESULTS: We identified 484 DTC tests (103 unique products), ranging from $A12.99 to $A1947 in cost (mean $A197.83; median $A148.50). Using our typology, we assigned the tests into one of four categories: tests with potential clinical utility (10.7%); tests with limited clinical utility (30.6%); non-evidence-based commercial 'health checks' (41.9%); and tests whose methods and/or target conditions are not recognised by the general medical community (16.7%). Of the products identified, 56% did not state that they offered pretest or post-test consultation, and 51% did not report analytical performance of the test or laboratory accreditation. CONCLUSIONS: This first-in-Australia study shows most DTC tests sold online have low potential clinical utility, with healthy consumers constituting the main target market. Harms may be caused by overdiagnosis, high rates of false positives and treatment decisions led by non-evidence-based tests, as well as financial costs of unnecessary and inappropriate testing. Regulatory mechanisms should demand a higher standard of evidence of clinical utility and efficacy for DTC tests. Better transparency and reporting of health outcomes, and the development of decision-support resources for consumers are needed.

Development of peanut, sesame and tree nut allergy in Polish children at high risk of food allergy: a protocol for a cross-sectional study.

INTRODUCTION: Peanut allergies cause serious health problems worldwide. A strong finding has shown that the early introduction of peanuts into the diet of infants at high risk of food allergy reduces the prevalence of peanut allergy. Allergies to peanuts, sesame and tree nuts have been shown to coexist in 60% of cases and vary according to geographical location and dietary habits. Insights into the prevalence of nut and seed allergies in societies with varying consumption levels are essential for developing population-specific weaning guidelines. Understanding the age at which peanut allergy develops is paramount for successful early introduction strategies. METHODS AND ANALYSIS: We will perform a cross-sectional study at two tertiary allergy centres in Warsaw and Bydgoszcz. Two hundred forty children aged 4-36 months with eczema or egg allergy will undergo an extensive assessment of their peanut, sesame and tree nut allergy status through skin testing, specific IgE measurements and oral food challenges. The primary outcome is the prevalence of peanut, sesame and tree nut allergies in Polish children at high risk of food allergy. Additionally, the timing of the development of peanut, sesame and tree nut allergies in the first 3 years of life in a high-risk population will be assessed. ETHICS AND DISSEMINATION: The Ethics Committee of the Medical University of Warsaw, Poland approved this protocol (KB/86/2021). The results of this study will be submitted to a peer-reviewed journal no later than 1 year after data collection. The abstract will be presented at relevant national and international conferences.Although the authors may be able to commit to journal submission no later than 1 year after data collection, publication dates remain beyond their control. TRIAL REGISTRATION NUMBER: NCT05662800.

Executive Summary: Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus.

BACKGROUND: Numerous laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. An expert committee compiled evidence-based recommendations for laboratory analysis in patients with diabetes. The overall quality of the evidence and the strength of the recommendations were evaluated. The draft consensus recommendations were evaluated by invited reviewers and presented for public comment. Suggestions were incorporated as deemed appropriate by the authors (see Acknowledgments in the full version of the guideline). The guidelines were reviewed by the Evidence Based Laboratory Medicine Committee and the Board of Directors of the American Association of Clinical Chemistry and by the Professional Practice Committee of the American Diabetes Association. CONTENT: Diabetes can be diagnosed by demonstrating increased concentrations of glucose in venous plasma or increased hemoglobin A1c (Hb A1c) in the blood. Glycemic control is monitored by the patients measuring their own blood glucose with meters and/or with continuous interstitial glucose monitoring devices and also by laboratory analysis of Hb A1c. The potential roles of noninvasive glucose monitoring; genetic testing; and measurement of ketones, autoantibodies, urine albumin, insulin, proinsulin, and C-peptide are addressed. SUMMARY: The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended.

Executive Summary: Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus.

BACKGROUND: Numerous laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. An expert committee compiled evidence-based recommendations for laboratory analysis in patients with diabetes. The overall quality of the evidence and the strength of the recommendations were evaluated. The draft consensus recommendations were evaluated by invited reviewers and presented for public comment. Suggestions were incorporated as deemed appropriate by the authors (see Acknowledgments in the full version of the guideline). The guidelines were reviewed by the Evidence Based Laboratory Medicine Committee and the Board of Directors of the American Association for Clinical Chemistry and by the Professional Practice Committee of the American Diabetes Association. CONTENT: Diabetes can be diagnosed by demonstrating increased concentrations of glucose in venous plasma or increased hemoglobin A1c (HbA1c) in the blood. Glycemic control is monitored by the patients measuring their own blood glucose with meters and/or with continuous interstitial glucose monitoring devices and also by laboratory analysis of HbA1c. The potential roles of noninvasive glucose monitoring; genetic testing; and measurement of ketones, autoantibodies, urine albumin, insulin, proinsulin, and C-peptide are addressed. SUMMARY: The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended.

Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus.

BACKGROUND: Numerous laboratory tests are used in the diagnosis and management of diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. APPROACH: An expert committee compiled evidence-based recommendations for laboratory analysis in screening, diagnosis, or monitoring of diabetes. The overall quality of the evidence and the strength of the recommendations were evaluated. The draft consensus recommendations were evaluated by invited reviewers and presented for public comment. Suggestions were incorporated as deemed appropriate by the authors (see Acknowledgments). The guidelines were reviewed by the Evidence Based Laboratory Medicine Committee and the Board of Directors of the American Association for Clinical Chemistry and by the Professional Practice Committee of the American Diabetes Association. CONTENT: Diabetes can be diagnosed by demonstrating increased concentrations of glucose in venous plasma or increased hemoglobin A1c (HbA1c) in the blood. Glycemic control is monitored by the people with diabetes measuring their own blood glucose with meters and/or with continuous interstitial glucose monitoring (CGM) devices and also by laboratory analysis of HbA1c. The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of ketones, autoantibodies, urine albumin, insulin, proinsulin, and C-peptide are addressed. SUMMARY: The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended.

Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus.

BACKGROUND: Numerous laboratory tests are used in the diagnosis and management of diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. APPROACH: An expert committee compiled evidence-based recommendations for laboratory analysis in screening, diagnosis, or monitoring of diabetes. The overall quality of the evidence and the strength of the recommendations were evaluated. The draft consensus recommendations were evaluated by invited reviewers and presented for public comment. Suggestions were incorporated as deemed appropriate by the authors (see Acknowledgments). The guidelines were reviewed by the Evidence Based Laboratory Medicine Committee and the Board of Directors of the American Association of Clinical Chemistry and by the Professional Practice Committee of the American Diabetes Association. CONTENT: Diabetes can be diagnosed by demonstrating increased concentrations of glucose in venous plasma or increased hemoglobin A1c (Hb A1c) in the blood. Glycemic control is monitored by the people with diabetes measuring their own blood glucose with meters and/or with continuous interstitial glucose monitoring (CGM) devices and also by laboratory analysis of Hb A1c. The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of ketones, autoantibodies, urine albumin, insulin, proinsulin, and C-peptide are addressed. SUMMARY: The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended.

Differences in the associations between psychoactive substance use and alexithymia: A series of Meta-analyses.

The present meta-analytic study examined the association between alexithymia and psychoactive substance use. Studies published from 1988 to August 20, 2022 were identified by a systematic search and 168 eligible studies were included in five meta-analyses. Results showed that (1) the correlation between substance use and alexithymia is small but significant (r = 0.177); (2) substance users have substantially higher alexithymia than nonusers (g = 0.545); (3) alexithymic participants have significantly but slightly higher levels of substance use than non-alexithymics (g = 0.242); (4) substance users are significantly but only slightly more likely to be alexithymic than nonusers (OR = 2.392); and (5) alexithymic individuals are not more likely to be substance users than non-alexithymics. Larger effects were observed among samples diagnosed with substance use disorder (SUD), and the use of depressants, alcohol, opiates, and illicit stimulants had stronger relation to alexithymia. We found a tendency for a larger association with problematic use as compared to other indicators (e.g., frequency and duration) of substance use. Among the components of alexithymia, difficulties in identifying feelings has the strongest association with substance use. Our findings support clinical practice by suggesting the improvement of emotion regulation in SUD.

Plasma arginine metabolites in health and chronic kidney disease.

BACKGROUND: Elevated plasma asymmetric and symmetric dimethylarginine (ADMA and SDMA) are risk factors for chronic kidney disease (CKD) and cardiovascular disease. Using plasma cystatin C (pCYSC)-based estimated glomerular filtration rate (eGFR) trajectories, we identified a cohort at high risk of poor kidney-related health outcomes amongst members of the Dunedin Multidisciplinary Health and Development Study (DMHDS). We therefore examined associations between methylarginine metabolites and kidney function in this cohort. METHODS: ADMA, SDMA, L-arginine and L-citrulline were measured in plasma samples from 45-year-olds in the DMHDS cohort by liquid chromatography-tandem mass spectrometry. RESULTS: In a healthy DMHDS subset (n = 376), mean concentrations were: ADMA (0.40 ± 0.06 µmol/L), SDMA (0.42 ± 0.06 µmol/L), L-arginine (93.5 ± 23.1 µmol/L) and L-citrulline (24.0 ± 5.4 µmol/L). In the total cohort (n = 857), SDMA correlated positively with serum creatinine (Pearson's r = 0.55) and pCYSC (r = 0.55), and negatively with eGFR (r = 0.52). A separate cohort of 38 patients with stage 3-4 CKD (eGFR 15-60 mL/min/1.73 m2) confirmed significantly higher mean ADMA (0.61 ± 0.11 µmol/L), SDMA (0.65 ± 0.25 µmol/L) and L-citrulline (42.7 ± 11.8 µmol/L) concentrations. DMHDS members classified as high-risk of poor kidney health outcomes had significantly higher mean concentrations of all four metabolites compared with individuals not at risk. ADMA and SDMA individually predicted high-risk of poor kidney health outcomes with areas under the ROC curves (AUCs) of 0.83 and 0.84, and together with an AUC of 0.90. CONCLUSIONS: Plasma methylarginine concentrations facilitate stratification for risk of CKD progression.

Analytical and Non-Analytical Variation May Lead to Inappropriate Antimicrobial Dosing in Neonates: An In Silico Study.

BACKGROUND: Therapeutic drug monitoring (TDM) of aminoglycosides and vancomycin is used to prevent oto- and nephrotoxicity in neonates. Analytical and nonanalytical factors potentially influence dosing recommendations. This study aimed to determine the impact of analytical variation (imprecision and bias) and nonanalytical factors (accuracy of drug administration time, use of non-trough concentrations, biological variation, and dosing errors) on neonatal antimicrobial dosing recommendations. METHODS: Published population pharmacokinetic models and the Australasian Neonatal Medicines Formulary were used to simulate antimicrobial concentration-time profiles in a virtual neonate population. Laboratory quality assurance data were used to quantify analytical variation in antimicrobial measurement methods used in clinical practice. Guideline-informed dosing recommendations based on drug concentrations were applied to compare the impact of analytical variation and nonanalytical factors on antimicrobial dosing. RESULTS: Analytical variation caused differences in subsequent guideline-informed dosing recommendations in 9.3-12.1% (amikacin), 16.2-19.0% (tobramycin), 12.2-45.8% (gentamicin), and 9.6-19.5% (vancomycin) of neonates. For vancomycin, inaccuracies in drug administration time (45.6%), use of non-trough concentrations (44.7%), within-subject biological variation (38.2%), and dosing errors (27.5%) were predicted to result in more dosing discrepancies than analytical variation (12.5%). Using current analytical performance specifications, tolerated dosing discrepancies would be up to 14.8% (aminoglycosides) and 23.7% (vancomycin). CONCLUSIONS: Although analytical variation can influence neonatal antimicrobial dosing recommendations, nonanalytical factors are more influential. These result in substantial variation in subsequent dosing of antimicrobials, risking inadvertent under- or overexposure. Harmonization of measurement methods and improved patient management systems may reduce the impact of analytical and nonanalytical factors on neonatal antimicrobial dosing.

Genomic Evidence for Direct Transmission of mecC-MRSA between a Horse and Its Veterinarian.

Methicillin-resistant Staphylococcus aureus bearing the mecC gene (mecC-MRSA) has been reported from animals and humans in recent years. This study describes the first mecC-MRSA isolates of human and equine origin in Hungary (two isolates from horses and one from a veterinarian, who treated one of the infected horses, but was asymptomatic). MRSA isolates were identified by cultivation and PCR detection of the species-specific spa gene and mecA/mecC methicillin resistance genes. The isolates were characterized by antibiotic susceptibility testing, MLST, spa, SCCmec typing, PFGE and whole genome sequencing (WGS). All three isolates belonged to the ST130-t843-SCCmec XI genotype, and carried the mecC and blaZ genes. Apart from beta-lactam drugs, they were sensitive to all tested antibiotics. The isolates of the infected horse and its veterinarian had the same PFGE pulsotype and showed only slight differences with WGS. Hence, this is the first description of direct transmission of a mecC-carrying MRSA between a horse and its veterinarian. The emergence of mecC in the country highlights the importance of the appropriate diagnostics in MRSA identification.