Conformal normal curvature and detection of masked observations in multivariate null intercept measurement error models.

Measurement errors occur very commonly in practice. After fitting the model, influence diagnostics is an important step in statistical data analysis. The most frequently used diagnostic method for measurement error models is the local influence. However, this methodology may fail to detect masked influential observations. To overcome this limitation, we propose the use of the conformal normal curvature with the forward search algorithm. The results are presented through easy to interpret plots considering different perturbation schemes. The proposed methodology is illustrated with three real data sets and one simulated data set, two of which have been previously analyzed in the literature. The third data set deals with the stability of the hygroscopic solid dosage in pharmaceutical processes to ensure the maintenance of product safety quality. In this application, the analytical mass balance is subject to measurement errors, which require attention in the modeling process and diagnostic analysis.

Variability and bias in microbiome metagenomic sequencing: an interlaboratory study comparing experimental protocols.

Several studies have documented the significant impact of methodological choices in microbiome analyses. The myriad of methodological options available complicate the replication of results and generally limit the comparability of findings between independent studies that use differing techniques and measurement pipelines. Here we describe the Mosaic Standards Challenge (MSC), an international interlaboratory study designed to assess the impact of methodological variables on the results. The MSC did not prescribe methods but rather asked participating labs to analyze 7 shared reference samples (5 × human stool samples and 2 × mock communities) using their standard laboratory methods. To capture the array of methodological variables, each participating lab completed a metadata reporting sheet that included 100 different questions regarding the details of their protocol. The goal of this study was to survey the methodological landscape for microbiome metagenomic sequencing (MGS) analyses and the impact of methodological decisions on metagenomic sequencing results. A total of 44 labs participated in the MSC by submitting results (16S or WGS) along with accompanying metadata; thirty 16S rRNA gene amplicon datasets and 14 WGS datasets were collected. The inclusion of two types of reference materials (human stool and mock communities) enabled analysis of both MGS measurement variability between different protocols using the biologically-relevant stool samples, and MGS bias with respect to ground truth values using the DNA mixtures. Owing to the compositional nature of MGS measurements, analyses were conducted on the ratio of Firmicutes: Bacteroidetes allowing us to directly apply common statistical methods. The resulting analysis demonstrated that protocol choices have significant effects, including both bias of the MGS measurement associated with a particular methodological choices, as well as effects on measurement robustness as observed through the spread of results between labs making similar methodological choices. In the analysis of the DNA mock communities, MGS measurement bias was observed even when there was general consensus among the participating laboratories. This study was the result of a collaborative effort that included academic, commercial, and government labs. In addition to highlighting the impact of different methodological decisions on MGS result comparability, this work also provides insights for consideration in future microbiome measurement study design.

(Re)defining Motor Competence: Empirical Exploration Based on a Moderated Mediation Approach.

Purpose: The aim of the study was to empirically support a broader motor competence moderated mediation approach in which motor coordination is the predictor variable and motor competence self-perception is the outcome variable, anxiety and self-esteem are mediator variables, and gender is the moderator variable. Method: 327 year-4 Primary Education pupils participated. A conditional processes analysis was performed by macro PROCESS v.3.4. Results: For the moderation effects, interactions appeared between motor coordination and gender when taking self-esteem, anxiety and motor competence self-perception as outcome variables. Interactions were found between self-esteem and gender when anxiety and motor competence self-perception were taken as outcome variables. An interaction appeared between anxiety and gender when motor competence self-perception was considered an outcome variable. A significant direct effect was noted between the motor coordination variable and motor competence self-perception for both genders. The moderated mediation indices supported the indirect conditional effects of motor coordination when partially and jointly bearing in mind the moderator effect of gender on motor competence self-perception by means of self-esteem and anxiety. Conclusions: The results reveal the importance of understanding motor competence by more globally contemplating not only students' motor learning, but also their cognitive and psycho-emotional reality.

International Consensus Criteria for Pediatric Sepsis and Septic Shock.

Importance: Sepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children. Objective: To update and evaluate criteria for sepsis and septic shock in children. Evidence Review: The Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria. Findings: Based on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4-respiratory, cardiovascular, coagulation, and/or neurological-organ systems that was not the primary site of infection. Septic shock was defined as children with sepsis who had cardiovascular dysfunction, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, which included severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. Children with septic shock had an in-hospital mortality rate of 10.8% and 33.5% in higher- and lower-resource settings, respectively. Conclusions and Relevance: The Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world.

Development and Validation of the Phoenix Criteria for Pediatric Sepsis and Septic Shock.

Importance: The Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach. Objective: To derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings. Design, Setting, and Participants: Multicenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged <18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set. Exposure: Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock. Main Outcomes and Measures: The primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity. Results: Among the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis and sepsis plus 1 or more cardiovascular point as criteria for septic shock resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria across differently resourced settings. Conclusions and Relevance: The novel Phoenix sepsis criteria, which were derived and validated using data from higher- and lower-resource settings, had improved performance for the diagnosis of pediatric sepsis and septic shock compared with the existing IPSCC criteria.

Factors associated with prolonged mechanical ventilation in children with pulmonary failure: Cohort study from the LARed Network registry.

OBJECTIVES: To identify factors associated with prolonged mechanical ventilation (pMV) in pediatric patients in pediatric intensive care units (PICUs). DESIGN: Secondary analysis of a prospective cohort. SETTING: PICUs in centers that are part of the LARed Network between April 2017 and January 2022. PARTICIPANTS: Pediatric patients on mechanical ventilation (IMV) due to respiratory causes. We defined IMV time greater than the 75th percentile of the global cohort. INTERVENTIONS: None. MAIN VARIABLES OF INTEREST: Demographic data, diagnoses, severity scores, therapies, complications, length of stay, morbidity, and mortality. RESULTS: 1698 children with MV of 8±7 days were included, and pIMV was defined as 9 days. Factors related to admission were age under 6 months (OR 1.61, 95% CI 1.17-2.22), bronchopulmonary dysplasia (OR 3.71, 95% CI 1.87-7.36), and fungal infections (OR 6.66, 95% CI 1.87-23.74), while patients with asthma had a lower risk of pIMV (OR 0.30, 95% CI 0.12-0.78). Regarding evolution and length of stay in the PICU, it was related to ventilation-associated pneumonia (OR 4.27, 95% CI 1.79-10.20), need for tracheostomy (OR 2.91, 95% CI 1.89-4.48), transfusions (OR 2.94, 95% CI 2.18-3.96), neuromuscular blockade (OR 2.08, 95% CI 1.48-2.93), high-frequency ventilation (OR 2.91, 95% CI 1.89-4.48), and longer PICU stay (OR 1.13, 95% CI 1.10-1.16). In addition, mean airway pressure greater than 13cmH2O was associated with pIMV (OR 1.57, 95% CI 1.12-2.21). CONCLUSIONS: Factors related to IMV duration greater than 9 days in pediatric patients in PICUs were identified in terms of admission, evolution, and length of stay.

Clinical decision support tools for paediatric sepsis in resource-poor settings: an international qualitative study.

OBJECTIVE: New paediatric sepsis criteria are being developed by an international task force. However, it remains unknown what type of clinical decision support (CDS) tools will be most useful for dissemination of those criteria in resource-poor settings. We sought to design effective CDS tools by identifying the paediatric sepsis-related decisional needs of multidisciplinary clinicians and health system administrators in resource-poor settings. DESIGN: Semistructured qualitative focus groups and interviews with 35 clinicians (8 nurses, 27 physicians) and 5 administrators at health systems that regularly provide care for children with sepsis, April-May 2022. SETTING: Health systems in Africa, Asia and Latin America, where sepsis has a large impact on child health and healthcare resources may be limited. PARTICIPANTS: Participants had a mean age of 45 years, a mean of 15 years of experience, and were 45% female. RESULTS: Emergent themes were related to the decisional needs of clinicians caring for children with sepsis and to the needs of health system administrators as they make decisions about which CDS tools to implement. Themes included variation across regions and institutions in infectious aetiologies of sepsis and available clinical resources, the need for CDS tools to be flexible and customisable in order for implementation to be successful, and proposed features and format of an ideal paediatric sepsis CDS tool. CONCLUSION: Findings from this study will directly contribute to the design and implementation of CDS tools to increase the uptake and impact of the new paediatric sepsis criteria in resource-poor settings.

Ultrastructural calibration model for proficiency testing.

Proficiency testing (PT) determines the performance of individual laboratories for specific tests or measurements and it is used to monitor the reliability of laboratories measurements. PT plays a highly valuable role as it provides objective evidence of the competence of the participant laboratories. In this paper, we propose a multivariate calibration model to assess equivalence among laboratories measurements in PT. Our method allows to deal with multivariate data, where the item under test is measured at different levels. Although intuitive, the proposed model is nonergodic, which means that the asymptotic Fisher information matrix is random. As a consequence, a detailed asymptotic analysis was carried out to establish the strategy for comparing the results of the participating laboratories. To illustrate, we apply our method to analyze the data from the Brazilian engine test group, PT program, where the power of an engine was measured by eight laboratories at several levels of rotation.

Frequency Variation and Dose Modification of Benznidazole Administration for the Treatment of Trypanosoma cruzi Infection in Mice, Dogs, and Nonhuman Primates.

Trypanosoma cruzi naturally infects a broad range of mammalian species and frequently results in the pathology that has been most extensively characterized in human Chagas disease. Currently employed treatment regimens fail to achieve parasitological cure of T. cruzi infection in the majority of cases. In this study, we have extended our previous investigations of more effective, higher dose, intermittent administration protocols using the FDA-approved drug benznidazole (BNZ), in experimentally infected mice and in naturally infected dogs and nonhuman primates (NHP). Collectively, these studies demonstrate that twice-weekly administration of BNZ for more than 4 months at doses that are ~2.5-fold that of previously used daily dosing protocols, provided the best chance to obtain parasitological cure. Dosing less frequently or for shorter time periods was less dependable in all species. Prior treatment using an ineffective dosing regimen in NHPs did not prevent the attainment of parasitological cure with an intensified BNZ dosing protocol. Furthermore, parasites isolated after a failed BNZ treatment showed nearly identical susceptibility to BNZ as those obtained prior to treatment, confirming the low risk of induction of drug resistance with BNZ and the ability to adjust the treatment protocol when an initial regimen fails. These results provide guidance for the use of BNZ as an effective treatment for T. cruzi infection and encourage its wider use, minimally in high value dogs and at-risk NHP, but also potentially in humans, until better options are available.

Frequency variation and dose modification of benznidazole administration for the treatment of Trypanosoma cruzi infection in mice, dogs and non-human primates.

Trypanosoma cruzi naturally infects a broad range of mammalian species and frequently results in the pathology that has been most extensively characterized in human Chagas disease. Currently employed treatment regimens fail to achieve parasitological cure of T. cruzi infection in the majority of cases. In this study, we have extended our previous investigations of more effective, higher dose, intermittent administration protocols using the FDA-approved drug benznidazole (BNZ), in experimentally infected mice and in naturally infected dogs and non-human primates (NHP). Collectively these studies demonstrate that twice-weekly administration of BNZ for more than 4 months at doses that are ∻2.5-fold that of previously used daily dosing protocols, provided the best chance to obtain parasitological cure. Dosing less frequently or for shorter time periods was less dependable in all species. Prior treatment using an ineffective dosing regimen in NHPs did not prevent the attainment of parasitological cure with an intensified BNZ dosing protocol. Furthermore, parasites isolated after a failed BNZ treatment showed nearly identical susceptibility to BNZ as those obtained prior to treatment, confirming the low risk of induction of drug resistance with BNZ and the ability to adjust the treatment protocol when an initial regimen fails. These results provide guidance for the use of BNZ as an effective treatment for T. cruzi infection and encourage its wider use, minimally in high value dogs and at-risk NHP, but also potentially in humans, until better options are available.

Qualitative analysis from the social referents perspective of the multidimensional construct of schoolchildren's motor competence.

Motor competence (MC) as a multidimensional construct is influenced by motor, cognitive, emotional and social variables. It is also determined by schoolchildren interacting with their own context. Thus pre-adolescence is a sensitive stage in development when physical, emotional and cognitive changes are manifested. By taking this context in accountn, the perception of the social referents close to schoolchildren allows for a deeper understanding of the role and influence of all these variables in a broader MC concept. For this purpose, a qualitative study was conducted by discussion groups and semistructured interviews, respectively, for teachers and family members in Primary Education. The content analysis was carried out according to the main study dimensions, associated with the motor, cognitive, affective-emotional and social domains. Both family members and teachers point out that the affective-emotional level has a stronger impact on the development of motor skills than the motor level. For children to develop their MC, it is necessary to create appropriate contexts in which family members and teachers are the main agents of influence. In conclusion, assessing MC in the educational sphere must have a more comprehensive and broad approach. It is necessary to bear in mind a larger number of variables involved in schoolchildren's motor development to make the most objective assessment possible and, likewise, to promote facilitating environments that help their development.

Prophylactic low-dose, bi-weekly benznidazole treatment fails to prevent Trypanosoma cruzi infection in dogs under intense transmission pressure.

Trypanosoma cruzi naturally infects a wide variety of wild and domesticated mammals, in addition to humans. Depending on the infection dose and other factors, the acute infection can be life-threatening, and in all cases, the risk of chagasic heart disease is high in persistently infected hosts. Domestic, working, and semi-feral dogs in the Americas are at significant risk of T. cruzi infection and in certain settings in the southern United States, the risk of new infections can exceed 30% per year, even with the use of vector control protocols. In this study, we explored whether intermittent low-dose treatment with the trypanocidal compound benznidazole (BNZ) during the transmission season, could alter the number of new infections in dogs in an area of known, intense transmission pressure. Preliminary studies in mice suggested that twice-weekly administration of BNZ could prevent or truncate infections when parasites were delivered at the mid-point between BNZ doses. Pre-transmission season screening of 126 dogs identified 53 dogs (42.1%) as T. cruzi infection positive, based upon blood PCR and Luminex-based serology. Serial monitoring of the 67 uninfected dogs during the high transmission season (May to October) revealed 15 (22.4%) new infections, 6 in the untreated control group and 9 in the group receiving BNZ prophylaxis, indicating no impact of this prophylaxis regimen on the incidence of new infections. Although these studies suggest that rigorously timed and more potent dosing regimen may be needed to achieve an immediate benefit of prophylaxis, additional studies would be needed to determine if drug prophylaxis reduced disease severity despite this failure to prevent new infections.

Characteristics of Medically Transported Critically Ill Children with Respiratory Failure in Latin America: Implications for Outcomes.

Several challenges exist for referral and transport of critically ill children in resource-limited regions such as Latin America; however, little is known about factors associated with clinical outcomes. Thus, we aimed to describe the characteristics of critically ill children in Latin America transferred to pediatric intensive care units for acute respiratory failure to identify risk factors for mortality. We analyzed data from 2,692 patients admitted to 28 centers in the Pediatric Collaborative Network of Latin America Acute Respiratory Failure Registry. Among patients referred from another facility (773, 28%), nonurban transports were independently associated with mortality (adjusted odds ratio = 9.4; 95% confidence interval: 2.4-36.3).

Quantitative 3D Imaging of Trypanosoma cruzi-Infected Cells, Dormant Amastigotes, and T Cells in Intact Clarified Organs.

Chagas disease is a neglected pathology that affects millions of people worldwide, mainly in Latin America. The Chagas disease agent, Trypanosoma cruzi (T. cruzi), is an obligate intracellular parasite with a diverse biology that infects several mammalian species, including humans, causing cardiac and digestive pathologies. Reliable detection of T. cruzi in vivo infections has long been needed to understand Chagas disease's complex biology and accurately evaluate the outcome of treatment regimens. The current protocol demonstrates an integrated pipeline for automated quantification of T. cruzi-infected cells in 3D-reconstructed, cleared organs. Light-sheet fluorescent microscopy allows for accurately visualizing and quantifying of actively proliferating and dormant T. cruzi parasites and immune effector cells in whole organs or tissues. Also, the CUBIC-HistoVision pipeline to obtain uniform labeling of cleared organs with antibodies and nuclear stains was successfully adopted. Tissue clearing coupled with 3D immunostaining provides an unbiased approach to comprehensively evaluate drug treatment protocols, improve the understanding of the cellular organization of T. cruzi-infected tissues, and is expected to advance discoveries related to anti-T. cruzi immune responses, tissue damage, and repair in Chagas disease.

Functional control of a 0.5 MDa TET aminopeptidase by a flexible loop revealed by MAS NMR.

Large oligomeric enzymes control a myriad of cellular processes, from protein synthesis and degradation to metabolism. The 0.5 MDa large TET2 aminopeptidase, a prototypical protease important for cellular homeostasis, degrades peptides within a ca. 60 Å wide tetrahedral chamber with four lateral openings. The mechanisms of substrate trafficking and processing remain debated. Here, we integrate magic-angle spinning (MAS) NMR, mutagenesis, co-evolution analysis and molecular dynamics simulations and reveal that a loop in the catalytic chamber is a key element for enzymatic function. The loop is able to stabilize ligands in the active site and may additionally have a direct role in activating the catalytic water molecule whereby a conserved histidine plays a key role. Our data provide a strong case for the functional importance of highly dynamic - and often overlooked - parts of an enzyme, and the potential of MAS NMR to investigate their dynamics at atomic resolution.

Latin American Consensus on the Management of Sepsis in Children: Sociedad Latinoamericana de Cuidados Intensivos Pediátricos [Latin American Pediatric Intensive Care Society] (SLACIP) Task Force: Executive Summary.

Objective: The aim of this study was to develop evidence-based recommendations for the diagnosis and treatment of sepsis in children in low- and middle-income countries (LMICs), more specifically in Latin America. Design: A panel was formed consisting of 27 experts with experience in the treatment of pediatric sepsis and two methodologists working in Latin American countries. The experts were organized into 10 nominal groups, each coordinated by a member. Methods: A formal consensus was formed based on the modified Delphi method, combining the opinions of nominal groups of experts with the interpretation of available scientific evidence, in a systematic process of consolidating a body of recommendations. The systematic search was performed by a specialized librarian and included specific algorithms for the Cochrane Specialized Register, PubMed, Lilacs, and Scopus, as well as for OpenGrey databases for grey literature. The GRADEpro GDT guide was used to classify each of the selected articles. Special emphasis was placed on search engines that included original research conducted in LMICs. Studies in English, Spanish, and Portuguese were covered. Through virtual meetings held between February 2020 and February 2021, the entire group of experts reviewed the recommendations and suggestions. Result: At the end of the 12 months of work, the consensus provided 62 recommendations for the diagnosis and treatment of pediatric sepsis in LMICs. Overall, 60 were strong recommendations, although 56 of these had a low level of evidence. Conclusions: These are the first consensus recommendations for the diagnosis and management of pediatric sepsis focused on LMICs, more specifically in Latin American countries. The consensus shows that, in these regions, where the burden of pediatric sepsis is greater than in high-income countries, there is little high-level evidence. Despite the limitations, this consensus is an important step forward for the diagnosis and treatment of pediatric sepsis in Latin America.

Challenges and health-care priorities for reducing the burden of paediatric sepsis in Latin America: a call to action.

Sepsis is a worldwide public health problem due to its high incidence and accompanying mortality, morbidity, and financial burden. It is a major cause of admission to paediatric intensive care units; despite advances in the diagnosis and treatment, both incidence and mortality are high in low-income and middle-income countries. There are several barriers in addressing the enormous burden of paediatric sepsis in these countries, which include: lack of data of incidence and mortality; unfamiliarity of sepsis by the lay public, leading to failure to seek care early, and by health professionals, leading to failure to treat emergently; and insufficient government funding for sepsis care programmes leading to inadequate staffing, material, and financial resources, and therefore, poor health systems. Socioeconomic inequalities, such as inequity and marked variation in income and education, high rates of malnutrition, high percentage of young population, and health systems that do not meet the population's demands also represent barriers in the care of children with sepsis in Latin America. In this Viewpoint, we draw attention to the problem of paediatric sepsis in Latin America and call for action to reduce the disease burden by proposing some solutions.

Comparison of Interleukin-6 Plasma Concentration in Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Pediatric Sepsis.

Importance: Multisystem Inflammatory Syndrome in Children (MIS-C) associated with SARS-CoV-2 infection is thought to be driven by a post-viral dysregulated immune response, where interleukin 6 (IL-6) might have a central role. In this setting, IL-6 inhibitors are prescribed as immunomodulation in cases refractory to standard therapy. Objective: To compare plasma IL-6 concentration between critically ill children with MIS-C and sepsis. Design: A retrospective cohort study from previously collected data. Setting: Individual patient data were gathered from three different international datasets. Participants: Critically ill children between 1 month-old and 18 years old, with an IL-6 level measured within 48 h of admission to intensive care. Septic patients were diagnosed according to Surviving Sepsis Campaign definition and MIS-C cases by CDC criteria. We excluded children with immunodeficiency or immunosuppressive therapy. Exposure: None. Main Outcome(s) and Measure(s): The primary outcome was IL-6 plasma concentration in MIS-C and sepsis group at admission to the intensive care unit. We described demographics, inflammatory biomarkers, and clinical outcomes for both groups. A subgroup analysis for shock in each group was done. Results: We analyzed 66 patients with MIS-C and 44 patients with sepsis. MIS-C cases were older [96 (48, 144) vs. 20 (5, 132) months old, p < 0.01], but no differences in sex (41 vs. 43% female, p = 0.8) compared to septic group. Mechanical ventilation use was 48.5 vs. 93% (p < 0.001), vasoactive drug use 79 vs. 66% (p = 0.13), and mortality 4.6 vs. 34.1% (p < 0.01) in MIS-C group compared to sepsis. IL-6 was 156 (36, 579) ng/dl in MIS-C and 1,432 (122, 6,886) ng/dl in sepsis (p < 0.01), while no significant differences were observed in procalcitonin (PCT) and c-reactive protein (CRP). 52/66 (78.8%) patients had shock in MIS-C group, and 29/44 (65.9%) had septic shock in sepsis group. Septic shock had a significantly higher plasma IL-6 concentration than the three other sub-groups. Differences in IL-6, CRP, and PCT were not statistically different between MIS-C with and without shock. Conclusions and Relevance: IL-6 plasma concentration was elevated in critically ill MIS-C patients but at levels much lower than those of sepsis. Furthermore, IL-6 levels don't discriminate between MIS-C cases with and without shock. These results lead us to question the role of IL-6 in the pathobiology of MIS-C, its diagnosis, clinical outcomes, and, more importantly, the off-label use of IL-6 inhibitors for these cases.

Influence of blood metabolites and body condition score at parturition on fertility and milk yield in Holstein cows / Influencia de metabolitos sanguíneos y condición corporal al parto sobre la fertilidad y producción de leche de vacas Holstein / Influência dos metabólitos sanguíneos e da condição corporal ao nascimento na fertilidade e produção de leite de vacas Holstein

Abstract Background: Variables associated with body tissue mobilization place dairy cows at greater risk of reproductive failure. Objective: To investigate the association between blood metabolites and body condition score (BCS) at the beginning of lactation and the reproductive efficiency and milk yield of Holstein cows in a hot environment. Methods: In total, 165 Holstein cows were selected for the study from which blood samples were taken to determine the concentration of various blood metabolites and their association with the reproductive efficiency and milk yield. Results: Cows with serum β-hydroxybutyrate (BHBA) ≤0.8 mmol/L one week postpartum were 3.3 times more likely to become pregnant at first service, and 2.2 times more likely to become pregnant before 80 d postpartum than cows with higher serum BHBA levels. The odds (OR 2.7; 95% CI 1.3-5.4; p<0.01) of a cow getting pregnant at first service were higher in cows with serum creatinine levels higher than 2.0 mg/dL one week postpartum than cows with lower blood levels of this metabolite. The BCS at 30 and 60 d postpartum that predicted pregnancy at first service and pregnancy to all services was 3.0. Blood urea nitrogen >15 mg/dL, creatinine <1.8 mg/dL, total protein ≤5.0 mg/dL one week postpartum, and >0.40 units of BCS loss during the first 30 d postpartum were critical threshold that predicted the likelihood of 305-d milk yield higher than 10,500 kg. Conclusions: Serum BHBA and creatinine one wk after calving as well as BCS 30 and 60 d post-calving provided reasonably accurate cut-off screening values to discriminate cows with better reproductive performance and higher 305-d milk yield.

Resumen Antecedentes: Las variables asociadas a mayor movilización de tejido corporal en vacas lecheras conducen a un mayor riesgo de falla reproductiva. Objetivo: Investigar la asociación entre los metabolitos sanguíneos y condición corporal (BCS) al comienzo de la lactancia y la eficiencia reproductiva y producción de leche de vacas Holstein en un ambiente caluroso. Métodos: En total, se seleccionaron 165 vacas Holstein de las cual se tomaron muestras de sangre para determinar la concentración de varios matabolitos sanguíneos, los cuales se asociaron con el desempeño reproductivo y producción de leche. Resultados: Las vacas con β-hidroxibutirato (BHBA) en suero ≤0,8 mmol/L una semana postparto tuvieron 3,3 veces más probabilidades de quedar preñadas en los primeros servicios, y 2,2 veces más probabilidades de quedar gestantes antes de los 80 días postparto que las vacas con mayores niveles séricos de BHBA. Las probabilidades (OR 2,7; IC 95% 1,3-5,4; p<0,01) de que una vaca se preñara en el primer servicio fueron mayores en vacas con niveles de creatinina en suero sanguíneo superiores a 2,0 mg/dL una semana postparto que las vacas con niveles más bajos de este metabolito en sangre. Una BCS de 3 a los 30 y 60 días postparto fue un buen predictor de la preñez al primer servicio y la gestación considerando todos los servicios. El nitrógeno ureico en sangre >15 mg/dL, la creatinina <1,8 mg/dL, la proteína total ≤5,0 mg/dL una semana después del parto y >0,40 unidades de pérdida de BCS durante los primeros 30 días postparto fueron los valores críticos para predecir una producción de leche a 305 días superior a 10.500 kg. Conclusiones: El BHBA y la creatinina en suero sanguíneo una semana postparto, así como la BCS 30 y 60 d después del parto, proporcionan valores razonablemente precisos para identificar las vacas que tendrán mejor desempeño reproductivo y mayor producción de leche a 305 días.

Resumo Antecedentes: A maior mobilização do tecido corporal das vacas leiteiras leva a um aumento do risco de falhas reprodutivas. Objetivo: Para investigar a relação entre os metabolitos sanguíneos e condição do corpo (BCS) para o início da lactação e eficiência reprodutiva e produção de leite de vacas Holstein num ambiente quente. Métodos: No total, foram selecionadas 165 vacas da raça Holandesa, das quais foram coletadas amostras de sangue para determinar a concentração de vários metabólitos sanguíneos, associados ao desempenho reprodutivo e à produção de leite das vacas. Resultados: As vacas com β-hidroxibutirato (BHBA) soro ≤0,8 mmol/L de uma semana após o nascimento foram 3,3 vezes mais probabilidade de engravidar nos primeiros serviços, e 2,2 vezes mais provável que seja grávida antes de 80 dias após o parto do que vacas com níveis séricos de BHBA mais elevados. As probabilidades (OR 2,7, IC de 95% 1,3-5,4, p<0,01) que uma vaca preñara primeiros serviços vacas foram maiores com níveis mais elevados de creatinina no soro do sangue >2,0 mg/dL, uma semana pós-parto do que vacas com níveis sanguíneos mais baixos deste metabolito. Um CC de 3 aos 30 e 60 dias pós-parto foi um bom predictor de gravidez no primeiro serviço e gestação, considerando todos os serviços. O azoto de ureia no sangue >15 mg/dL, creatinina <1,8 mg/dL e proteína total, ≤5,0 mg/dL uma semana após o parto e >0,40 unidades perda CC durante os primeiros 30 dias após o nascimento estavam valores críticos que previram produção de leite em 305 dias >10.500 kg. Conclusões: BHBA e creatinina sérica, uma semana após o parto, bem como CC 30 e 60 d após o parto, forneceram valores razoavelmente precisos para discriminar vacas com melhor desempenho reprodutivo e maior produção de leite em 305 dias.