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Resumen Introduccion El compromiso de la articulacion coxofemoral en la artritis reumatoide se asocia a discapacidad y menor calidad de vida. En la actualidad no existen estudios que evaluen sus alteraciones en etapas subclinicas. Objetivo Determinar la prevalencia del compromiso subclinico de cadera mediante el uso del ultrasonido. Material y metodos Estudio descriptivo de corte transversal, enfocado en pacientes con diagnostico establecido de artritis reumatoide, segun los criterios clasificatorios de la EULAR/ACR 2010, que presentaron o no dolor en la articulacion coxofemoral durante el examen fisico, comparados con individuos sanos. Se investigo la presencia de distension de la capsula articular, bursitis del iliopsoas, erosiones, osteofitos, remodelacion articular y senal Doppler de poder. Las imagenes fueron interpretadas por un reumatologo experto en US, cegado a las variables clinicas, demograficas y de laboratorio. Resultados Se evaluaron en total 234 caderas; 37 (31,6%) pacientes con artritis reumatoide sintomaticos de la cadera, 40 (34,1%) pacientes con artritis reumatoide subclinica y 40 (34,1%) sujetos sanos. La prevalencia de sinovitis de la capsula articular fue del 48,6% para los pacientes con artritis reumatoide sintomatica, del 20% para los pacientes con artritis reumatoide subclinica y del 15% para los sujetos sanos. El grupo de pacientes con artritis reumatoide subclinica presento una mayor frecuencia de osteofitos y remodelacion articular. Conclusiones Se confirmo el valor del ultrasonido en el diagnostico subclinico de la patologia inflamatoria de la articulacion coxofemoral. No se evidenciaron asociaciones significativas entre los hallazgos del US con la actividad de la enfermedad, ni con los valores de estudios de laboratorio.

El objetivo primordial de este artículo es probar si los flujos de capital conducen sistemáticamente al alza reciente en los precios de la vivienda en Colombia. Apoyado en el soporte teórico del modelo de Zanna (1996), se estiman dos modelos VEC aplicados a variables de carácter macroeconómico. Los resultados que se desprenden del análisis de las funciones impulso respuesta y descomposición de varianza, muestran que existe una evidencia débil para aceptar dicha hipótesis, por lo que se sugiere que las condiciones internas asociadas con la mayor regulación del sector hipotecario y con los fundamentales del precio son claves a la hora de explicar por qué los flujos de capital no juegan un rol tan activo como lo hicieron a finales de la década de 1990 y el por qué de los altos valores de las unidades residenciales en el país durante el último tiempo, respectivamente.

Background IFIs are a leading cause of morbidity and mortality in immunocompromised pediatric patients. Early diagnosis and initiation of therapy is critical for treatment success but is often hindered by difficulty obtaining tissue samples, lack of growth on culture and time required for culture positivity. Non-culture methods such as aspergillus galactomannan and 1-3 B-D glucan lack sensitivity and specificity. NGS has shown promise in identifying a wide array of pathogens. The Karius test is a NGS which can identify viral, bacterial, and fungal infections by detecting cell free pathogen DNA in peripheral blood with a rapid turnaround time. Over the past few years we have used the Karius test as an adjunct to our standard of care in the workup and treatment of IFI in our oncology population Methods We report our experience in using serial NGS testing for diagnosis of IFI as well as a means for monitoring clinical response to treatment in our pediatric hematological malignancy population. Results Between 12/1/20-12/31/21, 5 patients had serial NGS for IFI. Most common indication for testing was prolonged fever and neutropenia with abnormal imaging. Initial diagnosis was made by NGS in all 5 patients. All had tissue biopsies with fungal elements seen on path in 4 of 5 patients. Culture was positive in 3 of 5 patients (2 days, 10 days and 12 days post NGS testing result). One patient with persistent positive NGS testing was found to have resistance to treatment drug on susceptibility testing and subsequently had negative NGS testing once appropriate antifungals were started. A second patient had sterilization of cultures with concomitant negative NGS results but developed increasing fungal copies on NGS testing followed by positive culture when chemotherapy was resumed and subsequently died due to his infection. 4 of 5 patients had serial negative follow up NGS and continue to do well. Summary of Diagnostic Work-Up Conclusion In our small series of patients, NGS testing allowed for rapid diagnosis of IFIs and corresponded to clinical response to treatment. Future prospective studies will be needed to further evaluate the use of NGS in this patient population. Disclosures All Authors: No reported disclosures.

BACKGROUND Infections with Gram-positive bacteria, including acute bacterial skin and skin structure infections (ABSSSIs), are common in children. We describe a single-dose pharmacokinetics and safety study of tedizolid phosphate, a new oxazolidinone under investigation for the treatment of ABSSSIs in children, in hospitalized participants 2 to

Background We prospectively evaluated efficacy and safety of daptomycin versus active comparator in children with acute hematogenous osteomyelitis (AHO). Methods Randomized, controlled, double-blind, global, multicenter, phase 3 trial. Patients 1-17 years of age with suspected/confirmed AHO requiring hospitalization and intravenous therapy were randomized 1:1 to intravenous daptomycin (once-daily, age-adjusted doses) or comparator (vancomycin, nafcillin or equivalent) ≥4 days, followed by oral therapy (14-42 days total). Primary endpoint: protocol-defined clinical improvement by Day 5 in the modified intention-to-treat (MITT) population (confirmed AHO, ≥1 dose of study treatment); differences between study arms were evaluated using a prespecified 15% noninferiority margin for daptomycin. Results Seventy-three patients per arm received treatment. Pathogens were isolated from 62% of patients (83% methicillin-susceptible Staphylococcus aureus, 9% methicillin-resistant S. aureus [MRSA]). Clinical improvement by Day 5 was observed in 55/71 (78%) daptomycin- and 58/70 (83%) comparator-treated MITT patients (95% confidence interval [CI]: -19.4, 7.4). This difference was not statistically significant; however, daptomycin did not meet the prespecified 15% noninferiority margin, since the lower bound of the 95% CI extended below 15%. Overall, 82% of daptomycin and 87% of comparator patients achieved clinical cure at the test-of-cure visit (secondary endpoint). More comparator patients had treatment-emergent (63% vs. 46%) and treatment-related (18% vs. 7%) adverse events. Conclusions Differences between daptomycin and comparator for the primary endpoint were not statistically significant; however, prespecified noninferiority criteria for daptomycin were not met. With insufficient cases of confirmed MRSA, we could not evaluate daptomycin for MRSA AHO. Our nonvalidated protocol design yields valuable information for implementing future trials in AHO (ClinicalTrials.gov NCT01922011).

Background The antipseudomonal cephalosporin/β-lactamase inhibitor combination ceftolozane/tazobactam could be a potential treatment option for cystic fibrosis (CF) pulmonary exacerbations. The pharmacokinetics (PK) of ceftolozane/tazobactam in children with CF merits further evaluation. Methods This is a retrospective subgroup analysis of a phase 1, noncomparative trial that characterized PK, safety, and tolerability of single intravenous doses of ceftolozane/tazobactam in pediatric patients. This analysis compares ceftolozane and tazobactam plasma PK parameters, estimated from a population PK model, between patients with and without CF enrolled in that trial. Individual attainment of PK/pharmacodynamic (PD) targets of ceftolozane and tazobactam (free ceftolozane concentration >4 µg/mL for >30% and free tazobactam concentration >1 µg/mL for 20% of the dosing interval) in patients with and without CF were evaluated. Results The study enrolled 18 patients aged greater than or equal to 2 to less than 18 years old, which included 9 with CF. Weight-normalized ceftolozane PK parameters were similar between patients with CF (clearance: 0.16 L/h/kg, half-life: 1.54 hours, volume of distribution: 0.26 L/kg) and without CF (clearance: 0.15 L/h/kg, half-life: 1.62 hours, volume of distribution: 0.26 L/kg), as were most weight-normalized tazobactam PK parameters. Weight-normalized tazobactam clearance was higher in patients with CF (0.73 L/h/kg) than patients without CF (0.42 L/h/kg). All patients achieved the prespecified PK/PD targets for ceftolozane and tazobactam. Conclusions This retrospective analysis demonstrated generally similar weight-normalized plasma PK parameters for ceftolozane and tazobactam among children with and without CF; thus, projected doses for treatment of pediatric hospital-acquired/ventilator-associated pneumonia, which are higher than the pediatric complicated urinary tract infection/intra-abdominal infection doses, may be appropriate for treatment of CF pulmonary exacerbation.

Currently employed methods for qualifying population physiologically-based pharmacokinetic (Pop-PBPK) model predictions of continuous outcomes (e.g., concentration-time data) fail to account for within-subject correlations and the presence of residual error. In this study, we propose a new method for evaluating Pop-PBPK model predictions that account for such features. The approach focuses on deriving Pop-PBPK-specific normalized prediction distribution errors (NPDE), a metric that is commonly used for population pharmacokinetic model validation. We describe specific methodological steps for computing NPDE for Pop-PBPK models and define three measures for evaluating model performance: mean of NPDE, goodness-of-fit plots, and the magnitude of residual error. Utility of the proposed evaluation approach was demonstrated using two simulation-based study designs (positive and negative control studies) as well as pharmacokinetic data from a real-world clinical trial. For the positive-control simulation study, where observations and model simulations were generated under the same Pop-PBPK model, the NPDE-based approach denoted a congruency between model predictions and observed data (mean of NPDE = - 0.01). In contrast, for the negative-control simulation study, where model simulations and observed data were generated under different Pop-PBPK models, the NPDE-based method asserted that model simulations and observed data were incongruent (mean of NPDE = - 0.29). When employed to evaluate a previously developed clindamycin PBPK model against prospectively collected plasma concentration data from 29 children, the NPDE-based method qualified the model predictions as successful (mean of NPDE = 0). However, when pediatric subpopulations (e.g., infants) were evaluated, the approach revealed potential biases that should be explored.

Objective New treatments are needed for multidrug-resistant (MDR) gram-negative infections in neonates. Ceftolozane/tazobactam is a β-lactam/β-lactamase inhibitor combination that has broad-spectrum activity against most common gram-negative bacteria, including MDR strains. We evaluated pharmacokinetics (PK) and safety of ceftolozane/tazobactam in term and premature neonates and young infants. Study Design This is a subgroup analysis of a phase 1, noncomparative, open-label, multicenter study that characterized the PK, safety, and tolerability of a single intravenous (IV) dose of ceftolozane/tazobactam in pediatric patients with proven/suspected gram-negative infection or receiving perioperative prophylaxis. Results Seven patients were enrolled in Group A (birth [7 days postnatal] to 32 weeks gestation) and six patients were enrolled in Group B (birth [7 days postnatal] to Conclusion Among term and premature neonates and young infants, PK was comparable to older children and ceftolozane/tazobactam was generally well tolerated. An adaptable and flexible study design is necessary for enrollment in neonatal PK trials.

Based on in vitro susceptibilities and the concern for emergence of resistance and long-term safety, ampicillin plus gentamicin remains the recommended antibiotic regimen for early onset neonatal sepsis. Our objective was to identify potential limitations of this regimen based on clinical and pathogen characteristics while minimizing risks associated with prolonged antibiotic exposure. We identified 43 gram-negative pathogens in 42 patients. Escherichia coli ( E coli) occurred in 50% and Streptococcus agalactiae in 23.8% of patient. Ampicillin resistance was common, particularly in E coli (85.7%). Mortality was 23.8%, all due to E coli. We found that E coli is the most frequent pathogen and has a high mortality particularly in neonates < 1500 g; mortality is high with the current dosing strategy when E coli is resistant to ampicillin even when sensitive to gentamicin; resistance to gentamicin remains low but seems to be increasing while resistance to third-generation cephalosporins remains very low.

Background Invasive candidiasis is the most common invasive fungal disease in children and adolescents, but there are limited pediatric-specific antifungal effectiveness data. We compared the effectiveness of echinocandins to triazoles or amphotericin B formulations (triazole/amphotericin B) as initial directed therapy for invasive candidiasis. Methods This multinational observational cohort study enrolled patients aged >120 days and Results Seven-hundred and fifty invasive candidiasis episodes were identified. After exclusions, 541 participants (235 in the echinocandin group and 306 in the triazole/amphotericin B group) remained. Crude failure rates at 14 days for echinocandin and triazole/amphotericin B groups were 9.8% (95% confidence intervals [CI]: 6.0% to 13.6%) and 13.1% (95% CI: 9.3% to 16.8%), respectively. The adjusted 14-day risk difference between echinocandin and triazole/amphotericin B groups was −7.1% points (95% CI: −13.1% to −2.4%), favoring echinocandins. The risk difference was −0.4% (95% CI: −7.5% to 6.7%) at 30 days. Conclusions In children with invasive candidiasis, initial directed therapy with an echinocandin was associated with reduced failure rate at 14 days but not 30 days. These results may support echinocandins as initial directed therapy for invasive candidiasis in children and adolescents. Clinical Trials Registration NCT01869829.

The COVID-19 pandemic is a public health crisis that has the potential to exacerbate worldwide malnutrition. This study examines whether patients with a history of malnutrition are predisposed to severe COVID-19. To do so, data on 103,099 COVID-19 inpatient encounters from 56 hospitals in the United States between March 2020 and June 2020 were retrieved from the Cerner COVID-19 Dataset. Patients with a history of malnutrition between 2015 and 2019 were identified, and a random intercept logistic regression models for pediatric and adult patients were built controlling for patient demographics, socioeconomic status, admission vital signs, and related comorbidities. Statistical interactions between malnutrition and patient age were significant in both the pediatric [log-odds and 95% confidence interval: 0.094 (0.012, 0.175)] and adult [− 0.014 (− 0.021, − 0.006] models. These interactions, together with the main effect terms of malnutrition and age, imply higher odds for severe COVID-19 for children between 6 and 17 years with history of malnutrition. Even higher odds of severe COVID-19 exist for adults (with history of malnutrition) between 18 and 79 years. These results indicate that the long-term effect of malnutrition predisposes patients to severe COVID-19 in an age-dependent way.

Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified by age (1 to 80% and >76% of simulated pediatric patients following i.v. or oral administration, respectively. Intravenous and oral administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated and resulted in exposure in pediatric patients similar to that in adults. (This study has been registered at ClinicalTrials.gov under identifier NCT03241550).

Background Pediatric central nervous system (CNS) infections are potentially life-threatening and may incur significant morbidity. Identifying a pathogen is important, both in terms of guiding therapeutic management and in characterizing prognosis. Usual care testing by culture and polymerase chain reaction is often unable to identify a pathogen. We examined the systematic application of metagenomic next-generation sequencing (mNGS) for detecting organisms and transcriptomic analysis of cerebrospinal fluid (CSF) in children with central nervous system (CNS) infections. Methods We conducted a prospective multisite study that aimed to enroll all children with a CSF pleocytosis and suspected CNS infection admitted to 1 of 3 tertiary pediatric hospitals during the study timeframe. After usual care testing had been performed, the remaining CSF was sent for mNGS and transcriptomic analysis. Results We screened 221 and enrolled 70 subjects over a 12-month recruitment period. A putative organism was isolated from CSF in 25 (35.7%) subjects by any diagnostic modality. Metagenomic next-generation sequencing of the CSF samples identified a pathogen in 20 (28.6%) subjects, which were also all identified by usual care testing. The median time to result was 38 hours. Conclusions Metagenomic sequencing of CSF has the potential to rapidly identify pathogens in children with CNS infections., We examined the utility of next-generation sequencing in comparison to usual care in detecting a pathogenic organism in children with central nervous system infections.

Diagnosing prosthetic valve infective endocarditis in children is challenging. Transthoracic and transesophageal echocardiography can yield false-negative results. Data are lacking in paediatric multimodality imaging in prosthetic valve infective endocarditis. We present two children with repaired CHD where initial echocardiogram was non-diagnostic, while CT angiogram and 18F-fluorodeoxyglucose positron emission tomography in combination with CT angiography, respectively, confirmed the diagnosis of endocarditis affecting clinical management.

BACKGROUND: Therapies against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its life-threatening respiratory infection coronavirus disease 2019 (COVID-19) have been evaluated, including COVID-19 convalescent plasma (CCP). Multiple large reports of CCP treatment in adults exist. Pediatric data on CCP safety and efficacy are limited. METHODS: Single-center prospective, open-label trial looking at safety, antibody kinetics and outcomes of CCP (10 mL/kg, max 1 unit) treatment for COVID-19 in hospitalized pediatric patients with moderate to severe disease or at high risk for serious illness. RESULTS: Thirteen patients were enrolled. No infusion-related adverse events occurred. No hematological or metabolic adverse events were noted during hospitalization or at 3-weeks. Ten patients had clinical improvement by day 7 (WHO eight-category ordinal severity scale for COVID-19). Following CCP, anti-SARS-CoV-2 anti-nucleocapsid IgG increased significantly at 24 hours and high levels were sustained at 7- and 21-days. Transient IgM response was noted. Twelve patients (92.3%) were discharged home, 9 (75%) by day 7 post-CCP. One remained on invasive ventilatory support 42 days after CCP and was eventually discharged to an intermediate care facility. The single patient death was retrospectively confirmed to have had brain death before CCP. CONCLUSION: CCP was well tolerated in pediatric patients, resulted in rapid antibody increase, and did not appear to interfere with immune responses measured at 21 days. More pediatric data are necessary to establish the efficacy of CCP, but our data suggest benefit in moderate to severe COVID-19 when used early. Other immunological or antiviral interventions may be added as supported by emerging data.

This study was designed to develop and validate an early warning system for sepsis based on a predictive model of critical decompensation. Data from the electronic medical records for 537,837 visits to a pediatric Emergency Department (ED) from March 2013 to December 2019 were collected. A multiclass stochastic gradient boosting model was built to identify early warning signs associated with death, severe sepsis, non-severe sepsis, and bacteremia. Model features included triage vital signs, previous diagnoses, medications, and healthcare utilizations within 6 months of the index ED visit. There were 483 patients who had severe sepsis and/or died, 1102 had non-severe sepsis, 1103 had positive bacteremia tests, and the remaining had none of the events. The most important predictors were age, heart rate, length of stay of previous hospitalizations, temperature, systolic blood pressure, and prior sepsis. The one-versus-all area under the receiver operator characteristic curve (AUROC) were 0.979 (0.967, 0.991), 0.990 (0.985, 0.995), 0.976 (0.972, 0.981), and 0.968 (0.962, 0.974) for death, severe sepsis, non-severe sepsis, and bacteremia without sepsis respectively. The multi-class macro average AUROC and area under the precision recall curve were 0.977 and 0.316 respectively. The study findings were used to develop an automated early warning decision tool for sepsis. Implementation of this model in pediatric EDs will allow sepsis-related critical decompensation to be predicted accurately after a few seconds of triage.

Background Mycobacterium species, specifically M. abscessus and M. chelonae (MABs), are known to contaminate water systems and are uncommon causes of health care–associated infection, but morbidity can be significant and treatment complex. Methods Odontogenic MAB infections occurred in patients following pulpotomy procedures at dental clinic A from 1 January to 6 September 2016. We identified confirmed and probable cases using culture data, imaging, pathology results, and surgical findings. Epidemiologic and clinical data including demographics, symptoms, laboratory findings, treatment regimens, and outcomes were extracted. Results Of 1082 at-risk patients, 71 case patients (22 confirmed; 49 probable) were identified. Median age was 6 years. Median symptom onset was 85 days postpulpotomy. Pain and/or swelling on admission occurred in 79%. On imaging, 49 of 70 had abnormalities of the mandible or maxilla, 13 of 70 had lymphadenopathy, and 19 of 68 had pulmonary nodules. Seventy were hospitalized (average of 8.5 days). Intravenous antibiotics were administered to 32 cases for a median length of 137 days. Clofazimine was administered to 29 patients as part of their multidrug regimen. Antibiotic treatment was associated with many adverse effects. Treated children showed evidence of jaw healing with resolved/improving pulmonary nodules at 1-year follow-up. Conclusions This is the largest outbreak of invasive MAB infections associated with a pediatric dental practice. While infections were indolent, patients suffered medical and surgical consequences of treatment, including permanent tooth loss. Identification of this outbreak led to a change in water standards for pediatric dental procedures in California. Enhanced national dental water quality standards are needed to prevent future outbreaks.

This clinical practice guideline for the diagnosis and treatment of acute hematogenous osteomyelitis (AHO) in children was developed by a multidisciplinary panel representing Pediatric Infectious Diseases Society (PIDS) and the Infectious Diseases Society of America (IDSA). This guideline is intended for use by healthcare professionals who care for children with AHO, including specialists in pediatric infectious diseases, orthopedics, emergency care physicians, hospitalists, and any clinicians and healthcare providers caring for these patients. The panel’s recommendations for the diagnosis and treatment of AHO are based upon evidence derived from topic-specific systematic literature reviews. Summarized below are the recommendations for the diagnosis and treatment of AHO in children. The panel followed a systematic process used in the development of other IDSA and PIDS clinical practice guidelines, which included a standardized methodology for rating the certainty of the evidence and strength of recommendation using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. A detailed description of background, methods, evidence summary and rationale that support each recommendation, and knowledge gaps can be found online in the full text.

Background The COVID-19 pandemic led to world-wide restrictions on social activities to curb the spread of this disease. Very little is known about the impact of these restrictions on trauma centers. Our objective was to determine the effect of the pandemic-associated lockdown on trauma admissions, patient’s demographics, mechanisms of injury, injury severity, and outcomes in the Puerto Rico Trauma Hospital. Methods An IRB-approved quasi-experimental study was performed to assess the impact of the restrictions by comparing trauma admissions during the lockdown (March 15, 2020 – June 15, 2020) with a control period (same period in 2017–2019). Comparisons were done using the Pearson’s chi-square test, Fisher exact test, or Mann-Whitney U test, as appropriate. A negative binomial model was fitted to estimate the incidence rate ratio for overall admissions among pre-lockdown and during-lockdown periods. Statistical significance was set at p Results A total of 308 subjects were admitted during the quarter of study for 2017; 323, for 2018; 347, for 2019; and 150, for 2020. The median (interquartile range) age of patients rose significantly from 40 (33) years to 49 (30) years (p p = 0.026). Moreover, the proportion of severe cases decreased, as measured by an injury severity score (ISS) > 15 (37.3% vs. 26.8%; p = 0.014); while there were no differences in the median hospital length of stay and the mortality rate between the comparison groups. Finally, the decrease in overall admissions registered during the lockdown accounts for a 59% (IRR 0.41; 95% CI 0.31–0.54) change compared to the pre-lockdown period, when controlling for sex, age, mechanism of injury, and ISS. Conclusions Following periods of social isolation and curfews, trauma centers can expect drastic reductions in their overall patient volume with associated changes in trauma patterns. Our findings will help inform new interventions and improve healthcare preparedness for future or similar circumstances.

Taxa of the family Cactaceae presents morphological and reproductive characteristics, which are used by rural communities in arid and semi-arid areas, for food, medicinal and ornamental purposes. The objectives were to identify the most used species and to relate the socioeconomic factors of the informants with their knowledge of the species. To this end, 262 semi-structured interviews were applied, with questions such as name, age, gender, educational level, source of employment, among others; eight categories of use were established: agro-ecological, agricultural, commercial, environmental service, food, medicinal, ornamental and technological; three indexes were calculated, relative importance, the value of use for each of the species and wealth of knowledge of the interviewees. Nine species are reported, from which eight are used as food and ornamental, standing out Opuntia ficus-indica for its diversity of uses, while Cylindropuntia tunicata does not report any utility. Variables such as age and residence time showed a significant relationship with the number of plants used by the interviewees. It is expected to contribute to the preservation of cacti, local knowledge and encourage large-scale cultivation since species such as Mammillaria columbiana, Melocactus andinus, and Melocactus curvispinus are being used in an unsustainable way, which could cause their local extinction.

Congenital syphilis still represents a worldwide public health problem. If left untreated, it can lead to fetal demise and high neonatal morbidity and mortality. Unfortunately, in the last decade, there has been a resurgence of cases in the U.S. This review discusses the ongoing problem of this preventable congenital infection, vertical transmission and clinical manifestations while providing a guidance for the evaluation and management of infants born to mothers with reactive serologic tests for syphilis.

We report a case of a 15-year-old female presenting with a serious multisystemic inflammatory illness during a surge of SARS-CoV-2 (COVID-19) cases in our county. The initial clinical findings of sore throat and neck stiffness, followed by signs of sepsis, raised suspicion of Lemierre syndrome early in her hospital course. However, the presence of severe respiratory distress, multifocal pneumonia with pleural effusion on chest radiograph, acute kidney injury, and the discovery of coronary artery ectasia, pointed to the new entity "multisystem inflammatory syndrome in children (MIS-C)." Immune modulatory treatment was thus considered. However, progressive neck pain and swelling, coupled with the eventual growth of Fusobacterium necrophorum on blood culture, eventually led to the correct diagnosis of Lemierre syndrome.

espanolEste trabajo busca aportar evidencia empirica en favor del teorema del minimax a partir de los datos procedentes de los cobros de penales en los partidos de varias ligas de futbol profesional de America Latina. En linea con la mayor parte de la literatura sobre el tema, los resultados obtenidos indican que las implicaciones de equilibrio del teorema no se cumplen a cabalidad. Particularmente, los jugadores parecen conectar sus elecciones actuales con las realizadas previamente por su rival. Estos hechos ponen de manifiesto que no solo la experiencia cuenta para jugar minimax en el plano real. El contexto y las habilidades cognitivas tambien son relevantes. EnglishThis paper seeks to provide empirical evidence for the minimax theorem from data set of penalty kicks in matches in several leagues of professional soccer in latin america. in line with most of the literature on the topic, the results indicate that the implications of equi-librium are not fully met. Particularly, some players seem to display significant dependence on the past choices of their opponents. These facts show that the experience is not the only key factor to play a minimax strategy in the real ground. The context and cognitive skills are also relevan.

Nineteen patients 1 month to

Drug-resistant Gram-negative bacteria are a growing threat to children; thus new antibiotics are needed to treat infections caused by these pathogens. Ceftolozane/tazobactam is active against many Gram-negative pathogens and is approved for treatment of complicated intra-abdominal and urinary tract infections in adults, but has not been evaluated in children.This phase 1, noncomparative, open-label, multicenter study characterized the pharmacokinetics (by noncompartmental analysis), safety, and tolerability of single intravenous doses of ceftolozane/tazobactam in pediatric patients (birth [7 days postnatal] to18 years of age) with proven/suspected Gram-negative infection or receiving perioperative prophylaxis (clinicaltrials.gov NCT02266706). Patients were enrolled into 1 of 6 age groups to receive a single, age-based ceftolozane/tazobactam dose, with timed blood sample collection for determining plasma concentrations of ceftolozane and tazobactam. Safety and tolerability were also evaluated.Thirty-seven patients received study drug; 34 were included in the pharmacokinetic population. Ceftolozane and tazobactam pharmacokinetic parameters were generally comparable for patients 3 months to18 years of age. Patients from birth (7 days postnatal) to3 months of age had lower clearance than older children, likely due to the immature renal function of these young infants. No deaths, study drug-related serious adverse events, or clinically significant laboratory abnormalities were observed after administration of ceftolozane/tazobactam.The doses evaluated in this study yielded ceftolozane/tazobactam exposure levels generally comparable with those in adults. Single doses of ceftolozane/tazobactam were well-tolerated, and no safety concerns were identified. These data informed pharmacokinetic/pharmacodynamic models to derive pediatric dose recommendations for phase 2 ceftolozane/tazobactam clinical trials.

Introduction A novel Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the pathogen responsible for a serious, life threatening respiratory infection (COVID-19) initially reported in Wuhan, China which rapidly spread worldwide resulting in global pandemic. Multiple immunological and pharmacological therapies have been evaluated with variable results. Convalescent plasma has been used in previous outbreaks such as Influenza 1918 and 2009, Ebola, MERS and SARS with good efficacy and safety reported. There have been multiple large reports on the safety of COVID-19 convalescent plasma (CCP) for the treatment of this serious infection in the adults; controversy has ensued regarding its efficacy. Pediatric data on CCP use are limited. Methods We conducted a prospective, open label treatment trial using CCP (10 ml/kg up to 1 unit) for the treatment of COVID-19 in pediatric patients with moderate to severe disease or high risk for serious illness. Safety and antibody kinetics and outcome data were collected. Results Eighteen moderate to severe COVID19 pediatric patients were enrolled and received CCP early in their illness (median days of symptoms XX). We observed no infusion related adverse events, no hematological or metabolic adverse events were noted during the hospitalization and at 3 weeks after infusion follow up. Sixteen patients demonstrated significant clinical improvement by day seven post infusion, as measured by the WHO eight-category ordinal severity scale for COVID-19. Presence of SARS-COV-2 anti-nucleocapsid IgG was demonstrated in all CCP specimens, a significant increase in antibodies was demonstrated in CCP recipients 24 hours after receiving CCP. Sustained high levels of anti- SARS-COV-2 anti-nucleocapsid IgG was demonstrated at 7- and 21-days post-transfusion. A transient IgM response not associated with CCP was noted. Eleven (61.1%) patients were discharge to home by day 7 post CCP infusion. One patient remained on invasive ventilatory support 21 days after CCP infusion and was eventually discharged to an intermediate care facility, one patient died retrospectively confirmed to have been brain death before receiving CCP. Conclusion We conclude that CCP was well tolerated in pediatric patients. CCP resulted in rapid increase of antibodies and sustained levels 21 days after infusion suggesting that CCP did not interfere with patients own immune response. More data are necessary to establish efficacy of this intervention in children, but our patients clinical course suggests benefit of CCP. Pediatric patients with moderate to severe COVID-19 may benefit of CCP when used early in the course of illness in conjunction with other immunological or antiviral interventions as needed.

Mycobacterium abscessus infections can be challenging to treat. Clofazimine has excellent in vitro activity against M abscessus, but reports of its use, particularly in children, have been limited. In this study, clofazimine was given to 27 children during an outbreak of odontogenic mycobacterial infections and seemed to be well tolerated as part of a multidrug regimen.

Author(s): Arrieta, Antonio C; Sung, Lillian; Bradley, John S; Zwaan, C Michel; Gates, Davis; Waskin, Hetty; Carmelitano, Patricia; Groll, Andreas H; Lehrnbecher, Thomas; Mangin, Eric; Joshi, Amita; Kartsonis, Nicholas A; Walsh, Thomas J; Paschke, Amanda | Abstract: BACKGROUND:Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia. METHODS:This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to l18 years; AG2, 2 to l7 years; and AG3, 3 months to l2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7-28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL. RESULTS:The percentage of subjects meeting the PK target was l90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to l7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to l18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to l18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects' underlying diseases. CONCLUSION:The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT01716234.

Background Invasive candidiasis (IC) is an important cause of sepsis in premature infants and is associated with a high risk of death and neurodevelopmental impairment. Prevention of IC has become a major focus in very low birth weight infants, with fluconazole increasingly used as prophylaxis. Methods We identified all randomized, placebo-controlled trials evaluating fluconazole prophylaxis in premature infants conducted in the United States. We obtained patient-level data from the study investigators and performed an aggregated analysis. The occurrence of each endpoint in infants who received prophylaxis with fluconazole vs placebo was compared. Endpoints evaluated were IC or death, IC, death, Candida colonization, and fluconazole resistance among tested isolates. Safety endpoints evaluated included clinical and laboratory parameters. Results Fluconazole prophylaxis reduced the odds of IC or death, IC, and Candida colonization during the drug exposure period compared with infants given placebo: odds ratios of 0.48 (95% confidence interval [CI], .30-.78), 0.20 (95% CI, .08-.51), and 0.28 (95% CI, .18-.41), respectively. The incidence of clinical and laboratory adverse events was similar for infants who received fluconazole compared with placebo. There was no statistically significant difference in the proportion of tested isolates that were resistant to fluconazole between the fluconazole and placebo groups. Conclusions Fluconazole prophylaxis is effective and safe in reducing IC and Candida colonization in premature infants, and has no impact on resistance.

Background Pediatric central nervous system (CNS) infections are potentially life-threatening and may incur significant morbidity. Identifying a pathogen is important, both in terms of guiding therapeutic management, but also in characterizing prognosis. However, standard care testing by culture, serology, and PCR is often unable to identify a pathogen. We examined use of next generation sequencing (NGS) of cerebrospinal fluid (CSF) in detecting an organism in children with CNS infections. Methods We prospectively enrolled children with CSF pleocytosis and suspected CNS infection admitted to 3 tertiary pediatric hospitals. After standard care testing had been performed, the remaining CSF was submitted for analysis by NGS. Results We enrolled 70 subjects over a 12-month recruitment period. A putative organism was isolated from CSF in 24 (34.3%) subjects by any diagnostic modality. NGS of the CSF samples identified a pathogen in 20 (28.6%) subjects. False positive results by NGS were identified in 2 patients. There were no cases in which NGS alone identified a pathogen. In 4 cases, a putative organism was recovered by standard care testing of the CSF, but not by CSF NGS. CSF culture recovered a putative organism in 12 cases (12.1%). A CSF PCR multiplex panel was utilized for 51 subjects. An organism was detected in 15 of these (29.4%). Using a reference composite of standard care testing, we determined the sensitivity and specificity of CSF NGS to be 83.3% (95% CI, 62.6–95.3%) and 91.3% (95% CI, 79.2–97.6%) respectively. Conclusion Sequencing of CSF has the potential to rapidly and comprehensively identify infection with a single test. Further studies are needed to determine the optimal use of NGS for diagnosis of CNS infections. Disclosures All Authors: No reported disclosures

Background Treatment with corticosteroids is recommended for Duchenne muscular dystrophy (DMD) patients to slow the progression of weakness. However, chronic corticosteroid treatment causes significant morbidities. Vamorolone is a first-in-class anti-inflammatory investigational drug that has shown evidence of efficacy in DMD after 24 weeks of treatment at 2.0 or 6.0 mg/kg/day. Here, open-label efficacy and safety experience of vamorolone was evaluated over a period of 18 months in trial participants with DMD. Methods and findings A multicenter, open-label, 24-week trial (VBP15-003) with a 24-month long-term extension (VBP15-LTE) was conducted by the Cooperative International Neuromuscular Research Group (CINRG) and evaluated drug-related effects of vamorolone on motor outcomes and corticosteroid-associated safety concerns. The study was carried out in Canada, US, UK, Australia, Sweden, and Israel, from 2016 to 2019. This report covers the initial 24-week trial and the first 12 months of the VBP15-LTE trial (total treatment period 18 months). DMD trial participants (males, 4 to, In an interim analysis of a multi-center open-label study, Edward Smith and colleagues investigate motor outcomes and adverse events in patients with Duchenne muscular dystrophy treated with the novel anti-inflammatory drug vamorolone., Author summary Why was this study done? The standard-of-care pharmacological management of Duchenne muscular dystrophy (DMD) is high-dose corticosteroids (prednisone or deflazacort; about 0.5 to 0.9 mg/kg/day), but this treatment is associated with safety concerns. Vamorolone is a first-in-class steroidal drug that aims to retain or improve efficacy of corticosteroids, while decreasing safety concerns. Twenty-four-week treatment of DMD with vamorolone has been reported to show dose-responsive improvements in motor outcomes, but longer-term treatment and comparative safety profiles to corticosteroids have not been previously reported. What did the researchers do and find? Participants with DMD completing the 24-week dose-ranging study of vamorolone (VBP15-003; n = 46) were offered transition to standard of care (prednisone or deflazacort) or continued treatment with vamorolone with enrollment into a 2-year long-term extension study (VBP15-LTE). All participants (46/46) opted to continue treatment with vamorolone and enrolled in VBP15-LTE. We report data from the midpoint of the 2-year VBP15-LTE study (total of 18 months of vamorolone treatment in VBP15-003 + VBP15-LTE). All measures of efficacy (5 motor outcome tests) showed significant improvements from baseline to 18 months of vamorolone treatment by paired intragroup analyses. Three motor outcome tests could be compared to group-matched corticosteroid-naïve external comparators, and 2 showed significant vamorolone-associated improvement. Vamorolone treatment did not result in stunting of growth, as seen with prednisone and deflazacort. Vamorolone treatment showed fewer physician-reported adverse events (such as behavior change, hirsutism, and Cushingoid appearance) than these drugs. What do these findings mean? Vamorolone holds promise as a replacement for corticosteroid standard of care (prednisone and deflazacort) in DMD. Limitations of the study include the open-label design and use of external comparators.

ObjectiveTo study vamorolone, a first-in-class steroidal anti-inflammatory drug, in Duchenne muscular dystrophy (DMD).MethodsAn open-label, multiple-ascending-dose study of vamorolone was conducted in 48 boys with DMD (age 4–ResultsOral administration of vamorolone at all doses tested was safe and well tolerated over the 24-week treatment period. The 2.0–mg/kg/d dose group met the primary efficacy outcome of improved muscle function (time to stand; 24 weeks of vamorolone treatment vs natural history controls), without evidence of most adverse effects of glucocorticoids. A biomarker of bone formation, osteocalcin, increased in vamorolone-treated boys, suggesting possible loss of bone morbidities seen with glucocorticoids. Biomarker outcomes for adrenal suppression and insulin resistance were also lower in vamorolone-treated patients with DMD relative to published studies of glucocorticoid therapy.ConclusionsDaily vamorolone treatment suggested efficacy at doses of 2.0 and 6.0 mg/kg/d in an exploratory 24-week open-label study.Classification of evidenceThis study provides Class IV evidence that for boys with DMD, vamorolone demonstrated possible efficacy compared to a natural history cohort of glucocorticoid-naive patients and appeared to be tolerated.

Supplemental Digital Content is available in the text., Background: Amphotericin B deoxycholate (AmB-D) is standard of care treatment for neonatal invasive candidiasis (IC). Micafungin (MCA) has broad-spectrum fungicidal activity against Candida spp. We compared the efficacy and safety of intravenous MCA with intravenous AmB-D and assessed the pharmacokinetics of MCA in infants >2–120 days of age with proven IC in a phase 3, randomized, double-blind, multicenter, parallel-group, noninferiority study (NCT00815516). Methods: Infants were randomized 2:1 to MCA (10 mg/kg/d) or AmB-D (1 mg/kg/d) for ≥21 days. Primary efficacy endpoint was fungal-free survival (FFS) 1 week after last study drug dose. MCA population pharmacokinetics included simulated area under the curve (AUC) at steady state and maximum plasma concentration after 2-hour infusion. AUC pharmacodynamic target exposure was 170 µg·h/mL. Results: Thirty infants received MCA (n = 20) or AmB-D (n = 10). The trial was terminated early because of slow recruitment. FFS was observed in 12 of 20 [60%; 95% confidence interval (CI): 36%–81%] MCA-group infants and in 7 of 10 (70%; 95% CI: 35%–93%) AmB-D-group infants. The most common treatment-emergent adverse events were anemia [MCA: n = 9 (45%); AmB-D: n = 3 (30%)] and thrombocytopenia [n = 2 (10%) and n = 3 (30%), respectively]. Model-derived mean AUC at steady state for MCA was 399.3 ± 163.9 µg·h/mL (95% prediction interval: 190.3–742.3 µg/mL); steady state and maximum plasma concentration after 2-hour infusion was 31.1 ± 10.5 µg/mL (95% prediction interval: 17.0–49.7 µg/mL). MCA exposures were above the AUC pharmacodynamic target exposure. Conclusions: Within the study limitations, infants with IC treated with MCA achieved similar FFS compared with AmB-D. Both agents were safe and well tolerated.

Objectives Extremely premature infants are at high risk of developing invasive candidiasis; fluconazole prophylaxis is safe and effective for reducing invasive candidiasis in this population but further study is needed. We sought to better understand the effect of prophylactic fluconazole on a selection of fluconazole-resistant Candida species. Methods We evaluated the susceptibility to fluconazole of Candida isolates from premature infants ( Results Three hundred and sixty-one infants received fluconazole (n = 188) or placebo (n = 173). After the baseline period, Candida colonization was significantly lower in the fluconazole group compared with placebo during periods 1 (5% versus 27%; P Conclusions Fluconazole prophylaxis decreased Candida albicans and ‘non-albicans’ Candida colonization and was associated with a slightly higher fluconazole MIC for colonizing Candida isolates.

Preterm infants face health problems likely related to microbial exposures, including sepsis and necrotizing enterocolitis. However, the role of the gut microbiome in preterm infant health is poorly understood. Microbial colonization differs from that of healthy term babies because it occurs in the NICU and is often perturbed by antibiotics. We measured bacterial compositions and metabolomic profiles of 77 fecal samples from 32 preterm infants to investigate the differences between microbiomes in health and disease. Rather than finding microbial signatures of disease, we found that both the preterm infant microbiome and the metabolome were personalized and that the preterm infant gut microbiome is enriched in microbes that commonly dominate in the presence of antibiotics. These results contribute to the growing knowledge of the preterm infant microbiome and emphasize that a personalized view will be important to disentangle the health consequences of the preterm infant microbiome., The assembly and development of the gut microbiome in infants have important consequences for immediate and long-term health. Preterm infants represent an abnormal case for bacterial colonization because of early exposure to bacteria and frequent use of antibiotics. To better understand the assembly of the gut microbiota in preterm infants, fecal samples were collected from 32 very low birth weight preterm infants over the first 6 weeks of life. Infant health outcomes included health, late-onset sepsis, and necrotizing enterocolitis (NEC). We characterized bacterial compositions by 16S rRNA gene sequencing and metabolomes by untargeted gas chromatography-mass spectrometry. Preterm infant fecal samples lacked beneficial Bifidobacterium spp. and were dominated by Enterobacteriaceae, Enterococcus, and Staphylococcus organisms due to nearly uniform antibiotic administration. Most of the variance between the microbial community compositions could be attributed to the baby from which the sample derived (permutational multivariate analysis of variance [PERMANOVA] R2 = 0.48, P < 0.001), while clinical status (health, NEC, or late-onset sepsis) and overlapping times in the neonatal intensive care unit (NICU) did not explain a significant amount of variation in bacterial composition. Fecal metabolomes were also found to be unique to the individual (PERMANOVA R2 = 0.43, P < 0.001) and weakly associated with bacterial composition (Mantel statistic r = 0.23 ± 0.05, P < 0.05). No measured metabolites were found to be associated with necrotizing enterocolitis, late-onset sepsis, or a healthy outcome. Overall, preterm infant gut microbial communities were personalized and reflected antibiotic usage. IMPORTANCE Preterm infants face health problems likely related to microbial exposures, including sepsis and necrotizing enterocolitis. However, the role of the gut microbiome in preterm infant health is poorly understood. Microbial colonization differs from that of healthy term babies because it occurs in the NICU and is often perturbed by antibiotics. We measured bacterial compositions and metabolomic profiles of 77 fecal samples from 32 preterm infants to investigate the differences between microbiomes in health and disease. Rather than finding microbial signatures of disease, we found that both the preterm infant microbiome and the metabolome were personalized and that the preterm infant gut microbiome is enriched in microbes that commonly dominate in the presence of antibiotics. These results contribute to the growing knowledge of the preterm infant microbiome and emphasize that a personalized view will be important to disentangle the health consequences of the preterm infant microbiome.