Pharmacokinetics and Optimal Dosing of Levofloxacin in Children for Drug-Resistant Tuberculosis: An Individual Patient Data Meta-Analysis.

BACKGROUND: Each year 25 000-32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children. METHODS: Levofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)-recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses. RESULTS: Data from 242 children (2.8 years [0.2-16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing <24 kg and under <10 years, resulting in approximately half of the exposure in adults. Model-informed doses of 16-33 mg/kg for dispersible tablets or 16-50 mg/kg for nondispersible tablets were required to meet the AUC target without significantly exceeding the median adult Cmax. CONCLUSIONS: Revised weight-band dosing guidelines with doses of >20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses.

Perinatal Caffeine Administration Improves Outcomes in an Ovine Model of Neonatal Hypoxia-Ischemia.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy disproportionately affects low- and middle-income countries, where ≈96% of affected infants reside. The current standard of care, therapeutic hypothermia, is frequently ineffective in this setting, likely because injury may be occurring earlier during labor. Here, we studied the pharmacokinetics, safety, and efficacy of perinatal caffeine administration in near-term lambs following global ischemic injury to support the development of earlier treatment strategies targeting the fetus in utero as well as the infant postnatally. METHODS: Ewes were randomly assigned to receive either 1 g IV caffeine citrate or placebo before delivery and placental transport assessed. Near-term lambs (141-143 days) of both sexes were subjected to severe global hypoxia-ischemia utilizing an acute umbilical cord occlusion model. Lambs that received caffeine in utero also received 20 mg/kg IV caffeine citrate following resuscitation and 10 mg/(kg·d) IV for 2 days. An additional cohort received 60 mg/kg followed by 30 mg/(kg·d) (low dose versus high dose) postnatally. Biochemical, histological, and neurological outcome measures in lambs were assessed over a 6-day period. RESULTS: Perinatal caffeine administration demonstrated excellent placental transport kinetics and was well tolerated with lamb plasma levels comparable to those targeted in neonates with apnea of prematurity. Caffeine administration resulted in a systemic immunomodulatory effect, evidenced by significant reductions in proinflammatory IP-10 levels. Treated lambs demonstrated improved neurodevelopmental outcomes, while histological analysis revealed that caffeine reduced gray matter injury and attenuated inflammation in the cingulate and parasagittal cortex. This neuroprotective effect was greater and via a different mode of action than we previously reported for azithromycin. A higher caffeine dosing regimen demonstrated significant toxicity. CONCLUSIONS: Perinatal caffeine administration is well tolerated, attenuates systemic and brain inflammation, and contributes to improvements in histological and neurological outcomes in an ovine model of neonatal hypoxic-ischemic encephalopathy.

Perinatal Azithromycin Provides Limited Neuroprotection in an Ovine Model of Neonatal Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Hypoxic-ischemic brain injury/encephalopathy affects about 1.15 million neonates per year, 96% of whom are born in low- and middle-income countries. Therapeutic hypothermia is not effective in this setting, possibly because injury occurs significantly before birth. Here, we studied the pharmacokinetics, safety, and efficacy of perinatal azithromycin administration in near-term lambs following global ischemic injury to support earlier treatment approaches. METHODS: Ewes and their lambs of both sexes (n=34, 141-143 days) were randomly assigned to receive azithromycin or placebo before delivery as well as postnatally. Lambs were subjected to severe global hypoxia-ischemia utilizing an acute umbilical cord occlusion model. Outcomes were assessed over a 6-day period. RESULTS: While maternal azithromycin exhibited relatively low placental transfer, azithromycin-treated lambs recovered spontaneous circulation faster following the initiation of cardiopulmonary resuscitation and were extubated sooner. Additionally, peri- and postnatal azithromycin administration was well tolerated, demonstrating a 77-hour plasma elimination half-life, as well as significant accumulation in the brain and other tissues. Azithromycin administration resulted in a systemic immunomodulatory effect, demonstrated by reductions in proinflammatory IL-6 (interleukin-6) levels. Treated lambs exhibited a trend toward improved neurodevelopmental outcomes while histological analysis revealed that azithromycin supported white matter preservation and attenuated inflammation in the cingulate and parasagittal cortex. CONCLUSIONS: Perinatal azithromycin administration enhances neonatal resuscitation, attenuates neuroinflammation, and supports limited improvement of select histological outcomes in an ovine model of hypoxic-ischemic brain injury/encephalopathy.

Defining Longer-Term Outcomes in an Ovine Model of Moderate Perinatal Hypoxia-Ischemia.

Hypoxic-ischemic encephalopathy (HIE) is the leading cause of neonatal morbidity and mortality worldwide. Approximately 1 million infants born with HIE each year survive with cerebral palsy and/or serious cognitive disabilities. While infants born with mild and severe HIE frequently result in predictable outcomes, infants born with moderate HIE exhibit variable outcomes that are highly unpredictable. Here, we describe an umbilical cord occlusion (UCO) model of moderate HIE with a 6-day follow-up. Near-term lambs (n = 27) were resuscitated after the induction of 5 min of asystole. Following recovery, lambs were assessed to define neurodevelopmental outcomes. At the end of this period, lambs were euthanized, and brains were harvested for histological analysis. Compared with prior models that typically follow lambs for 3 days, the observation of neurobehavioral outcomes for 6 days enabled identification of animals that recover significant neurological function. Approximately 35% of lambs exhibited severe motor deficits throughout the entirety of the 6-day course and, in the most severely affected lambs, developed spastic diparesis similar to that observed in infants who survive severe neonatal HIE (severe, UCOs). Importantly, and similar to outcomes in human neonates, while initially developing significant acidosis and encephalopathy, the remainder of the lambs in this model recovered normal motor activity and exhibited normal neurodevelopmental outcomes by 6 days of life (improved, UCOi). The UCOs group exhibited gliosis and inflammation in both white and gray matters, oligodendrocyte loss, neuronal loss, and cellular death in the hippocampus and cingulate cortex. While the UCOi group exhibited more cellular death and gliosis in the parasagittal cortex, they demonstrated more preserved white matter markers, along with reduced markers of inflammation and lower cellular death and neuronal loss in Ca3 of the hippocampus compared with UCOs lambs. Our large animal model of moderate HIE with prolonged follow-up will help further define pathophysiologic drivers of brain injury while enabling identification of predictive biomarkers that correlate with disease outcomes and ultimately help support development of therapeutic approaches to this challenging clinical scenario.

Resident training in a new robotic thoracic surgery program.

BACKGROUND: The volume of robot-assisted operations has drastically increased over the past decade. New programs have focused on training surgeons, whereas resident training has lagged behind. The objective of this study was to evaluate our institutional experience with resident participation in thoracic robotic surgery cases since the initiation of our program. METHODS: The first 100 robotic thoracic surgery cases at our institution were retrospectively reviewed and categorized into three sequential cohorts. Procedure type, patient and operative characteristics, level of resident participation (primary surgeon [PS] or assistant), and postoperative variables were evaluated. RESULTS: Of the first 100 cases, 38% were lung resections, 23% were esophageal operations, and 20% were sympathectomies. The distribution of cases changed over time with the proportion of pulmonary resections significantly increasing. Patient age (P < 0.05), body mass index (P = not significant [NS]), and comorbidities (P = NS) increased over time. Resident participation as PS increased from 33%-59% between the early and late cohorts (P < 0.05). A subset analysis of the 20 lobectomies (7 attending PS, 13 residents) showed similar patient characteristics (P = NS): age (67 versus 69), body mass index (29.5 versus 26.1), and American Society of Anesthesiologists category (2.8 versus 2.8). Operative and postoperative characteristics were also similar (P = NS) regardless of PS: operative time (260 versus 249 min), estimated blood loss (187 versus 203 mL), and length of stay (4.8 versus 4.7 d). CONCLUSIONS: Residents can participate as the PS in a variety of thoracic operations during the implementation of a robotics program. Operative time, estimated blood loss, and length of stay were similar regardless of level of resident participation.

Prognostic Implications of Delirium After Left Ventricular Assist Device Implantation: A Retrospective Study.

BACKGROUND: In critically ill patients, delirium is a prognostic indicator of morbidity and mortality. OBJECTIVE: This study investigates the impact of a delirium diagnosis on outcomes after left ventricular assist device (LVAD) implantation. METHODS: This retrospective study included all adult patients who received LVADs at our institution between January 2016 and December 2020. We compared preimplantation characteristics between the two groups, with and without a diagnosis of delirium, and compared their outcomes, including 1-month, 6-month, and in-hospital mortality, as well as reintubation rate, length of stay, discharge disposition, and readmission rates. RESULTS: In total, 361 patients (26.7% women and 75.8% African American) received durable LVADs. Ninety-four patients (26.1%) were diagnosed with delirium during the index admission. Preimplantation demographic characteristics, past medical and psychiatric conditions, Interagency Registry for Mechanically Assisted Circulatory Support Profile, and laboratory values did not differ between the two groups with and without a diagnosis of delirium; older age (59 vs 56; P = 0.03) was associated with delirium. Delirium diagnosis was associated with higher 1-month (P = 0.007), 6-month (P = 0.004), and in-hospital mortality (P < 0.001), unplanned reintubations (P < 0.001), and a lower likelihood of discharge home (P = 0.03). Total hospital and intensive care unit length of stay were higher in patients with a diagnosis of delirium, though these results were not statistically significant. Readmission to the hospital after index admission was quicker in patients with a diagnosis of delirium, but this result was not statistically significant. CONCLUSIONS: In this study, a diagnosis of delirium during the LVAD implantation admission was associated with higher mortality, adverse postsurgical outcomes, and unfavorable discharge dispositions. Future prospective research is needed to validate the prognostic implications of delirium in both the short and long term. Additionally, there is a need to identify modifiable risk factors associated with delirium to promote early diagnosis and implement evidence-based management strategies to enhance outcomes within this population.

Comparing the efficacy in reducing brain injury of different neuroprotective agents following neonatal hypoxia-ischemia in newborn rats: a multi-drug randomized controlled screening trial.

Intrapartum hypoxia-ischemia leading to neonatal encephalopathy (NE) results in significant neonatal mortality and morbidity worldwide, with > 85% of cases occurring in low- and middle-income countries (LMIC). Therapeutic hypothermia (HT) is currently the only available safe and effective treatment of HIE in high-income countries (HIC); however, it has shown limited safety or efficacy in LMIC. Therefore, other therapies are urgently required. We aimed to compare the treatment effects of putative neuroprotective drug candidates following neonatal hypoxic-ischemic (HI) brain injury in an established P7 rat Vannucci model. We conducted the first multi-drug randomized controlled preclinical screening trial, investigating 25 potential therapeutic agents using a standardized experimental setting in which P7 rat pups were exposed to unilateral HI brain injury. The brains were analysed for unilateral hemispheric brain area loss after 7 days survival. Twenty animal experiments were performed. Eight of the 25 therapeutic agents significantly reduced brain area loss with the strongest treatment effect for Caffeine, Sonic Hedgehog Agonist (SAG) and Allopurinol, followed by Melatonin, Clemastine, ß-Hydroxybutyrate, Omegaven, and Iodide. The probability of efficacy was superior to that of HT for Caffeine, SAG, Allopurinol, Melatonin, Clemastine, ß-hydroxybutyrate, and Omegaven. We provide the results of the first systematic preclinical screening of potential neuroprotective treatments and present alternative single therapies that may be promising treatment options for HT in LMIC.

Effect of Clemastine on Neurophysiological Outcomes in an Ovine Model of Neonatal Hypoxic-Ischemic Encephalopathy.

Originally approved by the U.S. Food and Drug Administration (FDA) for its antihistamine properties, clemastine can also promote white matter integrity and has shown promise in the treatment of demyelinating diseases such as multiple sclerosis. Here, we conducted an in-depth analysis of the feasibility, safety, and neuroprotective efficacy of clemastine administration in near-term lambs (n = 25, 141-143 days) following a global ischemic insult induced via an umbilical cord occlusion (UCO) model. Lambs were randomly assigned to receive clemastine or placebo postnatally, and outcomes were assessed over a six-day period. Clemastine administration was well tolerated. While treated lambs demonstrated improvements in inflammatory scores, their neurodevelopmental outcomes were unchanged.

A Changing Landscape: Exploring Resident Perspectives on Pursuing Pediatric Hospital Medicine Fellowships.

BACKGROUND: Pediatric Hospital Medicine (PHM) was approved as a subspecialty in 2016. Perspectives of pediatric and combined pediatric residents regarding barriers and facilitators to pursuing PHM fellowships have not previously been assessed. METHODS: A survey to explore residents' perspectives on PHM fellowships, with questions regarding demographics, likelihood of pursuing PHM after fellowship introduction, and influencing factors was distributed to pediatric and combined pediatric residents via program directors. RESULTS: The survey was distributed to an estimated 2657 residents. A total of 855 (32.2%) residents completed the survey; 89% of respondents had at least considered a career in PHM, and 79.4% reported that the introduction of the PHM fellowship requirement for subspecialty certification made them less likely to pursue PHM. Intent to practice in a community setting or only temporarily practice PHM, Combined Internal Medicine and Pediatric trainee status, and high student loan burden were associated with decreased likelihood of pursuing PHM (P < .05). Most respondents reported that forfeited earnings during fellowship, family and student loan obligations, and perceived sufficiency of residency training discouraged them from pursuing PHM fellowship. Half of respondents valued additional training in medical education, quality improvement, hospital administration, research, and clinical medicine. CONCLUSIONS: Many survey respondents expressed interest in the opportunity to acquire new skills through PHM fellowship. However, the majority of respondents reported being less likely to pursue PHM after the introduction of fellowship requirement for board certification, citing financial and personal opportunity costs. Understanding factors that residents value and those that discourage residents from pursuing PHM fellowship training may help guide future iterations of fellowship design.

Reduced paraspinous muscle area is associated with post-colectomy complications in children with ulcerative colitis.

BACKGROUND AND OBJECTIVES: Sarcopenia, defined as reduced muscle mass, is typically assessed by CT scans, which are infrequently performed in children. Using MRI to measure sarcopenia, we determined the association with postoperative complications after colectomy for ulcerative colitis (UC). METHODS: Clinical and preoperative MRI data for 13-18-year-old UC patients who underwent colectomy were retrospectively reviewed. Bilateral paraspinous muscle area (PSMA) and psoas muscle area (PMA) at L3 vertebra were measured and averaged. Composite complications were infection, wound dehiscence, postoperative leak/abscess, prolonged ileus, pulmonary embolism, venous thromboembolism, or readmission. RESULTS: Twenty-nine patients with average age 15.9±1.36years and weight 61.5±19.8kg had a preoperative MRI. The 18/29(62%) with complications had significantly reduced PSMA (4.71±1.44 vs 5.64±1.38cm2, p=0.04) and PMA (7.16±2.60 vs 8.93±2.44, p=0.04). When stratified and compared to highest PSMA, patients with lowest PSMA had increased complication rates (88% vs 29%, p=0.04). There were no differences in age, BMI, albumin, CRP, ESR, or preoperative steroid or anti-TNFα use. Odds of complication in the lowest tertile were 25.0-fold higher than the highest tertile (p=0.04, 95% CI=1.2-520.73). CONCLUSION: This is the first study to show low PSMA on MRI is associated with complications and increased hospital stay after colectomy in children with UC. LEVELS OF EVIDENCE: Level III retrospective comparative study.

A Preliminary Investigation of a Specialized Music Therapy Model for Children with Disabilities Delivered in a Classroom Setting.

Music therapy is gaining popularity as an intervention strategy for children with developmental disabilities, including autism spectrum disorder (ASD). This study was a pilot investigation of a classroom-based music-based intervention, Voices Together®, for improving communication skills in children with ASD and children with intellectual disabilities. Four local public elementary school special education classrooms, serving 5 children with a classification of autistic disorder and 32 children with intellectual disability without autism, were randomly selected to receive one of two levels of exposure to Voices Together music therapy: "long-term" (15 weeks beginning in January 2015 (Time 1), n = 14) or "short-term" (7 weeks beginning 7 weeks later in February (Time 2), n = 17). Using observational ratings, investigators reliably scored participants live in terms of their level of verbal responsiveness to prompts during three songs featured each week of the program. Both groups demonstrated increases in verbal responses over time; however, only the long-term group demonstrated significant within-group increases. Preliminary findings suggest that music therapy delivered in a classroom in 45-minute weekly sessions for 15 weeks can promote improvements in verbal responsiveness among individuals with autism and other developmental disabilities. Findings warrant further investigation into the efficacy of classroom-based music therapy programs.

KRAS insertion mutations are oncogenic and exhibit distinct functional properties.

Oncogenic KRAS mutations introduce discrete amino acid substitutions that reduce intrinsic Ras GTPase activity and confer resistance to GTPase-activating proteins (GAPs). Here we discover a partial duplication of the switch 2 domain of K-Ras encoding a tandem repeat of amino acids G60_A66dup in a child with an atypical myeloproliferative neoplasm. K-Ras proteins containing this tandem duplication or a similar five amino acid E62_A66dup mutation identified in lung and colon cancers transform the growth of primary myeloid progenitors and of Ba/F3 cells. Recombinant K-Ras(G60_A66dup) and K-Ras(E62_A66dup) proteins display reduced intrinsic GTP hydrolysis rates, accumulate in the GTP-bound conformation and are resistant to GAP-mediated GTP hydrolysis. Remarkably, K-Ras proteins with switch 2 insertions are impaired for PI3 kinase binding and Akt activation, and are hypersensitive to MEK inhibition. These studies illuminate a new class of oncogenic KRAS mutations and reveal unexpected plasticity in oncogenic Ras proteins that has diagnostic and therapeutic implications.

KRAS Engages AGO2 to Enhance Cellular Transformation.

Oncogenic mutations in RAS provide a compelling yet intractable therapeutic target. Using co-immunoprecipitation mass spectrometry, we uncovered an interaction between RAS and Argonaute 2 (AGO2). Endogenously, RAS and AGO2 co-sediment and co-localize in the endoplasmic reticulum. The AGO2 N-terminal domain directly binds the Switch II region of KRAS, agnostic of nucleotide (GDP/GTP) binding. Functionally, AGO2 knockdown attenuates cell proliferation in mutant KRAS-dependent cells and AGO2 overexpression enhances KRAS(G12V)-mediated transformation. Using AGO2-/- cells, we demonstrate that the RAS-AGO2 interaction is required for maximal mutant KRAS expression and cellular transformation. Mechanistically, oncogenic KRAS attenuates AGO2-mediated gene silencing. Overall, the functional interaction with AGO2 extends KRAS function beyond its canonical role in signaling.