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Introduction: Remimazolam is an ultra-short-acting benzodiazepine sedative drug. This study aimed to compare the efficacy and safety of remimazolam with propofol for induction and maintenance of general anaesthesia in children undergoing elective surgery., Methods: Children (aged 3-6 y, ASA physical status 1 or 2, BMI 14-25 kg.m -2 ) undergoing elective surgery under general anaesthesia with tracheal intubation were eligible for inclusion. Children were allocated randomly using a web-based system to receive either remimazolam or propofol in a 3:1 ratio. After receiving fentanyl 3 μg.kg -1 , children received their allocated drug for both induction and maintenance of general anaesthesia. Induction doses were remimazolam 0.3 mg.kg -1 or propofol 2.5 mg.kg -1 , with a second dose given should they not achieve loss of consciousness. After neuromuscular blockade and tracheal intubation, maintenance anaesthesia was achieved with an infusion either remimazolam 1-3 mg.kg -1 .h -1 or propofol 4-12 mg.kg -1 .h -1 , alongside a remifentanil infusion (0.1-0.5 μg.kg -1 .min -1 ) titrated to surgical stimulus and haemodynamic parameters. Primary outcomes were the incidence of successful induction and maintenance of anaesthesia. Secondary outcomes included: time to loss of consciousness, awakening and tracheal extubation; incidence of emergence delirium and moderate or severe pain in post-anaesthesia care unit; incidence of negative behaviour change after surgery at postoperative day 3; and incidence of adverse events., Results: A total of 187 children were analysed (140 allocated to remimazolam and 47 to propofol). All children achieved successful induction of anaesthesia. Successful maintenance of anaesthesia was achieved in 139 (99%) children who received remimazolam compared with 46 (98%) who received propofol (rate difference 1.4%, 95%CI -2.9-5.8%, p = 0.441). Adverse events occurred in 27 (19%) children who received remimazolam and 23 (49%) who received propofol., Discussion: Remimazolam was well tolerated for the induction and maintenance of general anaesthesia in pre-school-age children and was non-inferior to propofol., (© 2024 Association of Anaesthetists.)

Background: The incidence of central venous catheter-related thrombosis and the long-term effects of thrombosis on catheterized veins in neonates is unknown. We therefore determined the incidence of central venous thrombosis, identified associated risk factors, and evaluated outcomes at 6 months., Methods: We enrolled neonates aged less than 28 days scheduled for major intestinal or cardiac surgery whom we expected to require central venous catheters for at least 48 hours. Catheter size, insertion method, and puncture site were determined by the attending anesthesiologist. The duration of catheterization was also determined by clinical need. Central venous thrombi were diagnosed by color Doppler ultrasound imaging within 48 hours after catheter removal; results were not shared with clinicians. Ultrasound examinations were repeated 1, 3, and 6 months after discharge., Results: We enrolled 188 neonates over 2 years. The median duration of catheter insertion was 12 days. 128 (68%) of the neonates had central venous thrombi at the catheter site, all of which were asymptomatic. Among patients with thrombi, 29 (23%) had complete vessel occlusion and 5 (4%) had venous stenosis at 6 months after discharge. Thrombi therefore spontaneously resolved by 6 months in 73% of the neonates. CVC/vein diameter ratio, duration of catheterization, and catheter dysfunction were independent risk factors for vessel thrombus. Complete vessel occlusion was most common in patients whose thrombus occupied more than 58% of the vessel at the initial assessment., Conclusions: Covert central venous thrombosis is frequent in neonates who have central venous catheters, and complications are most common in patients who have large intravascular thrombi. Neonates with large intravascular thrombi should be followed, and considered for anticoagulation., Competing Interests: Competing interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Background: Preventing emergence delirium is a clinical goal for pediatric anesthesia, yet there is no consensus on its prevention. This study investigated the hypothesis that a continuous infusion or a single bolus of remimazolam can reduce the incidence of emergence delirium in children., Methods: A total of 120 children aged 1 to 6 yr were randomly and equally allocated into three groups: group RC, which received a continuous infusion of remimazolam at 1 mg · kg-1 · h-1; group RB, which received a single bolus of remimazolam at 0.2 mg · kg-1 at the beginning of wound closure; and group C, which received a continuous infusion of saline at 1 ml · kg-1 · h-1 and a single bolus of saline at 0.2 ml · kg-1 at the beginning of sutures. The primary outcome was the incidence of emergence delirium assessed by the Pediatric Anesthesia Emergence Delirium scale. Secondary outcomes included the number of rescue propofol administrations in the postanesthesia care unit, recovery time, and adverse events., Results: Emergence delirium was observed in 14 of 40 (35%) patients in group C, 2 of 40 (5%) patients in group RC (vs. group C, P = 0.001; risk ratio, 95% CI: 0.14, 0.04 to 0.59), and 3 of 39 (7.7%) patients in group RB (vs. group C, P = 0.003; risk ratio, 95% CI: 0.22, 0.07 to 0.71). Ten of 40 patients in group C, 2 of 40 patients in group RC (vs. group C, P = 0.012; risk ratio, 95% CI: 0.20, 0.05 to 0.86), and 2 of 39 patients in group RB (vs. group C, P = 0.014; risk ratio, 95% CI: 0.21, 0.05 to 0.88) needed rescue propofol. No differences in the recovery time and adverse effects were detected., Conclusions: Both continuous infusion and single bolus administration of remimazolam can effectively reduce the occurrence of emergence delirium in children., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc., on behalf of the American Society of Anesthesiologists.)

Anticipating and addressing unexpected intraoperative events and anatomies are some of the most challenging aspects of pediatric urologic practice; uncontrolled hemorrhage is one of the most anxiety provoking and precarious. The increasing application of the robotic platform in pediatric urology adds another layer of complexity as surgeons are not immediately at the patient's bedside. Should hemorrhage occur in robotic cases, clear communication and seamless coordination between members of the operating room team are paramount to optimize patient safety and minimize errors. This is especially important in pediatric cases for which the margin of error is narrow. Non-technical skills, including leadership, decision-making, situational awareness, stress management, and team-communication, become increasingly critical. While many programs have focused on robotic training, few prepare the operating room team and surgical trainees to manage these unforeseen, emergent intraoperative scenarios. This review discusses the role of a multidisciplinary, in situ robot-to-open conversion simulation program in addressing this educational gap, ways to approach establishing these programs, and potential barriers., Competing Interests: Conflict of interest None., (Copyright © 2024 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background: Remimazolam, a new ultrashort-acting benzodiazepine, is becoming increasingly applied in general anesthesia. This study is designed to investigate the effect of remimazolam-based total intravenous anesthesia and sevoflurane-based inhalation anesthesia on emergence delirium in pediatric tonsillectomy and adenoidectomy. Methods and analysis: This is a monocentric, prospective, randomized, double-blind clinical trial. A total of 90 pediatric patients will be randomized to receive remimazolam-based total intravenous anesthesia (remimazolam group, n = 45) or sevoflurane-based inhalation anesthesia (sevoflurane group, n = 45). The primary outcome will be the incidence of emergence delirium, which will be evaluated using the Pediatric Anesthesia Emergence Delirium (PAED) scale. The secondary outcomes include the extubation time, recovery time, behavior change using the post-hospitalization behavior questionnaire for ambulatory surgery (PHBQ-AS), and adverse events. Ethics and dissemination: This study has been approved by the Institutional Review Board (IRB) of the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (2023-K-262-02). Clinical trial registration: ClinicalTrials.gov, identifier NCT06214117., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ma, Cai, Zhong, Chen, Wang, Lin, Wang and Liu.)

Background and Objective: Neuromuscular blocking agents are routinely used in laparoscopic surgery to optimize operative conditions. We compared the effect of a deep and moderate neuromuscular blockade (NMB) on surgical conditions and postoperative outcomes in children undergoing major laparoscopic surgery., Methods: Sixty children aged 2-14 years scheduled to undergo major laparoscopic surgery were randomly allocated to deep (post-tetanic count 1-2 twitches) or moderate (train-of-four 1-2 twitches) NMB groups. The anesthesia was maintained with propofol and remifentanil, and the NMB was maintained with a rocuronium continuous infusion. At the end of the operation, the NMB were antagonized with sugammadex. The intra-abdominal pressure, airway pressure, Leiden Surgical Rating Scale, intraoperative hemodynamics, drug usages, duration of surgery, postoperative recovery time, pain, and complications were compared between the groups., Results: The maximum and mean intra-abdominal pressure, the peak inspiratory pressure, and mean airway pressure were significantly lower in the deep NMB group than in the moderate NMB group (p < 0.001). The Leiden Surgical Rating Scale and the dosage of rocuronium were significantly higher in the deep NMB group than the moderate NMB group (p < 0.001). The intraoperative hemodynamics, duration of surgery, post-operative recovery time, pain, and the incidence rate of complications were not significantly different between the groups (p > 0.05)., Conclusions: A deep NMB provided better operative conditions and similar recovery profiles compared with a moderate NMB as reversed with sugammadex in children undergoing major laparoscopic surgery., Clinical Trial Registration: Chinese Clinical Trial Registry, No. ChiCTR2100053821., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

There is currently no consensus on the optimal perioperative pain management strategy involving specific opioids. This study aims to compare the postoperative analgesia, the associated side effects between nalbuphine and morphine in children undergoing laparoscopic surgery. One hundred ninety children were randomly assigned to nalbuphine (0.2 mg/kg) or morphine (0.2 mg/kg). Nalbuphine's analgesic effect was non-inferior to morphine, with similar total rescue analgesic consumption during PACU stay (0.03 ± 0.05mg vs. 0.04 ± 0.06 mg, p > 0.05). Nalbuphine group had a lower incidence of respiratory depression (RR ≤ 10/min) (4.8% vs. 38.6%, p < 0.001), PONV (2.4% vs. 18.1%, p = 0.002), and pruritus (0% vs. 16.9%, p < 0.001) than morphine. Additionally, nalbuphine showed a shorter laryngeal mask airway removal time (13.9 [12.7, 15.1]) compared with morphine (17.0 [15.1, 18.9], p = 0.011). Nalbuphine provides equipotent analgesia with significantly lower incidences of respiratory depression, PONV, and pruritus compared with morphine in pediatric laparoscopic surgery., Competing Interests: The authors declare that they have no conflict of interest., (© 2024 The Authors.)

Background: The main clinical manifestations of patients with Pierre Robin sequence (PRS) include micrognathia, the glossoptosis and dyspnoea. The difficulty of tracheal intubation (TI) in such patients is increased. Objective: The purpose of the study was to evaluate the reliability and efficacy of the PRS simulator. Methods: A PRS simulator was developed by using 3-dimensional (3D) printing technology under computer-aided design. A total of 12 anaesthesiologists each trained 5 times for TI on the PRS Training Simulator-1 and recorded the simulation time. After the training, they were randomly divided into three groups with a total of 12 nontrained anaesthesiologists, and the simulation was completed on PRS Simulator-2, 3 and 4. The simulation time was recorded, and the performance was evaluated by three chief anaesthesiologists. Then, all 24 anaesthesiologists completed the questionnaire. Results: A PRS simulator developed by 3D printing was used to simulate the important aspects of TI. The average number of years worked was 6.3 ± 3.1 years, and 66.7% were female. The time for the 12 anaesthesiologists to complete the training gradually decreased ( p < 0.01). Compared with the trained anaesthesiologists, the simulation time of TI in the nontrained anaesthesiologists was much longer (all p < 0.01). In addition, the simulation performance of the trained anaesthesiologists was relatively better (all p < 0.01). Conclusion: The reliability and efficacy of the PRS simulator is herein preliminarily validated, and it has potential to become a teaching and training tool for anaesthesiologists., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mao, Liu, Zhong, Qin, Ma, Zuo, Zhang and Yang.)

Introduction: This international survey explored the ongoing impact of COVID-19 on pediatric anesthesiology. It assessed COVID-19's impact on the practice of pediatric anesthesiology, staffing, job satisfaction, and retention at the beginning of 2022 and addressed what should be done to ameliorate COVID-19's impact and what initiatives hospitals had implemented., Methods: This survey focused on five major domains: equipment/medication, vaccination/testing, staffing, burnout, and economic repercussions. Pilot testing for questionnaire clarity was conducted by members of the Pediatric Anesthesia COVID-19 Collaborative. The survey was administered by e-mail to a representative of the 72 collaborative centers. Respondents were instructed to answer based on their institution's practice from February through April of 2022. Descriptive statistics with 95% confidence intervals are reported., Results: Seventy of seventy-two institutions participated in this survey (97% response rate). Fifty-nine (84%) were from the United States, and 11 (16%) included other countries. The majority experienced equipment (68%) and medication (60%) shortages. Many institutions reported staffing shortages in nursing (37%), perioperative staff (27%), and attending anesthesiologists (11%). Sixty-two institutions (89%) indicated burnout was a frequent topic of conversation among pediatric anesthesiologists. Forty-three institutions (61%) reported anesthesiologists leaving current practice and 37 (53%) early retirement. Twenty-eight institutions (40%) canceled elective cases. The major suggestions for improving job retention included improving financial compensation (76%), decreasing clinical time (67%), and increasing flexibility in scheduled clinical time (66%). Only a minority of institutions had implemented the following initiatives: improving financial compensation (19%), increased access to mental health/counseling services (30%), and assistance with child or elder care (7%). At the time of the survey, 34% of institutions had not made any changes., Conclusion: Our study found that COVID-19 has continued to impact pediatric anesthesiology. There are major discrepancies between what anesthesiologists believe are important for job satisfaction and faculty retention compared to implemented initiatives. Data from this survey provide insight for institutions and departments for addressing these challenges., (© 2023 John Wiley & Sons Ltd.)

Background: Enteral ibuprofen was first approved as a prescription drug in 1974 for the US market. An intravenous (IV) ibuprofen formulation is approved for use in children older than 6 months of age, but there are limited studies specifically evaluating the pharmacokinetics and safety in children 1-6 months of age., Aims: The primary purpose of this study was to evaluate the pharmacokinetics of IV ibuprofen in infants younger than 6 months of age. The secondary objective was to evaluate the safety of single and repeated doses of IV ibuprofen in infants younger than 6 months of age., Methods: This was an industry-sponsored multi-center study. Institutional Review Board approval and informed parental consent were obtained prior to enrollment. Hospitalized neonates and infants younger than 6 months of age with fever or expected postoperative pain were eligible. Enrolled patients received 10 mg/kg of IV ibuprofen every 6 h, with up to four doses per day. Patients were randomized to two sparse sampling technique pharmacokinetic sample time groups. Group 1 samples were drawn at 0, 30 min, and 2 h, while group 2 samples were drawn at 0 min, 1, and 4 h after administration., Results: A total of 24 children were enrolled in the study, with 15 male patients and 9 female patients. The median age of the cohort was 4.4 months (range 1.1-5.9 months), and the median weight was 5.9 kg (range 2.3-8.8 kg). The arithmetic mean and standard error for peak plasma ibuprofen concentration was 56.28 ± 2.77 µg/mL. Plasma levels declined rapidly with a mean elimination half-life of 1.30 h. Time to peak ibuprofen effect and concentration were similar when compared with older pediatric patients. Clearance and volume of distribution were also similar to those reported in older pediatric patients. No drug-related adverse events were reported., Conclusions: The pharmacokinetic and short-term safety profiles of IV ibuprofen in pediatric patients 1-6 months of age are comparable to those in children older than 6 months of age., Trial Registration: Clinicaltrials.gov Trial Registration number and date: NCT02583399-Registered July 2017., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: COVID-19 forced healthcare systems to make unprecedented changes in clinical care processes. The authors hypothesized that the COVID-19 pandemic adversely impacted timely access to care, perioperative processes, and clinical outcomes for pediatric patients undergoing primary appendectomy., Methods: A retrospective, international, multicenter study was conducted using matched cohorts within participating centers of the international PEdiatric Anesthesia COVID-19 Collaborative (PEACOC). Patients younger than 18 yr old were matched using age, American Society of Anesthesiologists Physical Status, and sex. The primary outcome was the difference in hospital length of stay of patients undergoing primary appendectomy during a 2-month period early in the COVID-19 pandemic (April to May 2020) compared with prepandemic (April to May 2019). Secondary outcomes included time to appendectomy and the incidence of complicated appendicitis., Results: A total of 3,351 cases from 28 institutions were available with 1,684 cases in the prepandemic cohort matched to 1,618 in the pandemic cohort. Hospital length of stay was statistically significantly different between the two groups: 29 h (interquartile range: 18 to 79) in the pandemic cohort versus 28 h (interquartile range: 18 to 67) in the prepandemic cohort (adjusted coefficient, 1 [95% CI, 0.39 to 1.61]; P < 0.001), but this difference was small. Eight centers demonstrated a statistically significantly longer hospital length of stay in the pandemic period than in the prepandemic period, while 13 were shorter and 7 did not observe a statistically significant difference. During the pandemic period, there was a greater occurrence of complicated appendicitis, prepandemic 313 (18.6%) versus pandemic 389 (24.1%), an absolute difference of 5.5% (adjusted odds ratio, 1.32 [95% CI, 1.1 to 1.59]; P = 0.003). Preoperative SARS-CoV-2 testing was associated with significantly longer time-to-appendectomy, 720 min (interquartile range: 430 to 1,112) with testing versus 414 min (interquartile range: 231 to 770) without testing, adjusted coefficient, 306 min (95% CI, 241 to 371; P < 0.001), and longer hospital length of stay, 31 h (interquartile range: 20 to 83) with testing versus 24 h (interquartile range: 14 to 68) without testing, adjusted coefficient, 7.0 (95% CI, 2.7 to 11.3; P = 0.002)., Conclusions: For children undergoing appendectomy, the COVID-19 pandemic did not significantly impact hospital length of stay., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Background: The nasopharynx is an easily accessible core-temperature monitoring site, but insufficient or excessive nasopharyngeal probe insertion can underestimate core temperature. Our goal was to estimate optimal nasopharyngeal probe insertion depth as a function of age., Methods: We enrolled 157 pediatric patients who had noncardiac surgery with endotracheal intubation in 5 groups: (1) newborn to 6 months old, (2) infants 7 months to 1 year old, (3) children 13 to 23 months old, (4) children 2 to 5 years old, and (5) children 6 to 12 years old. A reference esophageal temperature probe was inserted at an appropriate depth based on each patient's height. A nasopharyngeal temperature probe was inserted from the naris at 10 cm in newborn and infants, 15 cm in children aged 1 to 5 years old, and 20 cm in children who were 6 years or older. The study nasopharyngeal probes were withdrawn 1, 2.5, or 2 cm (depending on age) 10 times at 5-minute intervals. Optimal probe insertion distances were defined by limits of agreement (LOAs) between nasopharyngeal and esophageal temperatures <0.5 °C., Results: Optimal nasopharyngeal temperature probe position ranged from 6 to 10 cm in infants up to 6 months old, 7 to 8 cm in infants 7 to 12 months old, 7.5 to 12 cm in children 13 to 23 months old, and 10 to 12 cm in children aged 6 years and older. The 95% LOAs were <0.5 °C for all age categories except the 2- to 5-year-old group where the limits extended from -0.67 °C to 0.52 °C at 9 cm. At the optimal position within each age range, the bias (average nasopharyngeal-to-esophageal temperature difference) was ≤0.1 °C., Conclusions: Nasopharyngeal thermometers accurately measure core temperature, but only when probes are inserted a proper distance, which varies with age. As with much in pediatrics, nasopharyngeal thermometer insertion depths should be age appropriate., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2022 International Anesthesia Research Society.)

Purpose of Review: This review focuses on the challenges faced by acute care healthcare workers in the management of the normal and difficult pediatric airway during the COVID-19 pandemic and how these protocols and practices evolved during the pandemic. The current state of knowledge on timing of surgery and anesthesia is also discussed., Recent Findings: In the early days of the pandemic, information about the SARS-CoV-2 virus and disease process was scarce. Governmental, healthcare, and professional organizations created several guidelines to protect invaluable healthcare workers from the contagious virus while also delivering appropriate care to children with COVID-19. With the emergence of new studies and the deployment of new life-saving COVID-19 vaccines and other therapies, these guidelines evolved. The use of aerosol containment devices such as aerosol boxes and flexible barrier techniques was found to be ineffective in reliably containing virus particles while posing potential harm to both healthcare workers and patients. Also, the definition of aerosol-generating and dispersing medical procedures was vastly broadened. To date, use of appropriate personal protection equipment and COVID-19 vaccination are the most effective ways to protect healthcare workers and safely manage children infected with SARS-CoV-2 who require airway intervention., Summary: Evidence-based public health measures and appropriate personal protective equipment remain the best way to protect both healthcare workers and patients. As the virus and population evolve and COVID-19 vaccines become more widely available, clinicians must be willing to adapt to the emerging evidence of their impact on how safe pediatric perioperative care is delivered., Competing Interests: Competing InterestsThe authors have no financial or personal competing interests., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Design and analysis of clinical trials for rare and ultra-rare disease pose unique challenges to the practitioners. Meeting conventional power requirements is infeasible for diseases where sample sizes are inherently very small. Moreover, rare disease populations are generally heterogeneous and widely dispersed, which complicates study enrollment and design. Leveraging all available information in rare and ultra-rare disease trials can improve both drug development and informed decision-making processes., Main Text: Bayesian statistics provides a formal framework for combining all relevant information at all stages of the clinical trial, including trial design, execution, and analysis. This manuscript provides an overview of different Bayesian methods applicable to clinical trials in rare disease. We present real or hypothetical case studies that address the key needs of rare disease drug development highlighting several specific Bayesian examples of clinical trials. Advantages and hurdles of these approaches are discussed in detail. In addition, we emphasize the practical and regulatory aspects in the context of real-life applications., Conclusion: The use of innovative trial designs such as master protocols and complex adaptive designs in conjunction with a Bayesian approach may help to reduce sample size, select the correct treatment and population, and accurately and reliably assess the treatment effect in the rare disease setting., (© 2022. The Author(s).)

In this paper, we lay out the basic elements of Bayesian sample size determination (SSD) for the Bayesian design of a two-arm superiority clinical trial. We develop a flowchart of the Bayesian SSD that highlights the critical components of a Bayesian design and provides a practically useful roadmap for designing a Bayesian clinical trial in real world applications. We empirically examine the amount of borrowing, the choice of noninformative priors, and the impact of model misspecification on the Bayesian type I error and power. A formal and statistically rigorous formulation of conditional borrowing within the decision rule framework is developed. Moreover, by extending the partial borrowing power priors, a new borrowing-by-parts power prior for incorporating historical data is proposed. Computational algorithms are also developed to calculate the Bayesian type I error and power. Extensive simulation studies are carried out to explore the operating characteristics of the proposed Bayesian design of a superiority trial.

Introduction: The acute (symptomatic) apical abscess is characterized by pulp necrosis, rapid onset, spontaneous pain, percussion pain, pus formation, and tissue swelling. The etiopathology of acute apical abscesses includes active (lytic) herpesviruses and gram-negative anaerobic bacteria. The present study examined the potential of valacyclovir, an anti-herpesvirus agent, and systemic amoxicillin to manage the pain of acute apical abscesses., Methods: Twenty emergency patients with moderate to severe apical abscess pain received randomly either amoxicillin (1 g immediate dose followed by 500 mg, 4 times a day, totally 7 days) + valacyclovir (2 g immediate dose followed by 500 mg, twice a day, totally 3 days) ("valacyclovir" group, 10 patients) OR amoxicillin (1 g immediate dose followed by 500 mg, 4 times a day, totally 7 days) + placebo ("placebo" group, 10 patients). Daily telephone calls during the 6-day follow-up period assessed pain level on a numeric rating scale and analgesic intake. The Mann-Whitney and the Friedman statistical tests analyzed the outcome data., Results: At the baseline examination, all 10 valacyclovir and 9 placebo patients exhibited moderate to severe pain and 18 patients needed pain medication. On the first day after baseline, the valacyclovir group showed 2 patients with moderate/severe pain and 1 patient on pain medication, but the placebo group revealed as many as 8 patients with moderate/severe pain and 9 patients on pain medication. The difference in pain level and analgesic usage between the valacyclovir and the placebo group remained statistically significant during the entire post-baseline study period (P < .05)., Conclusion: The present study points to valacyclovir as a promising adjunctive agent in pain control with acute apical abscesses., (Copyright © 2021 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Background/aims: The evolution of Le Fort III and Monobloc procedures with utilization of distraction devices has resulted in shortened surgical times, greater facial advancements, and decreased transfusion requirements. The aim of this observational study was to utilize data from the multicenter Pediatric Craniofacial Surgery Perioperative Registry to present and compare patient characteristics and outcomes in children undergoing midface advancement with distraction osteogenesis., Methods: We queried the Pediatric Craniofacial Surgery Perioperative Registry for children undergoing midface advancement involving distractor application from June 2012 to September 2016. Data extracted included demographics, perioperative management, complications, fluid and transfusion volumes, and length of stay. The extracted patient characteristics and perioperative variables were summarized and compared., Results: The query yielded 72 cases from 11 institutions: 49 children undergoing Le Fort III and 23 undergoing Monobloc procedures. Monobloc patients were younger, weighed less, and more likely to have tracheostomies along with elevated intracranial pressure. Greater transfusion was observed in the Monobloc group for nearly all of the transfusion outcomes evaluated. Median ICU and hospital length of stay were 2 and 3 days longer, respectively, in the Monobloc group. Perioperative complications were not uncommon, occurring in 18% of patients in the Le Fort III group and 30% in the Monobloc group., Conclusion: Monobloc procedures were associated with greater transfusion and longer ICU and hospital length of stay. Perioperative complications were more prevalent in the Monobloc group., (© 2018 John Wiley & Sons Ltd.)

Objectives: Crisis resource management principles dictate appropriate distribution of mental and/or physical workload so as not to overwhelm any one team member. Workload during pediatric emergencies is not well studied. The National Aeronautics and Space Administration-Task Load Index is a multidimensional tool designed to assess workload validated in multiple settings. Low workload is defined as less than 40, moderate 40-60, and greater than 60 signify high workloads. Our hypothesis is that workload among both team leaders and team members is moderate to high during a simulated pediatric sepsis scenario and that team leaders would have a higher workload than team members., Design: Multicenter observational study., Setting: Nine pediatric simulation centers (five United States, three Canada, and one United Kingdom)., Patients: Team leaders and team members during a 12-minute pediatric sepsis scenario., Interventions: National Aeronautics and Space Administration-Task Load Index., Measurements and Main Results: One hundred twenty-seven teams were recruited from nine sites. One hundred twenty-seven team leaders and 253 team members completed the National Aeronautics and Space Administration-Task Load Index. Team leader had significantly higher overall workload than team member (51 ± 11 vs 44 ± 13; p < 0.01). Team leader had higher workloads in all subcategories except in performance where the values were equal and in physical demand where team members were higher than team leaders (29 ± 22 vs 18 ± 16; p < 0.01). The highest category for each group was mental 73 ± 13 for team leader and 60 ± 20 for team member. For team leader, two categories, mental (73 ± 17) and effort (66 ± 16), were high workload, most domains for team member were moderate workload levels., Conclusions: Team leader and team member are under moderate workloads during a pediatric sepsis scenario with team leader under high workloads (> 60) in the mental demand and effort subscales. Team leader average significantly higher workloads. Consideration of decreasing team leader responsibilities may improve team workload distribution.

Objectives: Pauses in cardiopulmonary resuscitation negatively impact clinical outcomes; however, little is known about the contributing factors. The objective of this study is to determine the frequency, duration, and causes for pauses during cardiac arrest., Design: This is a secondary analysis of video data collected from a prospective multicenter trial. Twenty-six simulated pediatric cardiac arrest scenarios each lasting 12 minutes in duration were analyzed by two independent reviewers to document events surrounding each pause in chest compressions., Setting: Ten children's hospitals across Canada, the United, and the United Kingdom., Subjects: Resuscitation teams composed of three healthcare providers trained in cardiopulmonary resuscitation., Interventions: A simulated pediatric cardiac arrest case in a 5 year old., Measurements and Main Results: The frequency, duration, and associated factors for each pause were recorded. Communication was rated using a four-point scale reflecting the team's shared mental model. Two hundred fifty-six pauses were reviewed with a median of 10 pauses per scenario (interquartile range, 7-12). Median pause duration was 5 seconds (interquartile range, 2-9 s), with 91% chest compression fraction per scenario (interquartile range, 88-94%). Only one task occurred during most pauses (66%). The most common tasks were a change of chest compressors (25%), performing pulse check (24%), and performing rhythm check (15%). Forty-nine (19%) of the pauses lasted greater than 10 seconds and were associated with shock delivery (p < 0.001), performing rhythm check (p < 0.001), and performing pulse check (p < 0.001). When a shared mental model was rated high, pauses were significantly shorter (mean difference, 4.2 s; 95% CI, 1.6-6.8 s; p = 0.002)., Conclusions: Pauses in cardiopulmonary resuscitation occurred frequently during simulated pediatric cardiac arrest, with variable duration and underlying causes. A large percentage of pauses were greater than 10 seconds and occurred more frequently than the recommended 2-minute interval. Future efforts should focus on improving team coordination to minimize pause frequency and duration.

Prolonged-release (PR) fampridine is approved to treat walking impairment in persons with multiple sclerosis (MS); however, treatment benefits may extend beyond walking. MOBILE was a phase 2, 24-week, double-blind, placebo-controlled exploratory study to assess the impact of 10mg PR-fampridine twice daily versus placebo on several subject-assessed measures. This analysis evaluated the physical and psychological health outcomes of subjects with progressing or relapsing MS from individual items of the Multiple Sclerosis Impact Scale (MSIS-29). PR-fampridine treatment (n=68) resulted in greater improvements from baseline in the MSIS-29 physical (PHYS) and psychological (PSYCH) impact subscales, with differences of 89% and 148% in mean score reduction from baseline (n=64) at week 24 versus placebo, respectively. MSIS-29 item analysis showed that a higher percentage of PR-fampridine subjects had mean improvements in 16/20 PHYS and 6/9 PSYCH items versus placebo after 24weeks. Post hoc analysis of the 12-item Multiple Sclerosis Walking Scale (MSWS-12) improver population (≥8-point mean improvement) demonstrated differences in mean reductions from baseline of 97% and 111% in PR-fampridine MSIS-29 PHYS and PSYCH subscales versus the overall placebo group over 24weeks. A higher percentage of MSWS-12 improvers treated with PR-fampridine showed mean improvements in 20/20 PHYS and 8/9 PSYCH items versus placebo at 24weeks. In conclusion, PR-fampridine resulted in physical and psychological benefits versus placebo, sustained over 24weeks., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: This article reviews the development of simulation-based training strategies to educate sedation providers., Recent Findings: Medical simulation has been utilized to train and evaluate providers in numerous domains related to sedation. Sedation providers come to the patient with a wide range of clinical training and experience and simulation can serve as a platform for achieving a baseline skill level and for periodic retraining. Although widely accepted by participants in simulation training, data demonstrating simulation's efficacy in improving sedation-related clinical outcomes are lacking., Summary: Simulation provides an opportunity for sedation providers to develop deliberative practice, to consider rare or challenging clinical conditions, and to benefit from directed feedback, in a manner that does not put patients in harm's way.

Aim: The variability in quality of CPR provided during cardiac arrest across pediatric institutions is unknown. We aimed to describe the degree of variability in the quality of CPR across 9 pediatric institutions, and determine if variability across sites would be affected by Just-in-Time CPR training and/or visual feedback during simulated cardiac arrest., Methods: We conducted secondary analyses of data collected from a prospective, multi-center trial. Participants were equally randomized to either: (1) No intervention; (2) Real-time CPR visual feedback during cardiac arrest or (3) Just-in-Time CPR training. We report the variability in median chest compression depth and rate across institutions, and the variability in the proportion of 30-s epochs of CPR meeting 2010 American Heart Association guidelines for depth and rate., Results: We analyzed data from 528 epochs in the no intervention group, 552 epochs in the visual feedback group, and 525 epochs in the JIT training group. In the no intervention group, compression depth (median range 22.2-39.2mm) and rate (median range 116.0-147.6 min(-1)) demonstrated significant variability between study sites (p<0.001). The proportion of compressions with adequate depth (0-11.5%) and rate (0-60.5%) also varied significantly across sites (p<0.001). The variability in compression depth and rate persisted despite use of real-time visual feedback or JIT training (p<0.001)., Conclusion: The quality of CPR across multiple pediatric institutions is variable. Variability in CPR quality across institutions persists even with the implementation of a Just-in-Time training session and visual feedback for CPR quality during simulated cardiac arrest., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Microaerophilic, neutrophilic, iron-oxidizing bacteria (FeOB) grow via the oxidation of reduced Fe(II) at or near neutral pH, in the presence of oxygen, making them relevant in numerous environments with elevated Fe(II) concentrations. However, the biochemical mechanisms for Fe(II) oxidation by these neutrophilic FeOB are unknown, and genetic markers for this process are unavailable. In the ocean, microaerophilic microorganisms in the genus Mariprofundus of the class Zetaproteobacteria are the only organisms known to chemolithoautotrophically oxidize Fe and concurrently biomineralize it in the form of twisted stalks of iron oxyhydroxides. The aim of this study was to identify highly expressed proteins associated with the electron transport chain of microaerophilic, neutrophilic FeOB. To this end, Mariprofundus ferrooxydans PV-1 was cultivated, and its proteins were extracted, assayed for redox activity, and analyzed via liquid chromatography-tandem mass spectrometry for identification of peptides. The results indicate that a cytochrome c4, cbb3-type cytochrome oxidase subunits, and an outer membrane cytochrome c were among the most highly expressed proteins and suggest an involvement in the process of aerobic, neutrophilic bacterial Fe oxidation. Proteins associated with alternative complex III, phosphate transport, carbon fixation, and biofilm formation were abundant, consistent with the lifestyle of Mariprofundus., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: The 12-question Multiple Sclerosis Walking Scale (MSWS-12v1) is a widely-used patient-reported outcome (PRO) measure of walking ability in multiple sclerosis (MS)., Objective: To estimate the magnitude of an important change in MSWS-12v1 scores for the interpretation of meaningful subject-level improvements across a 6-month trial of MS patients with walking disability., Methods: MOBILE was a 6-month exploratory study assessing fampridine's effect on walking ability in 132 people with MS. Three PRO measures assessed walking ability: MSWS-12v1, EuroQol 5-Dimension-5 Level (EQ-5D-5L) mobility question, and a patient global impression of change (PGIC) in overall walking ability. Pre-specified anchor- and distribution-based analyses estimated the MSWS-12v1 change scores representing an important change for participants. Results were triangulated to propose a single best value indicating meaningful improvement., Results: Using baseline to week 2 through week 24 change scores, anchor-based analyses demonstrated mean and median improvements of 5.2-6.6 (PGIC) and 9.7-13.4 (EQ-5D-5L mobility) points on the MSWS-12v1, indicating meaningful improvements. The distribution-based estimate was 6.8 points. Triangulation across the results suggested an 8-point reduction in MSWS-12v1 score represents an important subject-level change in these participants., Conclusion: In similar MS clinical trials, an 8-point improvement on the MSWS-12v1 is a reasonable estimate of meaningful improvement in walking ability.

Neonatal sepsis and meningitis (NSM) remains a leading cause worldwide of mortality and morbidity in newborn infants despite the availability of antibiotics over the last several decades. E. coli is the most common gram-negative pathogen causing NSM. Our previous studies show that α7 nicotinic receptor (α7 nAChR), an essential regulator of inflammation, plays a detrimental role in the host defense against NSM. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat this disease. Using the in vitro/in vivo models of the blood-brain barrier (BBB) and RNA-seq, we undertook a drug repositioning study to identify unknown antimicrobial activities for known drugs. We have demonstrated for the first time that memantine (MEM), a FDA-approved drug for treatment of Alzheimer's disease, could very efficiently block E. coli-caused bacteremia and meningitis in a mouse model of NSM in a manner dependent on α7 nAChR. MEM was able to synergistically enhance the antibacterial activity of ampicillin in HBMEC infected with E. coli K1 (E44) and in neonatal mice with E44-caused bacteremia and meningitis. Differential gene expression analysis of RNA-Seq data from mouse BMEC infected with E. coli K1 showed that several E44-increased inflammatory factors, including IL33, IL18rap, MMP10 and Irs1, were significantly reduced by MEM compared to the infected cells without drug treatment. MEM could also significantly up-regulate anti-inflammatory factors, including Tnfaip3, CISH, Ptgds and Zfp36. Most interestingly, these factors may positively and negatively contribute to regulation of NF-κB, which is a hallmark feature of bacterial meningitis. Furthermore, we have demonstrated that circulating BMEC (cBMEC) are the potential novel biomarkers for NSM. MEM could significantly reduce E44-increased blood level of cBMEC in mice. Taken together, our data suggest that memantine can efficiently block host inflammatory responses to bacterial infection through modulation of both inflammatory and anti-inflammatory pathways.

Importance: The quality of cardiopulmonary resuscitation (CPR) affects hemodynamics, survival, and neurological outcomes following pediatric cardiopulmonary arrest (CPA). Most health care professionals fail to perform CPR within established American Heart Association guidelines., Objective: To determine whether "just-in-time" (JIT) CPR training with visual feedback (VisF) before CPA or real-time VisF during CPA improves the quality of chest compressions (CCs) during simulated CPA., Design, Setting, and Participants: Prospective, randomized, 2 × 2 factorial-design trial with explicit methods (July 1, 2012, to April 15, 2014) at 10 International Network for Simulation-Based Pediatric Innovation, Research, & Education (INSPIRE) institutions running a standardized simulated CPA scenario, including 324 CPR-certified health care professionals assigned to 3-person resuscitation teams (108 teams)., Interventions: Each team was randomized to 1 of 4 permutations, including JIT training vs no JIT training before CPA and real-time VisF vs no real-time VisF during simulated CPA., Main Outcomes and Measures: The proportion of CCs with depth exceeding 50 mm, the proportion of CPR time with a CC rate of 100 to 120 per minute, and CC fraction (percentage CPR time) during simulated CPA., Results: The quality of CPR was poor in the control group, with 12.7% (95% CI, 5.2%-20.1%) mean depth compliance and 27.1% (95% CI, 14.2%-40.1%) mean rate compliance. JIT training compared with no JIT training improved depth compliance by 19.9% (95% CI, 11.1%-28.7%; P < .001) and rate compliance by 12.0% (95% CI, 0.8%-23.2%; P = .037). Visual feedback compared with no VisF improved depth compliance by 15.4% (95% CI, 6.6%-24.2%; P = .001) and rate compliance by 40.1% (95% CI, 28.8%-51.3%; P < .001). Neither intervention had a statistically significant effect on CC fraction, which was excellent (>89.0%) in all groups. Combining both interventions showed the highest compliance with American Heart Association guidelines but was not significantly better than either intervention in isolation., Conclusions and Relevance: The quality of CPR provided by health care professionals is poor. Using novel and practical technology, JIT training before CPA or real-time VisF during CPA, alone or in combination, improves compliance with American Heart Association guidelines for CPR that are associated with better outcomes., Trial Registration: clinicaltrials.gov Identifier: NCT02075450.

Although antibiotics treat bacteremia in inhalational anthrax, pathogenesis is mainly driven by bacterial exotoxins. Raxibacumab, an IgG1 monoclonal antibody, binds the protective antigen (PA) of Bacillus anthracis, thus blocking toxin effects and leading to improved survival in the rabbit and monkey models of inhalational anthrax. To assess raxibacumab's added benefit over levofloxacin (LVX) alone, rabbits surviving to 84 h after a challenge with 200 times the median (50%) lethal dose of B. anthracis spores were randomized to receive 3 daily intragastric LVX doses of 50 mg/kg of body weight, with the first LVX dose administered just prior to administration of a single intravenous dose of placebo or 40 mg/kg raxibacumab. The percentages of animals alive at 28 days following the last LVX dose were compared between the 2 treatment groups using a two-sided likelihood-ratio chi-square test. The 82% survival rate for the LVX-raxibacumab combination was higher than the 65% survival rate for LVX alone (P=0.0874). There were nearly 2-fold fewer deaths for the combination (7 deaths; n=39) than for LVX alone (13 deaths; n=37), and the survival time was prolonged for the combination (P=0.1016). Toxin-neutralizing-activity titers were similar for both treatment groups, suggesting that survivors in both groups were able to mount a toxin-neutralizing immune response. Microscopic findings considered consistent with anthrax were present in animals that died or became moribund on study in both treatment groups, and there were no anthrax-related findings in animals that survived. Overall, raxibacumab provided a meaningful benefit over antibiotic alone when administered late in the disease course., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Mutations in genes involved in DNA replication, such as flap endonuclease 1 (FEN1), can cause single-stranded DNA breaks (SSBs) and subsequent collapse of DNA replication forks leading to DNA replication stresses. Persistent replication stresses normally induce p53-mediated senescence or apoptosis to prevent tumour progression. It is unclear how some mutant cells can overcome persistent replication stresses and bypass the p53-mediated pathways to develop malignancy. Here we show that polyploidy, which is often observed in human cancers, leads to overexpression of BRCA1, p19arf and other DNA repair genes in FEN1 mutant cells. This overexpression triggers SSB repair and non-homologous end-joining pathways to increase DNA repair activity, but at the cost of frequent chromosomal translocations. Meanwhile, DNA methylation silences p53 target genes to bypass the p53-mediated senescence and apoptosis. These molecular changes rewire DNA damage response and repair gene networks in polyploid tumour cells, enabling them to escape replication stress-induced senescence barriers.

Background: Inhalational anthrax caused by Bacillus anthracis is associated with high mortality primarily due to toxin-mediated injury. Raxibacumab is a human IgG1lambda monoclonal antibody directed against protective antigen, a component of the anthrax toxin., Methods: We evaluated the efficacy of raxibacumab as a prophylactic agent and after disease onset in a total of four randomized, placebo-controlled studies conducted in rabbits and monkeys. Animals were exposed to an aerosolized target exposure of B. anthracis spores that was approximately 100 times (in the prophylactic studies) and 200 times (in the therapeutic-intervention studies) the median lethal dose. In the therapeutic-intervention studies, animals were monitored for the onset of symptoms. Animals with detectable protective antigen in serum, a significant increase in temperature, or both received a single intravenous bolus of placebo or raxibacumab at a dose of either 20 mg per kilogram of body weight or 40 mg per kilogram. The primary end point was survival at day 14 (in rabbits) or at day 28 (in monkeys). Safety studies were conducted with intravenous raxibacumab (40 mg per kilogram) in 333 healthy human volunteers., Results: In both rabbits and monkeys, the time to detection of protective antigen correlated with the time to bacteremia (r=0.9, P<0.001). In the therapeutic-intervention studies, the survival rate was significantly higher among rabbits that received raxibacumab at a dose of 40 mg per kilogram (44% [8 of 18]) than among rabbits that received placebo (0% [0 of 18]; P=0.003). Raxibacumab treatment also significantly increased survival in monkeys (64% [9 of 14], vs. 0% [0 of 12] with placebo; P<0.001). In human subjects, intravenous raxibacumab at a dose of 40 mg per kilogram had a half-life of 20 to 22 days and provided a maximum concentration of the drug in excess of levels that are protective in animals. Concentrations of raxibacumab provide a surrogate end point that should be predictive of clinical benefit., Conclusions: A single dose of raxibacumab improved survival in rabbits and monkeys with symptomatic inhalational anthrax. (ClinicalTrials.gov number, NCT00639678.), (2009 Massachusetts Medical Society)

Objective: To determine the association of plasma B lymphocyte stimulator (BLyS) levels, immunosuppressive therapy, and other clinical parameters with disease activity in systemic lupus erythematosus (SLE)., Methods: Two hundred forty-five SLE patients were evaluated prospectively over a 2-year period at 4 centers. Assessments were performed every 3-6 months. Univariate analysis was used to determine the association among the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, serum anti-double-stranded DNA (anti-dsDNA), and plasma BLyS levels. A multivariate repeated-measures model incorporating immunosuppressive therapy was utilized., Results: Ninety-two percent of the patients were female. Sixty-seven percent were white, 31% African American, and 2% Asian (all of these groups may include Hispanic). Mean values at baseline were as follows: age 41.5 years, disease duration 8.1 years, SELENA-SLEDAI 3.3 (median 2, range 0-18), BLyS 5.57 ng/ml, IgG 1,439 mg/dl, C3 104.4 mg/dl, and C4 21.3 mg/dl; among those positive for anti-dsDNA, the median titer was 1:40 (range 1:10-1:1,280). Univariate analysis showed that plasma BLyS levels were associated with anti-dsDNA titers (P = 0.0465) and SELENA-SLEDAI scores (P = 0.0002). In multivariate analyses, a greater increase in the SELENA-SLEDAI score from the previous visit was associated with higher BLyS levels at the previous visit (P = 0.0042) and with a greater increase in the BLyS level from the previous visit (P = 0.0007)., Conclusion: The findings of association between a greater increase in the BLyS level from the previous visit and a greater increase in the SELENA-SLEDAI score at the subsequent visit, and between an elevated BLyS level at the previous visit and a greater SELENA-SLEDAI score at the subsequent visit, demonstrate a relationship between circulating BLyS levels and SLE disease activity. These results lend support to the notion that BLyS is a candidate for therapeutic targeting in SLE.

Background: HGS004 is a fully human immunoglobulin (Ig) G4 monoclonal antibody against CC chemokine receptor 5 (CCR5) with robust in vitro activity against a diverse panel of CCR5-tropic human immunodeficiency virus type 1 (HIV-1) isolates., Methods: A single-blind, randomized, placebo-controlled study was conducted in patients infected with CCR5-tropic HIV-1 to evaluate the safety, pharmacokinetics, and antiviral activity of HGS004. Sixty-three subjects were randomized into 5 dose cohorts (0.4, 2, 8, 20, and 40 mg/kg) and received a single intravenous dose of HGS004 or placebo., Results: HGS004 was well tolerated, and no dose-limiting toxicities were observed. Pharmacokinetics were nonlinear across the 0.4-40-mg/kg dose range, with dose-proportional increases in maximum concentration, although the area under the curve increased more than proportionally to dose. High levels of receptor occupancy were observed for up to 28 days in the higher-dose cohorts. Plasma HIV-1 RNA reductions of >1 log(10) at day 14 were observed in 14 (54%) of 26 subjects in the 8-, 20-, and 40-mg/kg cohorts. In the 40-mg/kg cohort, 4 of 10 subjects had a >1 log(10) HIV-1 RNA reduction at day 28. Drug concentrations relative to isolate sensitivity (the ratio of the concentration at day 14 to IC(90)) predicted antiviral response on day 14., Conclusions: HGS004 is safe and well tolerated and demonstrates meaningful antiviral activity when administered to patients infected with CCR5-tropic HIV-1.

Introduction: This trial evaluated the safety, biologic activity, and pharmacokinetics of belimumab, a fully human monoclonal antibody that inhibits the biologic activity of the soluble form of the essential B-cell survival factor B-lymphocyte stimulator (BLyS) in patients with systemic lupus erythematosus (SLE)., Methods: Seventy patients with mild-to-moderate SLE were enrolled in a phase I, double-blind, randomized study and treated with placebo (n = 13) or belimumab (n = 57) at four different doses (1.0, 4.0, 10, and 20 mg/kg) as a single infusion or two infusions 21 days apart. Patients were followed for 84 to 105 days to assess adverse events, pharmacokinetics, peripheral blood B-cell counts, serology, and SLE disease activity. Data from the study were summarized using descriptive statistics. chi2 type tests were used to analyze discrete variables. The Kruskal-Wallis test, the Wilcoxon test, and the analysis of covariance were used to analyze the continuous variables, as appropriate. The analysis was performed on all randomized patients who received study agent., Results: The incidences of adverse events and laboratory abnormalities were similar among the belimumab and placebo groups. Belimumab pharmacokinetics were linear across the 1.0 to 20 mg/kg dose range. Long terminal elimination half-life (8.5 to 14.1 days), slow clearance (7 ml/day per kg), and small volume of distribution (69 to 112 ml/kg) were consistent with a fully human antibody. Significant reductions in median percentages of CD20+ B cells were observed in patients treated with a single dose of belimumab versus placebo (day 42: P = 0.0042; and day 84: P = 0.0036) and in patients treated with two doses of belimumab versus placebo (day 105: P = 0.0305). SLE disease activity did not change after one or two doses of belimumab., Conclusions: Belimumab was well tolerated and reduced peripheral B-cell levels in SLE patients. These data support further studies of belimumab in autoimmune disorders.

The tolerability, pharmacodynamic effects, and pharmacokinetics of belimumab (LymphoStat-B) were evaluated in cynomolgus monkeys. Belimumab is a fully human IgG1lambda antibody directed against B-lymphocyte stimulator (BLyS) protein. BLyS is a TNF family member that supports B-lymphocyte maturation and survival and has been implicated in the pathogenesis of autoimmune diseases and B-lymphocyte malignancies. Belimumab was developed to antagonize BLyS activity in autoimmune diseases and B-lymphocyte malignancies, where undesirable effects of B-lymphocyte activity may cause or contribute to disease. Pharmacodynamic effects of belimumab were monitored by immunophenotyping of peripheral blood. Pathology end points, including tissue immunophenotyping, are described after 13 and 26 weeks of treatment and after a 34-week treatment-free (recovery) period. Belimumab was safe and well tolerated in repeat-dose toxicology studies at 5-50 mg/kg for up to 26 weeks. Monkeys exposed to belimumab had significant decreases in peripheral blood B lymphocytes by 13 weeks of exposure, continuing into the recovery period, despite total lymphocyte counts similar to the controls. There were concomitant decreases in spleen and lymph node B-lymphocyte representation after 13 or 26 weeks of treatment with belimumab. Microscopically, monkeys treated with belimumab for 13 or 26 weeks had decreases in the number and size of lymphoid follicles in the white pulp of the spleen. All findings were generally reversible within a 34-week recovery period. These data confirm the specific pharmacologic activity of belimumab in reducing B lymphocytes in the cynomolgus monkey. The favorable safety profile and lack of treatment-related infections also support continued clinical development of belimumab.

Background: Inhibition of the binding of Bacillus anthracis protective antigen (PA) to its cellular receptor can abrogate the downstream toxin-mediated deleterious effects of the anthrax toxin. A fully human monoclonal antibody against B. anthracis PA, PAmAb, was previously shown to provide a survival advantage in rabbit and monkey models of inhalational anthrax., Methods: A randomized, single-blind, placebo-controlled, dose-escalation study with 105 healthy volunteers was conducted to evaluate the safety, pharmacokinetics, and biological activity of PAmAb. Subjects received PAmAb or placebo as a single intramuscular injection (11 subjects/cohort) or intravenous infusion (10 subjects/cohort). Three intramuscular dose levels (0.3, 1.0, and 3.0 mg/kg) and 5 intravenous dose levels (1.0, 3.0, 10, 20, and 40 mg/kg) were studied. Two separate intramuscular injection sites (gluteus maximus and vastus lateralis) were evaluated in the cohorts (hereafter, the "IM-GM" and "IM-VL" cohorts, respectively)., Results: PAmAb was well tolerated, with no dose-limiting adverse events. All adverse events were transient and mild to moderate in incidence and/or severity. The pharmacokinetics of PAmAb were linear within each route and site of administration but were significantly different between the IM-GM and IM-VL cohorts. The mean terminal elimination half-life ranged from 15 to 19 days. The bioavailability of PAmAb is approximately 50% for IM-GM injection and 71%-85% for IM-VL injection. The biological activity of PAmAb in serum, assessed using a cyclic adenosine monophosphate assay, correlated with serum concentrations., Conclusions: PAmAb is safe, well tolerated, and bioavailable after a single intramuscular or intravenous dose, which supports further clinical development of PAmAb as a novel therapeutic agent for inhalational anthrax.