Background Over 6000 children have an in‐hospital cardiac arrest in the United States annually. Most will not survive to discharge, with significant variability in survival across hospitals suggesting improvement in resuscitation performance can save lives. Methods and Results A prospective observational study of quality of chest compressions ( CC ) during pediatric in‐hospital cardiac arrest associated with development and implementation of a resuscitation quality bundle. Objectives were to: 1) implement a debriefing program, 2) identify impediments to delivering high quality CC , 3) develop a resuscitation quality bundle, and 4) measure the impact of the resuscitation quality bundle on compliance with American Heart Association ( AHA ) Pediatric Advanced Life Support CC guidelines over time. Logistic regression was used to assess the relationship between compliance and year of event, adjusting for age and weight. Over 3 years, 317 consecutive cardiac arrests were debriefed, 38% (119/317) had CC data captured via defibrillator‐based accelerometer pads, data capture increasing over time: (2013:13% [12/92] versus 2014:43% [44/102] versus 2015:51% [63/123], P <0.001). There were 2135 1‐minute cardiopulmonary resuscitation (CPR) epoch data available for analysis, (2013:152 versus 2014:922 versus 2015:1061, P <0.001). Performance mitigating themes were identified and evolved into the resuscitation quality bundle entitled CPR Coaching, Objective‐Data Evaluation, Action‐linked‐phrases, Choreography, Ergonomics, Structured debriefing and Simulation (CODE ACES 2 ). The adjusted marginal probability of a CC epoch meeting the criteria for excellent CPR (compliant for rate, depth, and chest compression fraction) in 2015, after CPR Coaching, Objective‐Data Evaluation, Action‐linked‐phrases, Choreography, Ergonomics, Structured debriefing and Simulation was developed and implemented, was 44.3% (35.3–53.3) versus 19.9%(6.9–32.9) in 2013; (odds ratio 3.2 [95% confidence interval:1.3–8.1], P =0.01). Conclusions CODE ACES 2 was associated with progressively increased compliance with AHA CPR guidelines during in‐hospital cardiac arrest.

Aging-related impairments of learning and memory can be ameliorated by 28 days of intracerebroventricular (icv) infusion of insulin-like growth factor-1 (IGF-1) in old rats. The present study investigated whether there is an aging-related synaptic decline in the stratum radiatum of hippocampal CA1 and whether IGF-1 can ameliorate that decline. Five young (4 months), five middle-aged (18 months) and five old (29 months) Fischer 344xBrown Norway rats received saline infusion; five old (29 months) rats received IGF-1 infusion for 28 days preceding sacrifice. Pyramidal neurons, total synaptic profiles as well as synaptic profiles in multiple spine bouton (MSB) complexes in CA1 were quantified stereologically with the physical disector technique and the postsynaptic density (PSD) length was determined as well. The results indicated a decrease of total synapses between middle and old age but a maintenance of PSD length and MSB synapses throughout life. IGF-1 infusion in old rats did not reverse the aging-related decline in total synapses but did increase PSD length and the number of MSB synapses. These changes in synaptic configurations are morphological correlates of enhanced synaptic efficacy. Thus, aging and IGF-1 affect different, but complementary, aspects of synapses in hippocampal CA1.

Central nervous system (CNS) tuberculosis (TB) is the most severe form of extra-pulmonary TB and disproportionately affects young children where the developing brain has a unique host response. New Zealand white rabbits were infected with Mycobacterium tuberculosis via subarachnoid inoculation at postnatal day 4-8 and evaluated until 4-6 weeks post-infection. Control and infected rabbit kits were assessed for the development of neurological deficits, bacterial burden, and postmortem microbiologic and pathologic changes. The presence of meningitis and tuberculomas was demonstrated histologically and by in vivo magnetic resonance imaging (MRI). The extent of microglial activation was quantified by in vitro immunohistochemistry as well as non-invasive in vivo imaging of activated microglia/macrophages with positron emission tomography (PET). Subarachnoid infection induced characteristic leptomeningeal and perivascular inflammation and TB lesions with central necrosis, a cellular rim and numerous bacilli on pathologic examination. Meningeal and rim enhancement was visible on MRI. An intense microglial activation was noted in M. tuberculosis-infected animals in the white matter and around the TB lesions, as evidenced by a significant increase in uptake of the tracer 124I-DPA-713, which is specific for activated microglia/macrophages, and confirmed by quantification of Iba-1 immunohistochemistry. Neurobehavioral analyses demonstrated signs similar to those noted in children with delayed maturation and development of neurological deficits resulting in significantly worse composite behavior scores in M. tuberculosis-infected animals. We have established a rabbit model that mimics features of TB meningitis in young children. This model could provide a platform for evaluating novel therapies, including host-directed therapies, against TB meningitis relevant to a young child's developing brain.

Caloric restriction (CR) attenuates aging-related degenerative processes throughout the body. It is less clear, however, whether CR has a similar effect in the brain, particularly in the hippocampus, an area important for learning and memory processes that often are compromised in aging. In order to evaluate the effect of CR on synapses across lifespan, we quantified synapses stereologically in the middle molecular layer of the dentate gyrus (DG) of young, middle aged and old Fischer 344 x Brown Norway rats fed ad libitum (AL) or a CR diet from 4 months of age. The results indicate that synapses are maintained across lifespan in both AL and CR rats. In light of this stability, we addressed whether aging and CR influence neurotransmitter receptor levels by measuring subunits of NMDA (NR1, NR2A and NR2B) and AMPA (GluR1, GluR2) receptors in the DG of a second cohort of AL and CR rats across lifespan. The results reveal that the NR1 and GluR1 subunits decline with age in AL, but not CR rats. The absence of an aging-related decline in these subunits in CR rats, however, does not arise from increased levels in old CR rats. Instead, it is due to subunit decreases in young CR rats to levels that are sustained in CR rats throughout lifespan, but that are reached in AL rats only in old age.

GREENWAY, FRANK L., DONNA H. RYAN, GEORGE A. BRAY, JENNIFER C. ROOD, ELIZABETH W. TUCKER, AND STEVEN R. SMITH. Pharmaceutical cost savings of treating obesity with weight loss medications. Obes Res. 1999;7:523-531. Objective: To evaluate, in compliant patients, the pharmaceutical costs of treating obesity with fenfluraminel mazindol, fenfluramine/phentermine, caffeine/ephedrine, or mazindol relative to the pharmaceutical costs of treating obesity-related comorbid conditions and reducing cardiovascular risk. Methods and Procedures:Subjects were between 18 and 60 years of age with a BMI of >30 kg/m2. Pharmaceutical costs were evaluated in 73 of 220 subjects taking medications for diabetes, hyperlipidemia, or hypertension before and after treatment using fenfluramine with mazindol or phentermine. The pharmaceutical cost of weight loss, cardiac risk reduction, and low-density lipoprotein (LDL) cholesterol reduction was calculated for fenfluramine with mazindol or phentermine, caffeine with ephedrine, or mazindol alone, and compared to approved lipid-lowering medications. Results: Losses of 6% to 10% of initial body weight reduced pharmacy costs $122.64/month for insulin treated diabetes, $42.92/month for sulfonylurea-treated diabetes, $6 1 .O7/month for hyperlipidemia treated with medication, and $0.20/month for hypertension treated with medication. Blood pressure and laboratory evidence of insulin resistance improved in all medication groups. Caffeine/ephedrine was most cost-effective of the three treatments in reducing weight, cardiac risk, and LDL cholesterol. Discussion: Obesity medications produced a substantial weight loss in compliant patients and resulted in a net phar-

Tuberculous meningitis is a serious, life-threatening disease affecting vulnerable populations, including HIV-infected individuals and young children. The US National Institutes of Health convened a workshop to identify knowledge gaps in the molecular and immunopathogenic mechanisms of tuberculous meningitis and to develop a roadmap for basic and translational research that could guide clinical studies.

Tuberculosis (TB) remains the single biggest infectious cause of death globally, claiming almost two million lives and causing disease in over 10 million individuals annually. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes with various physiological roles implicated as key factors contributing to the spread of TB. They are involved in the breakdown of lung extracellular matrix and the consequent release of Mycobacterium tuberculosis bacilli into the airways. Evidence demonstrates that MMPs also play a role in central nervous system (CNS) tuberculosis, as they contribute to the breakdown of the blood brain barrier and are associated with poor outcome in adults with tuberculous meningitis (TBM). However, in pediatric TBM, data indicate that MMPs may play a role in both pathology and recovery of the developing brain. MMPs also have a significant role in HIV-TB-associated immune reconstitution inflammatory syndrome in the lungs and the brain, and their modulation offers potential novel therapeutic avenues. This is a review of recent research on MMPs in pulmonary and CNS TB in adults and children and in the context of co-infection with HIV. We summarize different methods of MMP investigation and discuss the translational implications of MMP inhibition to reduce immunopathology.

Objectives: Since the beginning of the coronavirus disease 2019 pandemic, hundreds of thousands of patients have been treated in ICUs across the globe. The severe acute respiratory syndrome–associated coronavirus 2 virus enters cells via the angiotensin-converting enzyme 2 receptor and activates several distinct inflammatory pathways, resulting in hematologic abnormalities and dysfunction in respiratory, cardiac, gastrointestinal renal, endocrine, dermatologic, and neurologic systems. This review summarizes the current state of research in coronavirus disease 2019 pathophysiology within the context of potential organ-based disease mechanisms and opportunities for translational research. Data Sources: Investigators from the Research Section of the Society of Critical Care Medicine were selected based on expertise in specific organ systems and research focus. Data were obtained from searches conducted in Medline via the PubMed portal, Directory of Open Access Journals, Excerpta Medica database, Latin American and Caribbean Health Sciences Literature, and Web of Science from an initial search from December 2019 to October 15, 2020, with a revised search to February 3, 2021. The medRxiv, Research Square, and clinical trial registries preprint servers also were searched to limit publication bias. Study Selection: Content experts selected studies that included mechanism-based relevance to the severe acute respiratory syndrome–associated coronavirus 2 virus or coronavirus disease 2019 disease. Data Extraction: Not applicable. Data Synthesis: Not applicable. Conclusions: Efforts to improve the care of critically ill coronavirus disease 2019 patients should be centered on understanding how severe acute respiratory syndrome–associated coronavirus 2 infection affects organ function. This review articulates specific targets for further research.