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Gray-scale and color/power Doppler ultrasound (US) are the first-line imaging modalities to evaluate the spleen, gallbladder and pancreas in children. The increasing use of contrast-enhanced ultrasound (CEUS) as a reliable and safe method to evaluate liver lesions in the pediatric population promises potential for imaging other internal organs. Although CEUS applications of the spleen, gallbladder and pancreas have been well described in adults, they have not been fully explored in children. In this manuscript, we present an overview of the applications of CEUS for normal variants and diseases affecting the spleen, gallbladder and pancreas. We highlight a variety of cases as examples of how CEUS can serve in the diagnosis and follow-up for such diseases in children. Our discussion includes specific examination techniques; presentation of the main imaging findings in various benign and malignant lesions of the spleen, gallbladder and pancreas in children; and acknowledgment of the limitations of CEUS for these organs.

In the United States and across the globe, we are faced with a strange and new dichotomy made sharper by the pandemic. There are streets in nearly every city and town where boarded-up shops are next to others with "help wanted" signs. As businesses were closed or customers evaporated, millions were thrust out of work. As those businesses attempt to reopen, they are desperate for labor. How can those who were thrust out of manufacturing, services, hospitality, and retail move across those sectors or into other sectors where opportunities exist or will emerge? There has perhaps never been a clearer need for employers, government, and workers to identify needed and desired skills and competencies. It is also clear that there have never been more potential resources to make this happen. One such resource is credential transparency, which is achieved by publishing essential information about credentials and competencies that potential employees need and have, so that everyone can better understand what they represent and to what jobs they lead.

Contrast-enhanced ultrasound (CEUS) is increasingly being used in children. One of the most common referrals for CEUS performance is characterization of indeterminate focal liver lesions and follow-up of known liver lesions. In this setting, CEUS is performed with intravenous administration of ultrasound contrast agents (UCAs). When injected into a vein, UCA microbubbles remain confined within the vascular network until they dissipate. Therefore, visualization of UCA within the tissues and lesions corresponds to true blood flow. CEUS enables continuous, real-time observation of the enhancement pattern of a focal liver lesion, allowing in most cases for a definite diagnosis and obviating the need for further cross-sectional imaging or other interventional procedures. The recent approval of Lumason (Bracco Diagnostics, Monroe Township, NJ) for pediatric liver CEUS applications has spurred the widespread use of CEUS. In this review article we describe the role of CEUS in pediatric liver applications, focusing on the examination technique and interpretation of main imaging findings of the most commonly encountered benign and malignant focal liver lesions. We also compare the diagnostic performance of CEUS with other imaging modalities for accurate characterization of focal liver lesions. Supplementary Information The online version contains supplementary material available at 10.1007/s00247-021-04976-2.

Obesity is a prevalent childhood condition and The degree of adiposity appears likely to be an important covariate in the pharmacokinetics (PK) of many drugs. We undertook these studies to facilitate the evaluation and, where appropriate, quantification of the covariate effect of body fat percentage (BF%) on PK parameters in children. We examined two large databases to determine the values and variabilities of BF% in children with healthy body weights and in those with obesity, comparing the accuracy and precision of BF% estimation by both clinical methods and demographically-derived techniques. Additionally, we conducted simulation studies to evaluate the utility of the several methods for application in clinical trials. BF% was correlated with body mass index (BMI), but was highly variable among both children with healthy body weights and those with obesity. Bio-impedance and several demographically-derived techniques produced mean estimates of BF% that differed from dual x-ray absorptiometry (DEXA) by less than 1% (accuracy) and a standard deviation of 5% or less (precision). Simulation studies confirmed that when the differences in precision among the several methods were small compared with unexplained between-subject variability of a PK parameter, the techniques were of similar value in assessing the contribution of BF%, if any, as a covariate for that PK parameter. The combination of sex and obesity stage explained 68% of the variance of BF% with BMI. The estimation of BF% from sex and obesity stage can routinely be applied to PK clinical trials to evaluate the contribution of BF% as a potential covariate.

Poor oral health is common in the United States; however, it is much more common in African Americans, Hispanics, and other racial/ethnic minorities. Almost one in five low-income adults states that their mouth and teeth are in poor condition. Twenty-nine percent of Americans have no dental insurance. Patients who have active infections are at greater risk for prosthetic joint infection. Optimization in these vulnerable groups should focus on treating active infections, with a prioritization of free clinics, academic clinics, and websites, such as "The Neighborhood Navigator," and easily accessible surgical consults.

Medication administration errors that take place in the home are common, especially when liquid preparations are used and complex medication schedules with multiple medications are involved; children with chronic conditions are disproportionately affected. Parents and other caregivers with low health literacy and/or limited English proficiency are at higher risk for making errors in administering medications to children in their care. Recommended strategies to reduce home medication errors relate to provider prescribing practices; health literacy–informed verbal counseling strategies (eg, teachback and showback) and written patient education materials (eg, pictographic information) for patients and/or caregivers across settings (inpatient, outpatient, emergency care, pharmacy); dosing-tool provision for liquid medication measurement; review of medication lists with patients and/or caregivers (medication reconciliation) that includes prescription and over-the-counter medications, as well as vitamins and supplements; leveraging the medical home; engaging adolescents and their adult caregivers; training of providers; safe disposal of medications; regulations related to medication dosing tools, labeling, packaging, and informational materials; use of electronic health records and other technologies; and research to identify novel ways to support safe home medication administration.

We sought to determine hemodynamic mechanisms of exercise intolerance in a group of patients with the HeartWare ventricular assist device (VAD) compared to a group of heart failure patients. Twenty VAD and 22 heart failure patients underwent symptom-limited active straight leg raising exercise during right heart catheterization with thermodilution (TD), and upright cycling cardiopulmonary stress testing with cardiac output measurement by inert gas rebreathing (IGR) method. The TD and IGR exercise cardiac indexes were higher in VAD compared with heart failure group (both P < 0.05), although there was only a borderline increase in peak exercise oxygen consumption (VO2) (P = 0.06). Baseline and exercise right heart catheterization pressures were not significantly different between the two groups. The only significant independent predictors of peak VO2 in the heart failure group were exercise heart rate and cardiac index (both P < 0.05). In contrast, for the VAD group only, resting pulmonary arterial wedge and pulmonary arterial mean pressures were independently related to peak VO2 (both P < 0.05). Thus, in heart failure, exercise cardiac index is an important limitation to exercise capacity, and VADs increase exercise cardiac index. However, in VAD patients, this only produces limited benefits as increased pulmonary and pulmonary wedge pressures limit increases in exercise capacity.

There have been literature reports that some recommended meropenem dosage regimens may fail to meet therapeutic targets in some high‐risk children and adults. We evaluated this observation in children using literature studies conducted in infants and children. Observed and, as necessary, simulated data from the literature were combined, yielding a data set of 288 subjects (1 day to ~ 17 years). A population pharmacokinetic model was fit to the data and then used to simulate the recommended dosing regimens and estimate the proportion of subjects achieving recommended target exposures. A two‐compartment model best fit the data with weight, postnatal age, gestational age, and serum creatinine as covariates. The US Food and Drug Administration (FDA)‐approved dosing regimens achieved targets in ~ 90% or more of subjects less than 3 months of age for organisms with minimum inhibitory concentration (MIC)'s of 2 and 4 mg/L; however, only 68.4% and 41.7% of subjects older than 3 months and weighing 3 months" corrected to "less than 3 months".]. Moreover, for subjects weighing more than 50 kg, only 41.3% and 17% achieved these respective targets. Simulation studies were used to explore the impact of changing dose, dosing interval, and infusion duration on the likelihood of achieving therapeutic targets in these groups. Our findings illustrate that current dosing recommendations for children over 3 months of age fail to meet therapeutic targets in an unacceptable fraction of patients. Further investigation is needed to develop new dosing strategies in these patients.

Critical limb ischemia (CLI) is the most severe manifestation of peripheral artery disease (PAD) and is characterized by high rates of morbidity and mortality. As with most severe cardiovascular disease manifestations, Black individuals disproportionately present with CLI. Accordingly, there remains a clear need to better understand the reasons for this discrepancy and to facilitate personalized therapeutic options specific for this population. Gastrocnemius muscle was obtained from White and Black healthy adult volunteers and patients with CLI for whole transcriptome shotgun sequencing (WTSS) and enrichment analysis was performed to identify alterations in specific Reactome pathways. When compared to their race-matched healthy controls, both White and Black patients with CLI demonstrated similar reductions in nuclear and mitochondrial encoded genes and mitochondrial oxygen consumption across multiple substrates, indicating a common bioenergetic paradigm associated with amputation outcomes regardless of race. Direct comparisons between tissues of White and Black patients with CLI revealed hemostasis, extracellular matrix organization, platelet regulation, and vascular wall interactions to be uniquely altered in limb muscles of Black individuals. Among traditional vascular growth factor signaling targets, WTSS revealed only Tie1 to be significantly altered from White levels in Black limb muscle tissues. Quantitative reverse transcription polymerase chain reaction validation of select identified targets verified WTSS directional changes and supports reductions in MMP9 and increases in NUDT4P1 and GRIK2 as unique to limb muscles of Black patients with CLI. This represents a critical first step in better understanding the transcriptional program similarities and differences between Black and White patients in the setting of amputations related to CLI and provides a promising start for therapeutic development in this population.

Although left ventricular assist device (LVAD) improves functional capacity, on average LVAD patients are unable to achieve the aerobic capacity of normal healthy subjects or mild heart failure patients. The aim of this study was to examine if markers of right ventricular (RV) function influence maximal exercise capacity. This was a single-center prospective study that enrolled 20 consecutive HeartWare ventricular assist device patients who were admitted at the Freeman Hospital (Newcastle upon Tyne, United Kingdom) for a heart transplant assessment from August 2017 to October 2018. Mean peak oxygen consumption (Peak VO2) was 14.0 ± 5.0 ml/kg/min, and mean peak age and gender-adjusted percent predicted oxygen consumption (%VO2) was 40.0% ± 11.5%. Patients were subdivided into two groups based on the median peak VO2, so each group consisted of 10 patients (50%). Right-sided and pulmonary pressures were consistently higher in the group with poorer exercise tolerance. Patients with poor exercise tolerance (peak VO2 below the median) had higher right atrial pressures at rest (10.6 ± 6.4 vs. 4.3 mmHg ± 3.2; p = 0.02) and the increase with passive leg raising was significantly greater than those with preserved exercise tolerance (peak VO2 above the median). Patients with poor functional capacity also had greater RV dimensions (4.4 cm ± 0.5 vs. 3.7 cm ± 0.5; p = 0.02) and a higher incidence of significant tricuspid regurgitation (moderate or severe tricuspid regurgitation in five patients in the poor exercise capacity group vs. none in the preserved exercise capacity group; p = 0.03). In conclusion, echocardiographic and hemodynamic markers of RV dysfunction discriminate between preserved and nonpreserved exercise capacity in HeartWare ventricular assist device patients.

Compromised muscle mitochondrial metabolism is a hallmark of peripheral arterial disease, especially in patients with the most severe clinical manifestation — critical limb ischemia (CLI). We asked whether inflexibility in metabolism is critical for the development of myopathy in ischemic limb muscles. Using Polg mtDNA mutator (D257A) mice, we reveal remarkable protection from hind limb ischemia (HLI) due to a unique and beneficial adaptive enhancement of glycolytic metabolism and elevated ischemic muscle PFKFB3. Similar to the relationship between mitochondria from CLI and claudicating patient muscles, BALB/c muscle mitochondria are uniquely dysfunctional after HLI onset as compared with the C57BL/6 (BL6) parental strain. AAV-mediated overexpression of PFKFB3 in BALB/c limb muscles improved muscle contractile function and limb blood flow following HLI. Enrichment analysis of RNA sequencing data on muscle from CLI patients revealed a unique deficit in the glucose metabolism Reactome. Muscles from these patients express lower PFKFB3 protein, and their muscle progenitor cells possess decreased glycolytic flux capacity in vitro. Here, we show supplementary glycolytic flux as sufficient to protect against ischemic myopathy in instances where reduced blood flow–related mitochondrial function is compromised preclinically. Additionally, our data reveal reduced glycolytic flux as a common characteristic of the failing CLI patient limb skeletal muscle., Supplementary glycolytic flux is sufficient to protect against ischemic myopathy when reduced blood flow-related mitochondrial function is compromised pre-clinically.

Currently there is little research into the role of frustration in substance use disorders despite research showing that frustration tolerance in humans is associated with a lower likelihood of developing substance use problems, better outcomes in recovery and fewer relapses. In order to address this need, our studies use a rat model to focus on frustration-related behavior in natural reward and addiction-related behavioral procedures. Frustration is defined as when a subject is unable to achieve a reinforcer, receives less of a reinforcer than anticipated, or has to work harder to achieve a reinforcer. In these studies, bar-press durations increase when rats are in a state of frustration during self-administration of sucrose, fentanyl, or cocaine. These data also show that average bar-press durations do not correlate with the number of bar presses, meaning that press duration is an independent measurement that represents a behavioral construct distinct from craving, which is typically measured with number of bar presses. Essentially, these results support that bar press durations can be used as a real time measure of frustration as a 4(th) major facet of addiction-related behavior, adding to craving, impulsivity, and habit.

Nature has been using DNA to store biological data for millions of years, and finally humans are learning to use the same medium for our own data. In this paper, we survey the field of cellular DNA encoding, where encoding schemes are used to insert data into pcDNA and ncDNA areas while bypassing the biological restrictions associated with those areas. We first characterize the unique bio-restrictions associated with existing cellular DNA encoding schemes, then we contrast the schemes with respect to the restrictions they meet, supported features, and implementation details. We discuss the pros and cons of the implementation of each encoding scheme, and make recommendations accordingly. Finally, we highlight existing gaps, and provide our insight into future research directions.

Objective.To characterize hydroxychloroquine (HCQ) exposure in patients with rheumatic disease receiving longterm HCQ compared to target concentrations with reported antiviral activity against the coronavirus disease 2019 caused by SARS-CoV-2 (COVID-19).Method.We evaluated total HCQ concentrations in serum and plasma from published literature values, frozen serum samples from a pediatric systemic lupus erythematosus trial, and simulated concentrations using a published pharmacokinetic model during pregnancy. For each source, we compared observed or predicted HCQ concentrations to target concentrations with reported antiviral activity against SARS-CoV-2.Results.The average total serum/plasma HCQ concentrations were below the lowest SARS-CoV-2 target of 0.48 mg/l in all studies. Assuming the highest antiviral target exposure (total plasma concentration of 4.1 mg/l), all studies had about one-tenth the necessary concentration for in vitro viral inhibition. Pharmacokinetic model simulations confirmed that pregnant adults receiving common dosing for rheumatic diseases did not achieve target exposures; however, the models predict that a dosage of 600 mg once a day during pregnancy would obtain the lowest median target exposure for most patients after the first dose.Conclusion.We found that the average patient receiving treatment with HCQ for rheumatic diseases, including children and non-pregnant/pregnant adults, are unlikely to achieve total serum or plasma concentrations shown to inhibit SARS-CoV-2 in vitro. Nevertheless, patients receiving HCQ long term may have tissue concentrations far exceeding that of serum/plasma. Because the therapeutic window for HCQ in the setting of SARS-CoV-2 is unknown, well-designed clinical trials that include patients with rheumatic disease are urgently needed to characterize the efficacy, safety, and target exposures for HCQ.

Hydroxychloroquine is an oral drug prescribed to pregnant women with rheumatic disease to reduce disease activity and prevent flares. Physiologic changes during pregnancy may substantially alter drug pharmacokinetics. However, the effect of pregnancy on hydroxychloroquine disposition and the potential need for dose adjustment remains virtually unknown. We performed a population-pharmacokinetic analysis using samples from the Duke Autoimmunity in Pregnancy Registry from 2013 to 2016. We measured hydroxychloroquine concentration using high-performance liquid chromatography/tandem mass spectrometry and analyzed data using non-linear mixed-effect modeling. We calculated differences between pregnancy and postpartum empirical Bayesian estimates using paired t tests. We computed steady-state concentration profiles for hydroxychloroquine during pregnancy and postpartum using individual clinical data and empirical Bayesian estimates developed from the final pharmacokinetic model. We obtained 145 serum samples from 50 patients, 25 of whom had paired pregnancy and postpartum specimens. Five subjects had average concentrations (pregnancy and postpartum)

Practitioners of the variant of Plum Blossom Boxing preserved in Zhuzhai village, Henan province, China, include in their repertoires, along with choreographed sequences designed to enhance martial prowess, a comic routine that parodies genuine fighting techniques while “combatants” exchange taunts and boasts. The article argues that this performance is a folk drama that symbolically recounts folk history, focuses group identity, and establishes prestige within the regional martial arts hierarchy.

Limited efficacy of clinical interventions for peripheral arterial disease necessitates a better understanding of the environmental and genetic determinants of tissue pathology. Existing research has largely ignored the early skeletal muscle injury response during hind limb ischemia (HLI). We compared the hind limb muscle response, after 6 hours of ischemia, in two mouse strains that differ dramatically in their postischemic extended recovery: C57BL/6J and BALB/cJ. Perfusion, measured by laser Doppler and normalized to the control limb, differed only slightly between strains after HLI (

Background: Critical limb ischemia is a manifestation of peripheral artery disease that carries significant mortality and morbidity risk in humans, although its genetic determinants remain largely unknown. We previously discovered 2 overlapping quantitative trait loci in mice, Lsq-1 and Civq-1 , that affected limb muscle survival and stroke volume after femoral artery or middle cerebral artery ligation, respectively. Here, we report that a Bag3 variant (Ile81Met) segregates with tissue protection from hind-limb ischemia. Methods: We treated mice with either adeno-associated viruses encoding a control (green fluorescent protein) or 2 BAG3 (Bcl-2–associated athanogene-3) variants, namely Met81 or Ile81, and subjected the mice to hind-limb ischemia. Results: We found that the BAG3 Ile81Met variant in the C57BL/6 (BL6) mouse background segregates with protection from tissue necrosis in a shorter congenic fragment of Lsq-1 (C.B6– Lsq1-3 ). BALB/c mice treated with adeno-associated virus encoding the BL6 BAG3 variant (Ile81; n=25) displayed reduced limb-tissue necrosis and increased limb tissue perfusion compared with Met81- (n=25) or green fluorescent protein– (n=29) expressing animals. BAG3 Ile81 , but not BAG3 Met81 , improved ischemic muscle myopathy and muscle precursor cell differentiation and improved muscle regeneration in a separate, toxin-induced model of injury. Systemic injection of adeno-associated virus–BAG3 Ile81 (n=9), but not BAG3 Met81 (n=10) or green fluorescent protein (n=5), improved ischemic limb blood flow and limb muscle histology and restored muscle function (force production). Compared with BAG3 Met81 , BAG3 Ile81 displayed improved binding to the small heat shock protein (HspB8) in ischemic skeletal muscle cells and enhanced ischemic muscle autophagic flux. Conclusions: Taken together, our data demonstrate that genetic variation in BAG3 plays an important role in the prevention of ischemic tissue necrosis. These results highlight a pathway that preserves tissue survival and muscle function in the setting of ischemia.

Introduction Left Ventricular Assist Devices (LVAD) improve survival and functional capacity in patients with advanced heart failure (HF). However, there are potential complications. Purpose We sought to determine parameters of exercise intolerance in a group of patients with the HeartWare LVAD (HVAD) compared to a group of HF patients. Methods This was a single-centre parallel prospective group-study. Briefly, echocardiograms, right heart catheterisation (RHC) and cardiopulmonary exercise tests were performed in forty-two patients admitted for a heart transplant assessment between August2017 and October2018.Of them 20 belonged to the HVAD group and 22 to the HF group. Results In our study, HVAD patients had a better exercise capacity than HF patients, although no significant differences were noted (14.0±5.0 ml/kg/min vs 11.3±3.9 ml/kg/min, p=0.06). To determine exercise tolerance, both HVAD and HF groups were subdivided into 2 groups based on the median peak exercise oxygen consumption (peakVO2) for that group. The table shows the comparison between preserved and non-preserved exercise tolerance in HF and HVADpatients. First of all, in the HVADgroup, all resting RHC pressures were significantly lower in the preserved exercise capacity group. However, in HFpatients there were no statistically significant differences between both subgroups in right-sided pressures, but Thermodilution exercise-induced change in cardiac output (ΔCO) and cardiac index (ΔCI) was significantly higher in the patients with preserved exercise tolerance. Secondly, in the HVADgroup the right ventricle was significantly larger in the reduced exercise tolerance subgroup. Moreover, patients with lower peak VO2 had more significant tricuspid regurgitation. Nevertheless, in HFpatients none of the echocardiographic parameters were related to the exercise capacity. HF HVAD > Median Peak V02 < Median Peak V02 p > Median Peak V02 < Median Peak V02 p Thermodilution CO, l/min: • Rest 4.3±1.0 4.4±1.8 0.82 4.8±0.8 4.2±1.2 0.21 • Exercise 5.6±1.7 4.8±1.8 0.36 7.1±3.2 4.8±0.8 0.05 • ΔCO 1.26±1.0 0.26±0.7 0.02 2.2±2.5 0.4±0.7 0.05 Right Atrium pressure, mmHg 7.0±4.5 6.8±4.10 0.92 4.3±3.2 10.6±6.40 0.02 Mean Pulmonary Artery pressure, mmHg 26.4±12.6 26.5±10.9 0.97 16.8±5.4 30.5±12.5 0.01 Tricuspid Regurgitation, n (%): • None 1 (9) 1 (9) 1 (12) 0 (0) • Mild 7 (64) 8 (73) 7 (88) 4 (44) • Moderate 2 (18) 0 (0) 0 (0) 4 (44) • Severe 1 (9) 2 (18) 0.36 0 (0) 1 (12) 0.03 Right Ventricle Basal Diastolic Diameter, cm 4.0±1.0 4.1±1.0 0.83 3.7±0.5 4.4±0.5 0.02 Conclusion Right-sided parameters in the echocardiogram and RHC pressures discriminate between preserved and non-preserved exercise capacity in HVADpatients, but not in HFpatients. In these last patients only ΔCO and ΔCI were statistically correlated with peak exercise oxygen consumption Acknowledgement/Funding N. Bouzas-Cruz would like to thank the Spanish Society of Cardiology (Sociedad Española de Cardiología), for her research grant and fellowship

Depression is a common psychiatric disorder that has been poorly understood. Consequently, current antidepressant agents have clinical limitations. Until today, most have exhibited the slow onset of therapeutic action and, more importantly, their effect on remission has been minimal. Thus, the need to find new forms of therapeutic intervention is urgent. The inflammation hypothesis of depression is widely acknowledged and is one that theories the relationship between the function of the immune system and its contribution to the neurobiology of depression. In this research, we utilized an environmental isolation (EI) approach as a valid animal model of depression, employing biochemical, molecular, and behavioral studies. The aim was to investigate the anti-inflammatory effect of etanercept, a tumor necrosis factor-α inhibitor on a toll-like receptor 7 (TLR 7) signaling pathway in a depressive rat model, and compare these actions to fluoxetine, a standard antidepressant agent. The behavioral analysis indicates that depression-related symptoms are reduced after acute administration of fluoxetine and, to a lesser extent, etanercept, and are prevented by enriched environment (EE) housing conditions. Experimental studies were conducted by evaluating immobility time in the force swim test and pleasant feeling in the sucrose preference test. The mRNA expression of the TLR 7 pathway in the hippocampus showed that TLR 7, MYD88, and TRAF6 were elevated in isolated rats compared to the standard group, and that acute treatment with an antidepressant and anti-inflammatory drugs reversed these effects. This research indicates that stressful events have an impact on behavioral well-being, TLR7 gene expression, and the TLR7 pathway. We also found that peripheral administration of etanercept reduces depressive-like behaviour in isolated rats: this could be due to the indirect modulation of the TLR7 pathway and other TLRs in the brain. Furthermore, fluoxetine treatment reversed depressive-like behaviour and molecularly modulated the expression of TLR7, suggesting that fluoxetine exerts antidepressant effects partially by modulating the TLR7 signaling pathway.

Purpose Although Left Ventricular Assist Device (LVAD) improves functional capacity, on average LVAD patients are unable to achieve the aerobic capacity of normal healthy subjects or mild heart failure patients. The aim of this study was to examine if markers of right ventricular (RV) function influence maximal exercise capacity. Methods This was a single-centre prospective study that enrolled 20 consecutive HeartWare ventricular assist device (HVAD) patients who were admitted at the Freeman Hospital (Newcastle upon Tyne, United Kingdom) for a heart transplant assessment from August 2017 to October 2018. Results Mean peak oxygen consumption (Peak VO2) was 14.0 ± 5.0 ml/kg/min, and mean peak age and gender-adjusted percent predicted oxygen consumption (%VO2) was 40.0 ± 11.5 %. Patients were subdivided into 2 groups based on the median peak VO2, so each group consisted of 10 patients (50%). Right-sided and pulmonary pressures were consistently higher in the group with poorer exercise tolerance. Patients with poor exercise tolerance (peak VO2 below the median) had higher right atrial pressures at rest (10.6mmHg ± 6.4 versus 4.3mmHg ± 3.2, p= 0.02) and the increase with passive leg raising was significantly greater than those with preserved exercise tolerance (peak VO2 above the median). Patients with poor functional capacity also had greater RV dimensions (4.4 cm ± 0.5 versus 3.7 cm ± 0.5, p= 0.02) and a higher incidence of significant tricuspid regurgitation (TR) (moderate or severe TR in 5 patients in the poor exercise capacity group versus none in the preserved exercise capacity group, p=0.03). Conclusion Echocardiographic and hemodynamic markers of RV dysfunction discriminate between preserved and non-preserved exercise capacity in HVAD patients.

Left ventricular assist devices (LVADs) have become an established treatment for advanced heart failure, although with long-term support these patients are potentially exposed to serious complications. Our purpose was to assess the role of the neutrophil to lymphocyte ratio (NLR) in LVAD complications and to evaluate if higher values of NLR after 4-6 months on LVAD support (NLR 4_6m) are associated with worse prognosis. All consecutive patients who received a HeartWare LVAD (N = 188, age 50 ± 13 years), as bridge to transplant from December 2009 to January 2018 were included. Neutrophil to lymphocyte ratio was recorded pre-LVAD, post-LVAD, after 4-6 months on support and in case of a first adverse event to occur after the 4-6 months NLR was recorded. Median NLR values were pre-LVAD 4.26 (interquartile range [IQR], 3.1-6.9), at 1 day postoperative 11.6 (IQR, 8.3-16.6), and NLR 4_6m 4.4 (IQR, 3.0-6.4) (p < 0.001). Neutrophil to lymphocyte ratio increased significantly when patients had an infection, stroke, or pump thrombosis, as compared with the NLR 4_6m (all p < 0.05). Patients with NLR 4_6m ≥ median had higher rates of stroke and mortality. Survival time was shorter among patients with NLR 4_6m ≥ 4.4 (log-rank test p = 0.006). Neutrophil to lymphocyte ratio 4_6m was found to be predictive of increased mortality (area under the curve of 0.62, p = 0.007). After multivariate analysis, NLR 4_6m remained independently associated with increased mortality (hazard ratio [HR] 1.67; 95% confidence interval [CI], 1.03-2.7; p = 0.037). Neutrophil to lymphocyte ratio 4_6m values significantly increase in association with adverse events on LVAD support and are independently associated with mortality. This association suggests presence of inflammation adversely affects LVAD outcomes.

Spike timing-dependent plasticity (STDP) is a form of activity-dependent remodeling of synaptic strength that underlies memory formation. Despite its key role in dictating learning rules in the brain circuits, the molecular mechanisms mediating STDP are still poorly understood. Here, we show that spike timing-dependent long-term depression (tLTD) and A-type K(+) currents are modulated by pharmacological agents affecting the levels of active glycogen-synthase kinase 3 (GSK3) and by GSK3β knockdown in layer 2/3 of the mouse somatosensory cortex. Moreover, the blockade of A-type K(+) currents mimics the effects of GSK3 up-regulation on tLTD and occludes further changes in synaptic strength. Pharmacological, immunohistochemical and biochemical experiments revealed that GSK3β influence over tLTD induction is mediated by direct phosphorylation at Ser-616 of the Kv4.2 subunit, a molecular determinant of A-type K(+) currents. Collectively, these results identify the functional interaction between GSK3β and Kv4.2 channel as a novel mechanism for tLTD modulation providing exciting insight into the understanding of GSK3β role in synaptic plasticity.

We read with great interest the very thoughtful commentary by Drs. Joob and Wiwanitkit. We agree with the authors that, despite conflicting clinical data to date, it is possible that HCQ may have a protective effect in the setting of COVID-19. More importantly, we agree that optimal HCQ dosage and timing is a critical underpinning for clinical trials. However, we highlight several considerations regarding treatment with high dose HCQ.

Introduction: Medicine demands a sacrifice of physicians’ personal life, but culture has slowly changed towards valuing a balanced work life. Parental leave is linked to better physical and mental health, but policies and culture surrounding parental leave are largely unstudied in the Canadian Emergency Medicine landscape. Anecdotally, experiences vary widely. This study was designed to determine what proportion of Canadian Emergency Departments have formal parental leave policies (maternity, paternity, and other ex. adoption) and what proportion of Canadian EM physicians are satisfied with their department's parental leave policies. Methods: Two surveys were generated; one to assess attitudes and experiences of emergency physicians, and a second survey for department chiefs assessed the policies and their features. These were approved by the UBC REB and distributed through the CAEP Research Committee. Primary outcomes were physician satisfaction with their department's parental leave policy (4-5/5 Likert Scale), and departments with a formal parental leave policy (Y/N). Results: 38% (8/21) of department chiefs reported having a formal policy for maternity leave, 29% (6/21) for paternity leave, and 24% (5/21) other. The survey of Emergency Physicians revealed similar rates at 48% (90/187) maternity, 40% (70/184) paternity, 29% (53/181) other. Among physicians who were aware of them, 69% (62/90) were somewhat or very satisfied with the maternity leave policies, 58% (51/88) with paternity leave policies, and 48% (39/81) with other parental leave. Less than 10% were somewhat or very dissatisfied with any of these. Several department chiefs commented that they had never refused anyone parental leave, but have no formal policy. However, 87% (147/187) of physicians reported a formal maternity leave policy was somewhat or very important to them; similarly 80% (134/187) paternity leave. Less than 15% felt each was somewhat or extremely unimportant. Conclusion: Presence and type of parental leave policy varies across the country. Most physicians were satisfied with the support they had available, but the vast majority felt that a formal maternity and paternity leave policy itself was important. This study would suggest that, without actually changing practice, the introduction of a formal parental leave policy is of value. Our research group will use this data to collaborate on a template parental leave policy to be made available for this purpose.

[EN] Qualitative research in the social sciences typically requires a personal engagement with resource persons. The widely used participant-observation method requires that the researcher assume as far as possible the role of community member. Even when participant observation is not the chosen method, group members assign identities to investigators. Role assignment in martial contexts may range from the “intruder” who disrupts ongoing events (e.g., outsiders may not see “secret techniques”) to one who is allowed insider access, usually after having gone through some test or rite of passage. Data collected in “natural context” is ideal. The primary problem here is that act of observation inevitably changes phenomena under examination. The most effective means of gathering information in a natural context is by engaging in what is known in the Intelligence community as “deep cover” actually joining a community for the purpose of secretly gathering information. This, of course, brings with it serious ethical dilemmas. While it is clear that we must all address the issue of transparency vs. efficiency, most decisions actually are made on a case by case basis. I suggest that it may be time to develop a general set of guidelines to help us keep faith with informants and accomplish our academic goals of accurately depicting the martial cultures with which we engage.

The most severe manifestation of peripheral arterial disease (PAD) is critical limb ischemia (CLI). CLI patients suffer high rates of amputation and mortality; accordingly, there remains a clear need both to better understand CLI and to develop more effective treatments. Gastrocnemius muscle was obtained from 32 older (51-84 years) non-PAD controls, 27 claudicating PAD patients (ankle-brachial index [ABI] 0.65 ± 0.21 SD), and 19 CLI patients (ABI 0.35 ± 0.30 SD) for whole transcriptome sequencing and comprehensive mitochondrial phenotyping. Comparable permeabilized myofiber mitochondrial function was paralleled by both similar mitochondrial content and related mRNA expression profiles in non-PAD control and claudicating patient tissues. Tissues from CLI patients, despite being histologically intact and harboring equivalent mitochondrial content, presented a unique bioenergetic signature. This signature was defined by deficits in permeabilized myofiber mitochondrial function and a unique pattern of both nuclear and mitochondrial encoded gene suppression. Moreover, isolated muscle progenitor cells retained both mitochondrial functional deficits and gene suppression observed in the tissue. These findings indicate that muscle tissues from claudicating patients and non-PAD controls were similar in both their bioenergetics profile and mitochondrial phenotypes. In contrast, CLI patient limb skeletal muscles harbor a unique skeletal muscle mitochondriopathy that represents a potentially novel therapeutic site for intervention.

Objective.Pregnancies in women with active rheumatic disease often result in poor neonatal outcomes. Hydroxychloroquine (HCQ) reduces disease activity and flares; however, pregnancy causes significant physiologic changes that may alter HCQ levels and lead to therapeutic failure. Therefore, our objective was to evaluate HCQ concentrations during pregnancy and relate levels to outcomes.Methods.We performed an observational study of pregnant patients with rheumatic disease who were taking HCQ from a single center during 2013–2016. Serum samples were analyzed using high-performance liquid chromatography/mass spectrometry. Primary HCQ exposure was categorized as nontherapeutic (≤ 100 ng/ml) or therapeutic (> 100 ng/ml). Categorical outcomes were analyzed using Fisher’s exact test and continuous outcomes using linear regression models, Wilcoxon signed-rank test, Kruskal-Wallis test, t test, and ANOVA.Results.We analyzed 145 samples from 50 patients with rheumatic disease, 56% of whom had systemic lupus erythematosus (SLE). HCQ concentration varied widely among individuals at each trimester. Mean physician’s global assessment scores in patients with SLE were significantly higher in those with average drug levels ≤ 100 ng/ml compared to > 100 ng/ml (0.93 vs 0.32, p = 0.01). Of patients with SLE, 83% with average drug levels ≤ 100 ng/ml delivered prematurely (n = 6), compared to only 21% with average levels > 100 ng/ml (n = 19; p = 0.01). HCQ levels were not associated with prematurity or disease activity in non-SLE patients.Conclusion.With both high and low HCQ levels associated with preterm birth and disease activity in SLE, further study is necessary to understand HCQ disposition throughout pregnancy and to clarify the relationship between drug levels and outcomes.

The availability of multiple datasets comprising genome-scale RNAi viability screens in hundreds of diverse cancer cell lines presents new opportunities for understanding cancer vulnerabilities. Integrated analyses of these data to assess differential dependency across genes and cell lines are challenging due to confounding factors such as batch effects and variable screen quality, as well as difficulty assessing gene dependency on an absolute scale. To address these issues, we incorporated cell line screen-quality parameters and hierarchical Bayesian inference into DEMETER2, an analytical framework for analyzing RNAi screens (https://depmap.org/R2-D2). This model substantially improves estimates of gene dependency across a range of performance measures, including identification of gold-standard essential genes and agreement with CRISPR/Cas9-based viability screens. It also allows us to integrate information across three large RNAi screening datasets, providing a unified resource representing the most extensive compilation of cancer cell line genetic dependencies to date., Integrated analyses of multiple large-scale screenings can be complicated by batch effects and technical artefacts. McFarland et al. introduce DEMETER2, a hierarchical model coupled with model-based normalization, which allows the assessment of differential dependencies across genes and cell lines.

Psychological disorders are prevalent in patients with inflammatory bowel disease; the underlying mechanisms remain unknown. We tested the hypothesis that ulcerative colitis-like inflammation induced by dextran sodium sulfate (DSS) exacerbates the ongoing spontaneous activity in colon-projecting afferent neurons that induces abdominal discomfort and anxiety, and depressive-like behaviors in rats. In this study, we used the conditioned place preference and standard tests for anxiety- and depression-like behaviors. DSS rats developed anxiety- and depression-like behaviors 10 to 20 days after the start of inflammation. Single-fiber recordings showed an increase in the frequency of spontaneous activity in L6-S1 dorsal root ganglion (DRG) roots. Prolonged desensitization of transient receptor potential vanilloid 1 (TRPV1)-expressing colonic afferents by resiniferatoxin (RTX) suppressed the spontaneous activity, as well as the anxiety- and depressive-like behaviors. Reduction in spontaneous activity in colon afferents by intracolonic administration of lidocaine produced robust conditioned place preference (CPP) in DSS rats, but not in control rats. Patch-clamp studies demonstrated a significant decrease in the resting membrane potential, lower rheobase, and sensitization of colon-projecting L6-S1 DRG neurons to generate trains of action potentials in response to current injection in DSS rats. DSS inflammation upregulated the mRNA levels of transient receptor potential ankyrin 1 and TRPV1 channels and downregulated that of Kv1.1 and Kv1.4 channels. Ulcerative colitis-like inflammation in rats induces anxiety- and depression-like behaviors, as well as ongoing abdominal discomfort by exacerbating the spontaneous activity in the colon-projecting afferent neurons. Alterations in the expression of voltage- and ligand-gated channels are associated with the induction of mood disorders following colon inflammation.

Amiodarone is a first-line antiarrhythmic for life-threatening ventricular fibrillation or ventricular tachycardia in children, yet little is known about its pharmacokinetics (PK) in this population. We developed a population PK (PopPK) model using samples collected via an opportunistic study design of children receiving amiodarone per standard of care supplemented by amiodarone PK data from the literature. Both study data and literature data were predominantly from infants

Medication overdoses are a common, but preventable, problem among children. Volumetric dosing errors and the use of incorrect dosing delivery devices are 2 common sources of these preventable errors for orally administered liquid medications. To reduce errors and increase precision of drug administration, milliliter-based dosing should be used exclusively when prescribing and administering liquid medications. Teaspoon- and tablespoon-based dosing should not be used. Devices that allow for precise dose administration (preferably syringes with metric markings) should be used instead of household spoons and should be distributed with the medication.

The passage of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act has collectively resulted in an improvement in rational prescribing for children, including more than 800 labeling changes. However, off-label drug use remains an important public health issue for infants, children, and adolescents, because an overwhelming number of drugs still have no information in the labeling for use in pediatrics. The purpose of off-label use is to benefit the individual patient. Practitioners use their professional judgment to determine these uses. As such, the term “off-label” does not imply an improper, illegal, contraindicated, or investigational use. Therapeutic decision-making must always rely on the best available evidence and the importance of the benefit for the individual patient.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development convened an Asthma Group in response to the Best Pharmaceuticals for Children Act. The overall goal of the Best Pharmaceuticals for Children Act Program is to improve pediatric therapeutics through preclinical and clinical drug trials that lead to drug-labeling changes. Although significant advances have been made in the understanding and management of asthma in adults with appropriately labeled medications, less information is available on the management of asthma in children. Indeed, many medications are inadequately labeled for use in children. In general, the younger the child, the less information there is available to guide clinicians. Because asthma often begins in early childhood, it is incumbent on us to continue to address the primary questions raised in this review and carefully evaluate the medications used to manage asthma in children. Meanwhile, continued efforts should be made in defining effective strategies that reduce the risk of exacerbations. If the areas of defined need are addressed in the coming years, namely prevention of exacerbations and progression of disease, as well as primary intervention, we will see continuing reduction in asthma mortality and morbidity along with improved quality of life for children with asthma.

Codeine has been prescribed to pediatric patients for many decades as both an analgesic and an antitussive agent. Codeine is a prodrug with little inherent pharmacologic activity and must be metabolized in the liver into morphine, which is responsible for codeine’s analgesic effects. However, there is substantial genetic variability in the activity of the responsible hepatic enzyme, CYP2D6, and, as a consequence, individual patient response to codeine varies from no effect to high sensitivity. Drug surveillance has documented the occurrence of unanticipated respiratory depression and death after receiving codeine in children, many of whom have been shown to be ultrarapid metabolizers. Patients with documented or suspected obstructive sleep apnea appear to be at particular risk because of opioid sensitivity, compounding the danger among rapid metabolizers in this group. Recently, various organizations and regulatory bodies, including the World Health Organization, the US Food and Drug Administration, and the European Medicines Agency, have promulgated stern warnings regarding the occurrence of adverse effects of codeine in children. These and other groups have or are considering a declaration of a contraindication for the use of codeine for children as either an analgesic or an antitussive. Additional clinical research must extend the understanding of the risks and benefits of both opioid and nonopioid alternatives for orally administered, effective agents for acute and chronic pain.

Hot electron relaxation and coherent vibrational oscillations of gold nanostars (AuNS) were studied using femtosecond laser spectroscopy. Transient profiles feature a fast decay attributed to electron–phonon interaction and a slower decay due to phonon relaxation. Superimposed on the slow decay are oscillations attributed to coherent vibrations of the AuNS with a period dependent on probe wavelength, due to size variation of the AuNS. In addition, persistent spectral hole-burning studies indicate depletion of AuNS at the excitation wavelength and formation of redder-absorbing AuNS aggregates. In conjunction with experiments, theoretical calculations were carried out to gain insight into the coherent vibrational oscillations.

This study examined the influence of community-based dental education (CBDE) on dental students' perceived ability to treat underserved patients and their selection of community dental clinics as a first career path. In a 2009 survey, fourth-year dental students at the University of Michigan recorded their attitudes, skill level, and confidence in treating underserved patients before and after CBDE rotations and estimated what percentage of their practice they planned to devote to Medicaid-eligible patients. The first career choices of graduates from 2005 to 2010 were also correlated with the number of weeks the students spent in CBDE rotations. The results showed an improvement in student skill and confidence in treating low-income patients after the rotations. The examination of first career choices showed that, after three to five weeks of CBDE rotations, 5.6 percent of the students planned to practice in a community-based dental clinic. However, in 2009 when rotations were increased to eight weeks and included multiple clinic types, 11.8 percent of the students in 2009 and 16.5 percent in 2010 selected a community-based dental clinic as their preferred practice location. These findings suggest that CBDE improves dental students' skill and confidence level in treating underserved patients and that more time spent in CBDE rotations, specifically more than five weeks in multiple clinic types, may increase the number of graduates who select practice in community-based clinics as a first career choice.

Roux-en-Y gastric bypass (RYGB) has been shown to induce rapid and durable reversal of type 2 diabetes.The aim of the study was to investigate a possible mechanism for the remission of type 2 diabetes after RYGB.A cross-sectional, nonrandomized, controlled study was conducted. Surgery patients were studied before RYGB and 1 wk and 3 months after surgery.This study was conducted at East Carolina University.Subjects were recruited into three groups: 1) lean controls with no surgery [body mass index (BMI)25 kg/m²; n = 9], 2) severely obese type 2 diabetic patients (BMI35 kg/m²; n = 9), and 3) severely obese nondiabetic patients (BMI35 kg/m²; n = 9).Intervention was RYGB.One week after RYGB, diabetes was resolved despite continued insulin resistance (insulin sensitivity index was approximately 50% of lean controls) and reduced insulin secretion during an iv glucose tolerance test (acute insulin response to glucose was approximately 50% of lean controls). Fasting insulin decreased and was no different from lean control despite continued elevated glucose in the type 2 diabetic patients compared with lean.After RYGB, fasting insulin decreases to levels like those of lean control subjects and diabetes is reversed (fasting blood glucose125 mg/dl). This leads us to propose that 1) exclusion of food from the foregut corrects hyperinsulinemia and 2) fasting insulin is dissociated from the influence of fasting glucose, insulin resistance, and BMI. The mechanisms for reversal of diabetes in the face of reduced insulin remain a paradox.

Given the predicted shortages of dental faculty in the United States, it is important to retain faculty members. Mentoring could play a crucial role in this context. The objectives of this case study were to explore how a six-year mentoring program in the Department of Periodontics and Oral Medicine at the University of Michigan School of Dentistry changed faculty members’ perceptions of support from colleagues and their mentoring expectations. In addition, we sought to determine how junior versus senior faculty members and mentors versus mentees differed in their perceptions of faculty roles, their self-perceived competence, and their awareness of departmental expectations at the end of the program. Data were collected with self-administered surveys from twenty-five of the thirty-six faculty members in this department in 2002 (response rate: 69 percent) and from thirty-seven of the fifty-four faculty members in 2008 (response rate: 69 percent). The results showed that the perceptions of support from colleagues improved significantly over the six-year period. During the same time period, mentoring expectations increased. In 2008, junior faculty members as compared to senior faculty members remained less positive about their role as faculty members, felt less well prepared for their professional life, and were less aware of departmental expectations. In conclusion, a departmental mentoring program resulted in improved support from colleagues and increased expectations concerning mentoring experiences. However, future targeted interventions are needed to address the identified differences between junior and senior faculty members. Recommendations for faculty mentoring efforts are discussed.

Rising aminotransferases (ATs) [either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) are one of the first signs of hepatotoxicity following acetaminophen (APAP)] overdose (OD). However, the timing and speed of such rises are not well characterized, hampering early risk prediction.To describe the kinetics of AT release in acute APAP OD patients who develop hepatotoxicity despite treatment.A descriptive study of acute APAP OD patients with peak AT 1,000 IU/L taken from the derivation subset of the Canadian Acetaminophen Overdose Study (CAOS), a large, multicenter retrospective cohort of patients hospitalized for APAP poisoning.Of 2,488 hospital admissions for acute APAP OD, 94 met inclusion criteria. Treatment with acetylcysteine, mostly intravenously, was begun in all cases within 24 h of ingestion. The initial AT concentration was already elevated in most patients at presentation [median 211 (IQR 77-511) IU/L obtained at 15.3 (12.1-19.2) h postingestion], and exceeded 100 IU/L in almost all patients within 24 h of ingestion. Serum AT concentrations rose rapidly [doubling time 9.5 h (95% CI: 8.7-10.4 h)], especially in patients who developed AT 1,000 IU/L within 48 h of ingestion. Coagulopathy was worse in these patients and in those with an AT 250 IU/L during the first 12 h of treatment with acetylcysteine.An abnormal and rapidly doubling AT at presentation is more typical in severely poisoned patients, as judged by the effects on clotting. These data suggest that risk prediction instruments may be improved by incorporating both the serum AT concentration at initiation of antidotal therapy and its rate of change. Further studies using such an approach are warranted.

The first available predictors of hepatic injury following acetaminophen (APAP) overdose are the serum APAP and aminotransferases [AT, i.e., aspartate (AST) aminotransferase or alanine (ALT) aminotransferase].We describe the initial value, rate of change, and interrelationship between these biomarkers in patients who develop hepatotoxicity despite treatment following acute overdose. A new parameter, the APAP × AT multiplication product, is proposed for early risk stratification.We conducted a descriptive study of individuals selected from a multicenter retrospective cohort of patients hospitalized for APAP poisoning. We selected those acute APAP overdose patients who subsequently developed AT 1,000 IU/L. Rising serum AT values were compared to simultaneously measured (or estimated) falling serum APAP. The APAP × AT was expressed relative to initiation of acetylcysteine therapy and grouped by time to meeting hepatotoxicity criteria.In the 94 cases studied, serum APAP concentrations were still appreciable [median 570 (interquartile range (IQR) 314-983) μmol/L] at the time of the first measured AT [211 (77-511) IU/L at 15.3 (12.1-19.2) h post-ingestion], yielding an initial APAP × AT of 99,000 (52,000-240,000) μmol × IU/L(2). Because serum AT rose rapidly (doubling time 9.5 h ) and APAP fell slowly (half-life 4.8 h), the multiplication product remained elevated during the first 12-24 h of antidotal therapy, especially among patients who developed earlier hepatotoxicity (AT1,000 IU/L).The APAP × AT multiplication product, calculated at the time of presentation and after several h of antidotal therapy, holds promise as a new risk predictor following APAP overdose. It requires neither graphical interpretation nor accurate time of ingestion, two limitations to current risk stratification.

There is a great need for leaders in the dental profession. As technological advances make our world smaller and our lives faster and more complex, we as a profession face challenges and opportunities that are evolving. Many of the changes in the scope and mode of practice will require new and different approaches. Meeting these challenges will require changes in how we as dental professionals do business; interact with our patients, other stakeholders, and health care providers; and educate our future colleagues. The purposeful incorporation of leadership education into dental and dental hygiene curricula represents an important departure from existing paradigms-but will help prepare our students to address these challenges. This article provides an overview of the development of a Scholars Program in Dental Leadership (SPDL) at the University of Michigan School of Dentistry. Our aim for the program is to create a learning environment that fosters leadership development, so that students are prepared and motivated to assume leadership positions in the profession and their communities.

This article describes an Internet-based instructional tool designed to give predoctoral dental students a virtual simulation of clinical pediatric dentistry to develop their pediatric behavior management knowledge. Effectiveness of this tool was evaluated using two consecutive classes of junior dental students. The control group was exposed to the traditional behavior management curriculum (two lectures) in a spring term course. The next class of dental students was exposed to the two lectures and, in addition, completed the behavior management simulation during the following spring term. Both groups completed a two-part examination (objective section=18 questions; open-ended section=responses to a clinical situation) designed to test their behavior management knowledge. The simulation group performed significantly better in both parts of the examination (objective section: p=.028; open-ended section: p=.012). The simulation was evaluated by students and perceived by most to be an effective addition to the curriculum. It was concluded that the experimental behavior management simulation, when added to the traditional lecture curriculum, improved pediatric behavior management knowledge in predoctoral dental students.