Simulation-based curriculum development: lessons learnt in Global Health education.

BACKGROUND: Simulation based medical education (SBME) allows learners to acquire clinical skills without exposing patients to unnecessary risk. This is especially applicable to Emergency Medicine training programs where residents are expected to demonstrate proficiency in the management of time critical, low frequency, and highly-morbidity conditions. This study aims to describe the process through which a SBME curriculum was created, in a limited simulation resource setting at a 4-year Emergency Medicine (EM) residency program at the American University of Beirut Medical Center. METHODS: A case-based pilot simulation curriculum was developed following Kern's 6 step approach to curriculum design. The curricular objectives were identified through an anonymous survey of the program's residents and faculty. Curriculum outcomes were assessed, and the curriculum was revised to address curricular barriers. Evaluations of the revised curriculum were collected during the simulation sessions and through a whole revised curriculum evaluation at the end of the first year of its implementation. RESULTS: 14/20 residents (70%) and 8/8 faculty (100%) completed the needs assessment from which objectives for the pilot curriculum were developed and implemented through 6 2-h sessions over a 1-year period. Objectives were not met and identified barriers included cost, scheduling, resources, and limited faculty time. The revised curriculum addressed these barriers and 24 40-min sessions were successfully conducted during the following year. The sessions took place 3 at a time, in 2-h slots, using the same scenario to meet the objectives of the different learners' levels. 91/91 evaluations were collected from participants with overall positive results. The main differences between the pilot and the revised curricula included: a better understanding of the simulation center resources and faculty's capabilities. CONCLUSION: Simulation-based education is feasible even with limited-resources. However, understanding the resources available, and advocating for protected educator time are essential to implementing a successful EM simulation curriculum.

Non-invasive carbon dioxide monitoring in patients with cystic fibrosis during general anesthesia: end-tidal versus transcutaneous techniques.

INTRODUCTION: The gold standard for measuring the partial pressure of carbon dioxide remains arterial blood gas (ABG) analysis. For patients with cystic fibrosis undergoing general anesthesia or polysomnography studies, continuous non-invasive carbon dioxide monitoring may be required. The current study compares end-tidal (ETCO2), transcutaneous (TCCO2), and capillary blood gas carbon dioxide (Cap-CO2) monitoring with the partial pressure of carbon dioxide (PaCO2) from an ABG in patients with cystic fibrosis. METHODS: Intraoperatively, a single CO2 value was simultaneously obtained using ABG (PaCO2), capillary (Cap-CO2), TCCO2, and ETCO2 techniques. Tests for correlation (Pearson's coefficient) and agreement (Bland-Altman analysis) were performed. Data were further stratified into two subgroups based on body mass index (BMI) and percent predicted forced expiratory volume in 1 s (FEV1%). Additionally, the absolute difference in the TCCO2, ETCO2, and Cap-CO2 values versus PaCO2 was calculated. The mean ± SD differences were compared using a paired t test while the number of times the values were ≤ 3 mmHg and ≤ 5 mmHg from the PaCO2 were compared using a Fishers' exact test. RESULTS: The study cohort included 47 patients (22 males, 47%) with a mean age of 13.4 ± 7.8 years, median (IQR) BMI of 18.7 kg/m2 (16.7, 21.4), and mean FEV1% of 87.3 ± 18.3%. Bias (SD) was 4.8 (5.7) mmHg with Cap-CO2 monitoring, 7.3 (9.7) mmHg with TCCO2 monitoring, and 9.7 (7.7) mmHg with ETCO2 monitoring. Although there was no difference between the degree of bias in the population as a whole, when divided based on FEV1% and BMI, there was greater bias with ETCO2 in patients with a lower FEV1% and a higher BMI. The Cap-CO2 vs. PaCO2 difference was 5.2 ± 5.3 mmHg (SD), with 16 (48%) ≤ 3 mmHg and 20 (61%) ≤ 5 mmHg from the ABG value. The TCCO2-PaCO2 difference was 9.1 ± 7.2 mmHg (SD), with 11 (27%) ≤ 3 mmHg and 15 (37%) ≤ 5 mmHg from the ABG value. The ETCO2-PaCO2 mean difference was 11.2 ± 7.9 mmHg (SD), with 5 (12%) ≤ 3 mmHg and 11 (26%) ≤ 5 mmHg from the ABG value. CONCLUSIONS: While Cap-CO2 most accurately reflects PaCO2 as measured on ABG, of the non-invasive continuous monitors, TCCO2 was a more accurate and reliable measure of PaCO2 than ETCO2, especially in patients with worsening pulmonary function (FEV1% ≤ 81%) and/or a higher BMI (≥ 18.7 kg/m2).

Current perioperative care of infants with pyloric stenosis: comparison of survey results.

BACKGROUND: Considerable variation in the perioperative management of infants with pyloric stenosis (PS) led the authors to undertake a survey of pediatric anesthesiologists to determine if consensus-based guidelines could be developed. MATERIALS AND METHODS: Physicians who are members of the Society for Pediatric Anesthesia or the Association of Pediatric Anaesthetists of Great Britain and Ireland completed an online questionnaire through SurveyMonkey regarding current management of patients with PS. RESULTS: There were significant differences in the use of anticholinergic premedication, the selection of induction technique, and the use of adjuvant regional analgesia between the members of both organizations. CONCLUSIONS: The authors recommend creating an international multiinstitutional registry to prospectively record and track perioperative management of patients with PS to facilitate the development of clinical practice guidelines.

Analgesic effects of methadone and magnesium following posterior spinal fusion for idiopathic scoliosis in adolescents: a randomized controlled trial.

PURPOSE: To provide optimal conditions for neurophysiological monitoring and rapid awakening, remifentanil is commonly used during pediatric spinal surgery. However, remifentanil may induce hyperalgesia and increase postoperative opioid requirements. We evaluated the potential of methadone or magnesium to prevent remifentanil-induced hyperalgesia. METHODS: Using a prospective, randomized, blinded design, adolescents presenting for posterior spinal fusion to treat idiopathic scoliosis were assigned to receive desflurane with remifentanil alone (REMI), remifentanil + methadone (MET) (0.1 mg/kg IV over 15 min), or remifentanil + magnesium (MAG) (50 mg/kg bolus over 30 min followed by 10 mg/kg/h). Primary outcomes were opioid requirements and postoperative pain scores. Secondary outcomes included intraoperative anesthetic requirements, neurophysiological monitoring conditions, and emergence times. RESULTS: Data analysis included 60 patients. Total opioid requirement (hydromorphone) in the REMI group (received perioperatively and on the inpatient ward) was 0.34 ± 0.11 mg/kg compared to 0.26 ± 0.10 mg/kg in the MET group (95% confidence interval (CI) of difference: - 0.14, - 0.01; p = 0.035). The difference in opioid requirements between the REMI and MET group was related to intraoperative dosing (0.04 ± 0.02 mg/kg vs. 0.02 ± 0.01 mg/kg; 95% CI of difference: - 0.01, - 0.02; p = 0.003). No difference was noted in pain scores, and no differences were noted when comparing the REMI and MAG groups. CONCLUSION: With the dosing regimens in the current study, the only benefit noted with methadone was a decrease in perioperative opioid requirements. However, given the potential for hyperalgesia with the intraoperative use of remifentanil, adjunctive use of methadone appears warranted.

The Correlation of Two Cerebral Saturation Monitors With Jugular Bulb Oxygen Saturation in Children Undergoing Cardiopulmonary Bypass for Congenital Heart Surgery.

BACKGROUND: Near-infrared spectroscopy (NIRS) is a noninvasive monitoring technique that measures regional cerebral oxygen saturation (rSO2). OBJECTIVES: The primary aim was to compare the output of 2 NIRS-based cerebral oximetry devices, FORESIGHT (CAS Medical Systems Inc, Branford, Connecticut) and INVOS (Covidien, Boulder, Colorado), to venous oxygen saturations from the jugular venous bulb at cannulation and decannulation of the superior vena cava (SVC). Secondary objectives included evaluating correlations of cerebral saturation, as measured by the NIRS devices, with mean arterial blood pressure (MAP), measured by an invasive arterial line, and end-tidal CO2 (ETCO2). METHODS: Near-infrared spectroscopy, MAP, and ETCO2 data were collected at 13 defined events during each case when hemodynamic instability was expected. At SVC cannulation and decannulation, a 0.1 mL sample of blood was collected from the jugular bulb by the surgeon using a long angiocatheter. The oxygen saturation of these blood samples was measured using an AVOX device and compared with contemporaneous readings from the NIRS probes. Mixed-effects linear regression was used to correlate MAP or ETCO2 with cerebral oxygen saturation (by NIRS) at each time point. RESULTS: Children undergoing cardiopulmonary bypass for congenital heart surgery (n = 34) were enrolled in the study. At SVC cannulation, both INVOS ( r = .78) and FORESIGHT ( r = .59) were correlated with AVOX data at P < .001, although the correlation with INVOS was significantly stronger ( P = .003). At SVC decannulation, INVOS ( r = .68; P < .001) and FORESIGHT ( r = .60; P < .001) were similarly correlated with jugular venous rSO2. Correlations of rSO2 (by NIRS) with MAP and ETCO2 levels were stronger than correlations between rSO2 change and change in MAP or ETCO2. CONCLUSION: INVOS correlated more strongly than FORESIGHT with the jugular bulb rSO2 at SVC cannulation but may have underestimated oxygen saturation at low rSO2 values. Data from both NIRS devices were correlated with MAP and ETCO2 over the case duration.

Hemodynamic profile and behavioral characteristics during induction of anesthesia in pediatric patients with attention deficit hyperactivity disorder.

AIM: There is no consensus regarding the administration of stimulant drugs preoperatively, particularly in pediatric patients diagnosed with ADHD. The primary objective of the current study was to assess differences in blood pressure and heart rate before and after induction of anesthesia between patients on chronic amphetamine or methylphenidate therapy who receive their normal dose preoperatively compared to patients in whom the prescribed medication was withheld. Secondary objectives were to assess the anxiety level during the induction of anesthesia and the effect of premedication with midazolam. METHOD: Patients, ranging in age from 2 through 18 years, were enrolled if they were diagnosed with ADHD, were taking amphetamines or methylphenidate at any time in the 6 months prior to admission, and were undergoing an outpatient surgical or diagnostic procedure. The study cohort was divided into those who took their ADHD medications prior to surgery and those who did not take their medications preoperatively. The primary objective was addressed by comparing heart rate, systolic and diastolic BP, and mean arterial pressure before and during anesthetic induction between the two groups. Hypotension after anesthetic induction was defined as systolic blood pressure and mean arterial pressure <5th percentile for age. To address the secondary objectives, modified Yale Preoperative Anxiety Scale (mYPAS) scores assessed prior to induction and during induction were compared between groups. RESULTS: Fifty patients were enrolled, 14 of whom took their ADHD medication and 34 of whom did not take ADHD medication preoperatively. Two patients with unknown ADHD medication status were excluded from the primary analysis (stratification by medication withholding), but all 50 patients were used for the secondary analysis (stratification by midazolam use). There was no intraoperative hypotension in either group. Despite weak evidence for a difference in heart rate between the group receiving medication and the group with no medication (96.8 ± 14.0 vs 88.0 ± 14.0 beats/min; difference of means = 8.8; 95% CI of difference: 0.2, 17.7; P = 0.055), there was no evidence for differences between the groups in systolic BP, diastolic BP, or mean arterial pressure. There were no differences between groups in mYPAS at the two time periods assessed. CONCLUSION: The evidence suggests that continuing preoperative stimulant medication is not associated with cardiovascular instability in the pediatric population. The evidence suggests that withholding or allowing stimulant medication preoperatively does not improve behavior on anesthetic induction or reduce the need for anxiolytic medication. Research efforts should focus on perioperative management strategies that will decrease the likelihood of long-term behavioral issues.

Effects of partial sleep deprivation on reaction time in anesthesiologists.

BACKGROUND: Fatigue in anesthesiologists may have implications that extend beyond individual well-being. AIM: The aim of the present study was to evaluate the impact of sleep deprivation on the reaction time in anesthesiologists either after an overnight call or regular working hours. Moderation of this effect by coping strategies was observed. METHODS: Psychomotor vigilance test was used to assess reaction time in 23 anesthesiologists at two time-points: (i) on a regular non-call day and (ii) after a 17-h in-house call. Student's paired t-test was used to compare Psychomotor Vigilance Task data at these two moments. Change score regression was performed to determine the association between coping strategies, assessed using the Coping Strategy Indicator instrument, and decline in reaction time after night call. RESULTS: Twenty-one colleagues completed the psychomotor vigilance test measurements after two decided to end their participation for personal reasons. Post-call psychomotor vigilance test mean reaction time decreased by an average of 31.2 ms (95% CI: 0.5, 61.9; P = 0.047) when compared to regular day. Reliance on specific coping mechanisms, indicated by Coping Strategy Indicator scale scores, included problem-solving (28 ± 4), followed by seeking social support (23 ± 5) and avoidance (19 ± 4). The change score regression model (r2 = 0.48) found that greater reliance on avoidance was associated with greater increase in reaction time after night call. CONCLUSION: Reaction time increased considerably in anesthesiologists after a night call duty. Greater subjective reliance on avoidance as a coping strategy was associated with greater deterioration in performance.

Point-of-care testing for coagulation function: CoaguChek® XS System versus standard laboratory testing in pediatric patients with normal and abnormal coagulation function.

PURPOSE: Intraoperative abnormalities of coagulation function may occur for various reasons. In most scenarios, treatment is directed by laboratory parameters. Unfortunately, standard laboratory testing may take 1-2 h. The purpose of the current study was to evaluate a point-of-care testing device (CoaguChek® XS System) in pediatric patients. METHODS: Patients ranging in age from 2 to 18 years, undergoing posterior spinal fusion (PSF) or cardiac surgery using cardiopulmonary bypass (CPB) were eligible for inclusion. After CPB and/or the surgical procedure, 2.8 ml of blood was obtained and simultaneously tested on both the standard laboratory apparatus and the CoaguChek® XS System. RESULTS: The study cohort consisted of 100 patients (50 PSF and 50 cardiac cases) with 13 cases excluded, leaving 87 patients (49 PSF and 38 cardiac cases) for analysis. In PSF cases, reference laboratory international normalized ratio (INR) ranged from 0.98 to 1.77 while CoaguChek® XS INR ranged from 1.0 to 1.3. The correlation coefficient was 0.69. The results of the Bland-Altman analysis showed a bias of 0.09, precision of 0.1, and 95% limits of agreement ranging from -0.11 to 0.28. In cardiac cases, reference INR ranged from 1.68 to 14.19, while CoaguChek® XS INR ranged from 1.4 to 7.9. The correlation coefficient was 0.35. The results of the Bland-Altman analysis showed a bias of -1.8, precision of 2.1, and 95% limits of agreement ranging from -6.0 to 2.4. CONCLUSIONS: INR values obtained from CoaguChek® XS showed a moderate correlation with reference laboratory values within the normal range. However, in the presence of coagulopathy, the discrepancy was significantly greater, thereby making the CoaguChek® XS clinically unreliable.

Time to talk about work-hour impact on anesthesiologists: The effects of sleep deprivation on Profile of Mood States and cognitive tasks.

BACKGROUND: A physician's fatigue raises significant concerns regarding personal and patient safety. Effects of sleep deprivation on clinical performance and the quality of patient care are major considerations of today's health care environment. AIM: To evaluate the impact of partial sleep deprivation after a 17-h overnight call (3 pm-7 am) on the mood status and cognitive skills of anesthesiologists in an academic clinical hospital setting, as compared to these parameters during regular working hours. METHODS: Taking circadian rhythm into account, the following measures were assessed in 21 pediatric anesthesiologists at two time points over the course of the study; (i) between 7 and 8 am on a regular non call day, and (ii) between 7 and 8 am after a 17-h in-house call (3 pm-7 am). Six mood states were assessed using the Profile of Mood States. A Total Mood Disturbance (TMD) score was obtained as the sum of all mood scores minus vigor. The total score provides a global estimate of affective state. Simple cognitive tests were similarly administered to assess cognitive skills. A two-tailed paired t-test was used to compare data between regular and post call days. A P < 0.05 was used. RESULTS: The study cohort included 21 pediatric anesthesiologists at a tertiary care children's hospital. Tension, anger, fatigue, confusion, TMD, irritability, feeling jittery, and sleepiness were significantly affected (P < 0.05). A decrease in vigor, energy, and confidence was observed after a night call shift (P < 0.05). There was also a decrease in being "talkative" after the call shift (P < 0.05). CONCLUSION: Partial sleep deprivation affects the total mood status of anesthesiologists and impacts their cognitive skills. These findings are particularly relevant in a context of increased work expectation, particularly on clinical performance in our modern medical system. Such observations suggest that there may be changes that impact the safety of our patients and the quality of health care that is provided.

Utility of screening questionnaire, obesity, neck circumference, and sleep polysomnography to predict sleep-disordered breathing in children and adolescents.

BACKGROUND: Polysomnography (PSG) remains the gold standard for diagnosing obstructive sleep apnea (OSA) and sleep-disordered breathing in children. Yet, simple screening tools are needed as it is not feasible to perform PSG in all patients with possible OSA. AIM: The study adapted questions from the Pediatric Sleep Questionnaire-Sleep-Related Breathing Disorder (SRBD) Questionnaire to develop a predictive scale for OSA identified on PSG. We also tested whether adding anthropometric measurements (body mass index and neck circumference) improved prediction of OSA. METHODS: After IRB approval, OSA questionnaires and anthropometric measurements were collected on 948 consecutive patients scheduled for PSG, aged 4 months to 24.5 years (median = 8.5 years). The sample was reduced to 636 patients in the age range (6-18 years old) where normative values for neck circumference are defined. OSA was characterized using the obstructive apnea-hypopnea index (AHI). After identifying questions related to OSA in univariate logistic regression, multivariable models were fitted to select questions for a short scale, and points for exceeding body mass or neck circumference cutoffs were added to assess improvement in predictive value. RESULTS: A long scale of 16 questionnaire items was constructed using univariate models, while six items were selected for the short scale by multivariable regression. The short scale was associated with greater odds of moderate/severe OSA (OR = 1.964; 95% CI = 1.620, 2.381; P < 0.001) and attained good predictive value (area under receiver operating characteristics curve [AUC] = 0.74), which was not significantly improved by addition of BMI and neck circumference data (AUC = 0.75). CONCLUSIONS: We developed a six-question scale with good predictive utility for OSA. These findings may contribute to developing a preoperative clinical tool to help clinicians identify children with OSA for determining risk stratification and postoperative disposition.

Accuracy of noninvasive and continuous hemoglobin measurement by pulse co-oximetry during preoperative phlebotomy.

BACKGROUND: In recent years, the continuous noninvasive hemoglobin measurement has been offered by devices using advanced pulse oximetry technology. Accuracy has been established in healthy adults as well as in surgical and intensive care unit patients but not in the setting of acute hemorrhage. In this study, we evaluated the accuracy of such a device in the clinical setting of preoperative phlebotomy thereby mimicking a scenario of acute blood loss. METHODS: This prospective study included patients undergoing surgical repair of congenital heart disease (CHD) for whom preoperative phlebotomy was planned. Blood was removed after the induction of anesthesia and prior to the start of the surgical procedure. Replacement with crystalloid was guided by hemodynamic variables and cerebral oxygenation measured by near-infrared spectroscopy. Hemoglobin was measured by bedside whole blood analysis (total hemoglobin [tHb]) before and after phlebotomy, and concurrent measurements from the pulse co-oximeter (noninvasive, continuous, or spot-check testing of total hemoglobin [SpHb]) were recorded. RESULTS: The study cohort included 45 patients ranging in age from 3 months to 50 years. Preoperative phlebotomy removed an average of 9.2 mL/kg of blood that was replaced with an average of 7.2 mL/kg of crystalloid. The pre- and postphlebotomy tHb values were 13.0 ± 1.9 and 12.4 ± 1.8 g/dL, respectively. The absolute difference between the tHb and SpHb (▵Hb) was 1.2 ± 0.1 g/dL. Bland-Altman analysis revealed a bias of 0.1 g/dL, a precision of 1.5 g/dL, and 95% limits of agreement of -2.8 to 3.1 g/dL. In 52.2% of the sample sets, the SpHb was within 1 g/dL of the actual hemoglobin value (tHb), and in 80% of the sample sets, the SpHb was within 2 g/dL. No variation in the accuracy of the deviation was noted based on the patient's age, weight, or type of CHD (cyanotic versus acyanotic). CONCLUSION: The current study demonstrates that the accuracy of continuous, noninvasive hemoglobin measurement was not affected by acute blood loss simulated by preoperative phlebotomy. Although the device provided a clinically acceptable correlation with the actual hemoglobin value and offers the value of a continuous trend monitor, given the precision of the device, it does not appear that actual transfusion decisions can be based on the device alone.

Accuracy of the CNAP™ monitor, a noninvasive continuous blood pressure device, in providing beat-to-beat blood pressure measurements during bariatric surgery in severely obese adolescents and young adults.

BACKGROUND: During perioperative care, the continuous measurement of blood pressure (BP) provides superior physiological monitoring compared to intermittent techniques, especially for patients with comorbid conditions such as severe obesity. The current study prospectively assesses the accuracy of a continuous, noninvasive BP device in severely obese adolescents and young adults. METHODS: The technology evaluated was the CNAP Monitor 500, developed by CNSystems AG (Graz, Austria). The study cohort was composed of severely obese adolescents (body mass index ≥ 35 kg/m(2)) undergoing a surgical weight loss procedure (robotically assisted or laparoscopic vertical sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass). Systolic (sBP), diastolic (dBP), and mean arterial (MAP) blood pressure readings were captured from an intraoperatively placed radial arterial cannula (AC) and the CNAP device at regular intervals (once per minute) during anesthetic care. RESULTS: The study cohort consisted of 18 severely obese subjects undergoing weight loss surgery. A total of 2,159 pairs each of sBP, dBP, and MAP values obtained. The correlation coefficient between the AC and the CNAP device was 0.655, 0.667, and 0.783 for the sBP, dBP, and MAP, respectively. The CNAP values (sBP, dBP, MAP) were ≤5 mmHg from the AC values in 33, 40, and 41% of the values, respectively. The difference was more than 10 mmHg (sBP, dBP, MAP) in 39, 28, and 25% of the values, respectively. Using a Bland-Altman analysis, the precision and bias for the sBP, dBP, and MAP were 0.3 ± 14.2, -1.3 ± 9.5, and -0.6 ± 8.6 mmHg, respectively. CONCLUSION: When compared to previous studies in the adult population, the accuracy of the CNAP device in a cohort of severely obese adolescents undergoing weight loss surgery was slightly less than previously reported. The current data demonstrate a clinically useful trend of the CNAP device with arterial values in this challenging patient population in whom an arterial cannula may at times be difficult.

Top Ten Tips Palliative Clinicians Should Know About Rural Palliative Care in the United States.

Palliative care improves outcomes, yet rural residents often lack adequate and equitable access. This study provides practical tips to address palliative care (PC)-related challenges in rural communities. Strategies include engaging trusted community partners, addressing cultural factors, improving pediatric care, utilizing telehealth, networking with rural teams including caregivers, and expanding roles for nurses and advanced practice providers. Despite complex barriers to access, providers can tailor PC to be patient-centered, respect local values, and bridge gaps. The "Top 10" format emphasizes the relevant issues to enable clinicians to provide optimal care for people from rural areas.

Accuracy of the CNAP™ monitor, a noninvasive continuous blood pressure device, in providing beat-to-beat blood pressure readings in pediatric patients weighing 20-40 kilograms.

BACKGROUND: During perioperative care, the continuous measurement of blood pressure (BP) provides superior physiologic monitoring to intermittent techniques. However, such monitoring requires placement of an intraarterial catheter, which may be time-consuming or associated with adverse events and technical difficulty. A noninvasive, continuous BP monitoring device has been studied in the adult population. This study prospectively assesses its accuracy in pediatric patients, weighing 20-40 kg. METHODS: The technology evaluated is the CNAP™ Monitor 500, developed by CNSystems AG (Graz, Austria). The study cohort included pediatric patients weighing between 20 and 40 kg, scheduled for surgery for which arterial line (AL) placement was planned. Systolic (sBP), diastolic (dBP), and mean arterial (MAP) blood pressure readings were captured from the AL and the CNAP™ device every minute during anesthetic care. RESULTS: The study cohort consisted of 20 patients (11 weighing between 30 and 40 kg and 9 weighing between 20 and 29.9 kg) with a mean age of 9.8 ± 3.4 years (range, 6-16 years) and weight of 29.8 ± 6.1 kg (range, 20.9-38.7 kg). There were a total of 1076 pairs each of sBP, dBP, and MAP values in the 20-29.9 kg group. The absolute difference between the sBP, dBP, and MAP was 9.8 ± 8.5, 6.8 ± 5.3, and 6.7 ± 6.2 mmHg, respectively. The correlation coefficient between the AL and the CNAP™ device was 0.48, 0.60, and 0.64 for the sBP, dBP, and MAP, respectively. The CNAP™ values (sBP, dBP, MAP) were ≤5 mmHg from the AL values in 38.6%, 48.5%, and 55.0% of the values, respectively. In the 30-40 kg group, there were a total of 2737 pairs of sBP, dBP, and MAP values. The absolute difference between the sBP, dBP, and MAP was 11.5 ± 9.3, 7.5 ± 5.3, and 7.9 ± 6.6 mmHg, respectively. The correlation coefficient between the arterial cannula and the CNAP™ device was 0.48, 0.45, and 0.51 for the sBP, dBP, and MAP, respectively. CNAP™ readings were ≤5 mmHg from the AL values (sBP, dBP, MAP) in 29.0%, 41.9%, and 40.5% of the values, respectively. CONCLUSION: Although some variation in its accuracy was noted, the CNAP™ device provides a noninvasive and continuous blood pressure reading which appears to be within clinically useful limits. It may be that modification of the finger cuffs is needed to improve its absolute accuracy as our clinical experience demonstrated that achieving an effective fit with the cuffs was at times difficult.

Signs and Behaviors to Identify Impairment and Drug Diversion.

Substance use disorder in health care professionals may adversely affect patient care. To reduce the risks of harm, raising awareness among all staff for early identification and response is a primary goal. Knowledgeable co-workers play an essential role to identify signs and behaviors indicating at-risk substance use by observed impairment or suspicion of drug diversion and report to a supervisor. Response protocol for a timely, confidential, safe and non-punitive intervention can help connect the clinician to needed assessment and treatment help and potentially save a life and provide a hopeful outcome to retain their license and career.

The siRNA sequence and guide strand overhangs are determinants of in vivo duration of silencing.

The use of short interfering RNAs (siRNA) in animals for target validation or as potential therapeutics is hindered by the short physical half-life when delivered as unencapsulated material and in turn the short active half-life of siRNAs in vivo. Here we demonstrate that the character of the two 3'-overhang nucleotides of the guide strand of siRNAs is a determinant of the duration of silencing by siRNAs both in vivo and in tissue culture cells. We demonstrate that deoxyribonucleotides in the guide strand overhang of siRNAs have a negative impact on maintenance of both the in vitro and in vivo activity of siRNAs over time. Overhangs that contain ribonucleotides or 2'-O-methyl modified nucleotides do not demonstrate this same impairment. We also demonstrate that the sequence of an siRNA is a determinant of the duration of silencing of siRNAs directed against the same target even when those siRNAs have equivalent activities in vitro. Our experiments have determined that a measurable duration parameter exists, distinct from both maximum silencing ability and the potency of siRNAs. Our findings provide information on incorporating chemically modified nucleotides into siRNAs for potent, durable therapeutics and also inform on methods used to select siRNAs for therapeutic and research purposes.

siRNA-induced liver ApoB knockdown lowers serum LDL-cholesterol in a mouse model with human-like serum lipids.

Increased serum apolipoprotein (apo)B and associated LDL levels are well-correlated with an increased risk of coronary disease. ApoE⁻/⁻ and low density lipoprotein receptor (LDLr)⁻/⁻ mice have been extensively used for studies of coronary atherosclerosis. These animals show atherosclerotic lesions similar to those in humans, but their serum lipids are low in apoB-containing LDL particles. We describe the development of a new mouse model with a human-like lipid profile. Ldlr CETP⁺/⁻ hemizygous mice carry a single copy of the human CETP transgene and a single copy of a LDL receptor mutation. To evaluate the apoB pathways in this mouse model, we used novel short-interfering RNAs (siRNA) formulated in lipid nanoparticles (LNP). ApoB siRNAs induced up to 95% reduction of liver ApoB mRNA and serum apoB protein, and a significant lowering of serum LDL in Ldlr CETP⁺/⁻ mice. ApoB targeting is specific and dose-dependent, and it shows lipid-lowering effects for over three weeks. Although specific triglycerides (TG) were affected by ApoB mRNA knockdown (KD) and the total plasma lipid levels were decreased by 70%, the overall lipid distribution did not change. Results presented here demonstrate a new mouse model for investigating additional targets within the ApoB pathways using the siRNA modality.

Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity.

BRAF(V600E) is the most frequent oncogenic protein kinase mutation known. Furthermore, inhibitors targeting "active" protein kinases have demonstrated significant utility in the therapeutic repertoire against cancer. Therefore, we pursued the development of specific kinase inhibitors targeting B-Raf, and the V600E allele in particular. By using a structure-guided discovery approach, a potent and selective inhibitor of active B-Raf has been discovered. PLX4720, a 7-azaindole derivative that inhibits B-Raf(V600E) with an IC(50) of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 preferentially inhibits the active B-Raf(V600E) kinase compared with a broad spectrum of other kinases, and potent cytotoxic effects are also exclusive to cells bearing the V600E allele. Consistent with the high degree of selectivity, ERK phosphorylation is potently inhibited by PLX4720 in B-Raf(V600E)-bearing tumor cell lines but not in cells lacking oncogenic B-Raf. In melanoma models, PLX4720 induces cell cycle arrest and apoptosis exclusively in B-Raf(V600E)-positive cells. In B-Raf(V600E)-dependent tumor xenograft models, orally dosed PLX4720 causes significant tumor growth delays, including tumor regressions, without evidence of toxicity. The work described here represents the entire discovery process, from initial identification through structural and biological studies in animal models to a promising therapeutic for testing in cancer patients bearing B-Raf(V600E)-driven tumors.