Evaluation of Treatment Patterns and Maintenance Dose Titration Among Patients With Crohn's Disease Initiating Biologics With 3 Years of Follow-Up.

Background: There is limited real-world evidence on treatment patterns of patients with Crohn's disease (CD) initiating biologics with an extensive follow-up period. This study describes persistence and dose titration among CD patients with 3 years of follow-up. Methods: This retrospective observational study was conducted using the STATinMED RWD Insights all-payer medical and pharmacy data. Adult patients with at least 1 CD medical claim and at least 1 medical/pharmacy claim for a biologic (adalimumab [ADA], certolizumab pegol (CZP), infliximab [IFX] and its biosimilar products [IFX-BS], ustekinumab [UST], and vedolizumab [VDZ]) between September 2016 and October 2018 were identified. Commercially insured patients with continuous capture for at least 12 months before and at least 36 months after biologics initiation were selected. Confirmed CD patients were included in the final cohort. Baseline patient characteristics and treatment patterns over the 3-year follow-up period were evaluated. Results were summarized using means and SD or counts and percentages. Results: A total of 2309 confirmed patients with CD were identified (847 [36.7%] IFX, 534 [23.1%] ADA, 486 [21.1%] VDZ, 394 [17.1%] UST, 85 [3.7%] CZP, and 72 [3.1%] IFX-BS). CZP and IFX-BS were excluded due to small sample sizes. Approximately half of CD patients were between ages 35 and 54. Patients on UST had a higher Charlson Comorbidity Index score. Common comorbidities (>10%) included anemia, anxiety, depression, and hypertension. Persistence over 3 years' follow-up was highest for UST (61.4%) patients, followed by VDZ (58.0% ), ADA (52.1% , and IFX (48.1%). The discontinuation rate without switch or restart was highest for ADA (37.3%), followed by UST (30.7%), IFX (28.1%), and VDZ (25.3%). Over the 3 years of follow-up, the dose titration rate was highest for IFX (76.5%) and lowest for UST (50.8%). In particular, UST had the lowest dose escalation rate (35.5%) and highest dose-reduction rate (16.5%). Conclusions: Patients with CD on UST had the highest persistence and lowest dose escalation across different biologic users over the 3-year follow-up period, possibly suggesting a better clinical response of UST. Future studies with longer follow-up adjusting for confounders are needed to better understand treatment patterns among biologics users.

Motivational Guest Speaker Presentation as an Anti-Stigma Intervention for US Army Soldiers.

Stigma towards mental illness represents a significant challenge. No specific anti-stigma military training curricula currently exists. An infantry division sought to reduce stigma by inviting 2 guest speakers to address Soldiers. The intervention was designed on social contact theory and executed as a quality improvement project. The intervention was speakers self-disclosing their own mental health struggles and having the audience contact with persons from the stigmatized group. Postintervention evaluation (N=361) demonstrated significant reduction in stigma scores (t=8.128, df=329, P<.001, 2-tailed, d=0.3), and effect size was greatest (d=1.17) among those with greater baseline stigma scores. Soldiers also reported positive perceptions of help-seeking behaviors. Given these findings, other units could conduct these type of training events to target stigma toward mental illness.

Risk stratification of survival in injured patients with cardiopulmonary resuscitation within the first hour of arrival to trauma centre: retrospective analysis from the national trauma data bank.

BACKGROUND: The purpose of this study was to evaluate overall survival and associated survival factors for patients with trauma who had cardiopulmonary resuscitation (CPR) within 1 hour after arrival to a hospital. METHODS: Retrospective patient data was retrieved from the 2007-2010 edition of the US National Trauma Data Bank. Inhospital survival was the primary outcome; only patients with a known outcome were included in the analysis. Summary statistics and univariate analyses were first reported. Eighty per cent of the patients were then randomly selected and used for multivariate logistic regression analysis. The identified risk factors were further assessed for discrimination and calibration with the remaining patients with trauma using area under the curve (AUC) analysis and a Hosmer-Lemeshow test. RESULTS: From 19 310 total cases that were reviewed, only 2640 patients required CPR within 1 hour of hospital arrival and met the additional inclusion criteria. Of these patients, 2309 (87.5%) died and 331 (12.5%) survived to discharge. There were statistical differences for race (p=0.003), initial systolic BP (p<0.001), initial pulse (p<0.001), cause of injury (p<0.001), presence of head injury (p=0.02), Injury Severity Score (ISS) (p<0.001), Glasgow Coma Scale (GCS) total score (p<0.001) and GCS motor score (p<0.001); though not all were clinically significant. The multiple logistic regression model (AUC=0.72) identified lower ISS, higher GCS motor score, Caucasian race, American College of Surgeons (ACS) level 2 trauma designation and higher initial SBP as the most predictive of survival to hospital discharge. CONCLUSION: Approximately 13% of patients who had CPR within an hour of arrival to a trauma centre survived their injury. Therefore, implementation of an aggressive first hour in-hospital resuscitation strategy may result in better survival outcomes for this patient population.

Gene expression of catabolic inflammatory cytokines peak before anabolic inflammatory cytokines after ACL injury in a preclinical model.

BACKGROUND: The response of the joint to anterior cruciate ligament (ACL) injury has not been fully characterized. In particular, the characterization of both catabolic factors, including interleukin-6 (IL-6), interleukin-8 (IL-8), and markers of ongoing tissue damage (CRP), and anabolic factors, including vascular endothelial growth factor (VEGF), transforming growth factor ß-induced (TGFßI), and the presence of CD163+ macrophages, have not been well defined. In this study, we hypothesized ACL injury would catalyze both catabolic and anabolic processes and that these would have different temporal profiles of expression. METHODS: Adolescent Yucatan minipigs were subjected to ACL transection. Within the joint, gene expression levels of IL-6, IL-8, VEGF, and TGFßI were quantified in the synovium, ligament, and provisional scaffold located between the torn ligament ends at days 1, 5, 9, and 14 post-injury. Macrophage infiltration was also assessed in the joint tissues over the two week period. Serum C-reactive protein (CRP) levels were measured at multiple time points between 1 hour to 14 days after injury. RESULTS: Increases in IL-6 and IL-8 gene expression peaked at day 1 after injury in the synovium and ligament. CRP levels were significantly increased at day 3 before returning to pre-injury levels. VEGF and TGFßI gene expression did not significantly increase until day 9 in the synovium and were unchanged in the other tissues. CD163+ macrophages increased in the ligament and synovium until day 9. CONCLUSION: Taken together, these results suggest that the response within the joint is primarily catabolic in the first three days after injury, switching to a more anabolic phase by nine days after injury. The effect of medications which alter these processes may thus depend on the timing of administration after injury.

Expression of modulators of extracellular matrix structure after anterior cruciate ligament injury.

The ability of the anterior cruciate ligament (ACL) to heal after injury declines within the first 2 weeks after ACL rupture. To begin to explore the mechanism behind this finding, we quantified the expression of genes for collagen I and III, decorin, tenascin-C, and alpha smooth muscle actin, as well as matrix metalloproteinase (MMP)-1 and -13 gene expression within multiple tissues of the knee joint after ACL injury in a large animal model over a 2-week postinjury period. Gene expression of collagen I and III, decorin, and MMP-1 was highest in the synovium, whereas the highest MMP-13 gene expression levels were found in the ACL. The gene expression for collagen and decorin increased over the 2 weeks to levels approaching that in the ligament and synovium; however, no significant increase in either of the MMPs was found in the provisional scaffold. This suggests that although the ACL and synovium up-regulate both anabolic and catabolic factors, the provisional scaffold is primarily anabolic in function. The relative lack of provisional scaffold formation within the joint environment may thus be one of the key reasons for ACL degradation after injury.

Outcomes in hospitalized pediatric patients with systemic lupus erythematosus.

OBJECTIVE: Disparities in outcomes among adults with systemic lupus erythematosus (SLE) have been documented. We investigated associations between sociodemographic factors and volume of annual inpatient hospital admissions with hospitalization characteristics and poor outcomes among patients with childhood-onset SLE. METHODS: By using the Pediatric Health Information System, we analyzed admissions for patients aged 3 to <18 years at index admission with ≥ 1 International Classification of Diseases, Ninth Revision code for SLE from January 2006 to September 2011. Summary statistics and univariable analyses were used to examine demographic characteristics of hospital admissions, readmissions, and lengths of stay. We used multivariable logistic regression analyses, controlling for patient gender, age, race, ethnicity, insurance type, hospital volume, US census region, and severity of illness, to examine risk factors for poor outcomes. RESULTS: A total of 10,724 admissions occurred among 2775 patients over the study period. Hispanic patients had longer lengths of stay, more readmissions, and higher in-hospital mortality. In multivariable analysis, African American race was significantly associated with ICU admission. African American race and Hispanic ethnicity were associated with end-stage renal disease and death. Volume of patients with SLE per hospital and hospital location were not significantly associated with outcomes. CONCLUSIONS: In this cohort of hospitalized children with SLE, race and ethnicity were associated with outcomes. Further studies are needed to elucidate the relationship between sociodemographic factors and poor outcomes in patients with childhood-onset SLE.

Ultrasonography-guided bilateral rectus sheath block vs local anesthetic infiltration after pediatric umbilical hernia repair: a prospective randomized clinical trial.

IMPORTANCE: Regional anesthetic techniques can be used to alleviate postoperative pain in children undergoing pediatric surgical procedures. Use of ultrasonographic guidance for bilateral rectus sheath block (BRSB) has been shown to improve immediate pain scores and reduce use of postoperative analgesia in the postanesthesia care unit (PACU). OBJECTIVE: To compare efficacy of ultrasonography-guided BRSB and local anesthetic infiltration (LAI) in providing postoperative analgesia after pediatric umbilical hernia repair. DESIGN: Prospective, observer-blinded, randomized clinical trial. SETTING: Tertiary-referral urban children's hospital. PARTICIPANTS: Eligible children 3 to 12 years of age undergoing elective umbilical hernia repair from November 16, 2009, through May 31, 2011. INTERVENTIONS: Ropivacaine hydrochloride administered at the conclusion of surgery as LAI by the surgeon (n = 25) or as ultrasonography-guided BRSB by the anesthesiologist (n = 27). MAIN OUTCOMES AND MEASURES: Scores on the FACES Pain Rating Scale measured at 10-minute intervals and all use of analgesic medications in the PACU. RESULTS: Median FACES scores in the PACU were lower in the BRSB group compared with the LAI group at 10 minutes (0 vs 1; P = .04), 30 minutes (0 vs 1; P = .01), and 40 minutes or later (0 vs 1; P = .03). Fewer doses of opioid and nonopioid medications were given to the BRSB group compared with the LAI group (5 vs 11 doses for opioids; 5 vs 10 for nonopioids). CONCLUSIONS AND RELEVANCE: In the PACU, ultrasonography-guided BRSB after umbilical hernia repair in children is associated with lower median FACES scores and decreased use of opioid and nonopioid medications compared with LAI. Future studies could examine the use of longer-acting anesthetic agents with ultrasonography-guided BRSB. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01015053.

Biostatistics in clinical decision making for cardiothoracic radiologists.

Cardiothoracic radiologists are intuitively aware of sensitivity and specificity as they pertain to diagnostic tests involving clinical information. However, many cardiothoracic radiologists are unfamiliar with odds ratios, likelihood ratios, predictive values, and receiver operating characteristic (ROC) curves, which provide more information about the performance of a test. Our article will first review the fundamental concepts of sensitivity, specificity, predictive values, and likelihood ratios. The ROC curve methodology will be covered with an emphasis on creating a look-up table, a straightforward table that communicates important information to the clinician to aid in diagnosis. The article reviews sensitivity and specificity, as well as predictive values, logistic regression, and ROC curves, using conceptual principles without unnecessary mathematical rigor. We will apply principles of sensitivity and specificity to continuous measurements by constructing ROC curves in order to tie together key ideas in diagnostic decision making. Three clinical examples are presented to illustrate these fundamental statistical concepts: predictors of pulmonary embolism in children, use of dobutamine-cardiac magnetic resonance imaging to identify impaired ventricular function in patients who have suffered a myocardial infarction, and diagnostic accuracy of 64-multidetector row computed tomography to identify occluded vessels in adult patients with suspected coronary artery disease. In addition, a glossary is provided at the end of the article with key terms important in diagnostic imaging. An understanding of the concepts presented will assist cardiothoracic radiologists in critically discerning the usefulness of diagnostic tests and how these statistics can be applied to make judgments and decisions that are essential to clinical practice.

Progressive structural and biomechanical changes in elastin degraded aorta.

Aortic aneurysm is an important clinical condition characterized by common structural changes such as the degradation of elastin, loss of smooth muscle cells, and increased deposition of fibrillary collagen. With the goal of investigating the relationship between the mechanical behavior and the structural/biochemical composition of an artery, this study used a simple chemical degradation model of aneurysm and investigated the progressive changes in mechanical properties. Porcine thoracic aortas were digested in a mild solution of purified elastase (5 U/mL) for 6, 12, 24, 48, and 96 h. Initial size measurements show that disruption of the elastin structure leads to increased artery dilation in the absence of periodic loading. The mechanical properties of the digested arteries, measured with a biaxial tensile testing device, progress through four distinct stages termed (1) initial-softening, (2) elastomer-like, (3) extensible-but-stiff, and (4) collagen-scaffold-like. While stages 1, 3, and 4 are expected as a result of elastin degradation, the S-shaped stress versus strain behavior of the aorta resulting from enzyme digestion has not been reported previously. Our results suggest that gradual changes in the structure of elastin in the artery can lead to a progression through different mechanical properties and thus reveal the potential existence of an important transition stage that could contribute to artery dilation during aneurysm formation.

Congenital diaphragmatic hernia associated with esophageal atresia: incidence, outcomes, and determinants of mortality.

BACKGROUND: Congenital diaphragmatic hernia (CDH) and esophageal atresia (EA) are fairly common congenital anomalies, but the occurrence of both is exceedingly rare, with only anecdotal cases reported in the English literature. The primary objective of the current study is to assess the incidence and outcomes of CDH/EA using the Congenital Diaphragmatic Hernia Study Group registry. STUDY DESIGN: The Congenital Diaphragmatic Hernia Study Group registry was queried from January 2000 through August 2011. Patients with CDH/EA were identified. The primary end point was survival and the secondary end point was seeking to identify variables that might explain variances in outcomes. RESULTS: During the study period, 4,888 patients were reported to the Congenital Diaphragmatic Hernia Study Group registry. Twenty-three (0.5%) had an associated EA, with an overall survival significantly lower than the registry mean (26.1% vs 70.3%; p < 0.001). These patients had significantly lower birth weights (1.8 vs 2.94 kg), more cardiac abnormalities, and more chromosomal abnormalities (p < 0.001). Only 6 of the 23 CDH/EA patients had a CDH repair. In addition, the cohort had significantly fewer primary CDH repairs (4.3% vs 39.3%; p < 0.001). Logistic regression analysis identified birth weight, cardiac abnormalities, repair, and surfactant administration to be significantly associated with adverse outcomes. Esophageal atresia was the only variable not independently associated with survival. CONCLUSIONS: In patients with both CDH and EA, survival is significantly lower than other patients with CDH, but not uniformly lethal, therefore, intent to treat is a viable approach. Although the association of CDH with EA has a substantial impact on survival, it is the presence of low birth weight, cardiac and chromosomal abnormalities, surfactant use, and larger defects--and not the mere presence of EA--that influences the outcomes of this unique cohort.

Physical activity level improves after periacetabular osteotomy for the treatment of symptomatic hip dysplasia.

BACKGROUND: Hip pain secondary to acetabular dysplasia can prevent participation in recreational activities. QUESTIONS/PURPOSES: We retrospectively evaluated the physical activity level and pain after periacetabular osteotomy (PAO) for the treatment of symptomatic hip dysplasia. METHODS: Forty-seven female and four male patients with a mean age of 27 years underwent a PAO. Physical activity (UCLA) and pain (WOMAC) were assessed preoperatively, at 1 year, and at minimum 2 years postoperatively. Multivariable linear regression identified substantial, independent factors associated with postoperative activity level. RESULTS: The UCLA activity scores were on average higher at 1 year and remained higher at minimum 2 years when compared with preoperative scores. Mean postoperative WOMAC pain scores assessed at 1 year and at least 2 years were lower than mean preoperative scores. Age and preoperative physical activity level were strong independent predictors for activity level at 1 year and at minimum 2 years after surgery. Postoperative pain level was a moderate predictor for the level of activity at minimum 2-year followup. CONCLUSIONS: Physical activity level improves after PAO. Younger age and higher activity levels before surgery and lower level of pain after surgery are predictive factors for postoperative level of activity in the short term. The data presented here may be useful to counsel the active young adult with symptomatic hip dysplasia about the improvement of level of activity to be expected after PAO. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Injuries in Irish dance.

Irish dance is growing in popularity and competitiveness; however, very little research has focused specifically on this genre of dance. The purpose of this study was to analyze the types of dance injuries incurred by Irish dancers. A chart review was performed to identify all injuries associated with Irish dance seen in the sports medicine or orthopaedic clinics at the investigators' hospital over an 11-year period. "Injury" was defined as any dance-related pain or disorder that led to evaluation in the clinics. Survey data were also collected from study participants. Ultimately, 255 patients from over 30 different schools of dance were seen with injuries directly related (726 clinic visits) or partially related (199 visits) to Irish dance. Participants ranged in age from 4 to 47, with 95% (243/255) under the age of 19. These 255 patients received 437 diagnoses. Almost 80% of the injuries (348/437) were attributable to overuse, and 20.4% were acute and traumatic injuries (89/437). Ninety-five percent (95.9%) of injuries involved the hip or lower extremity. The most common sites were the foot (33.2%), ankle (22.7%), knee (19.7%), and hip (14.4%). Typical diagnoses were tendon injury (13.3%), apophysitis (11.4%), patellofemoral pain and instability (10.8%), stress injury (10.1%), and muscle injury (7.8%). The majority of traumatic injuries were seen in clinic within 3 weeks, but less than a quarter of overuse injuries were seen that quickly. The most common treatment, prescribed to 84.3% of patients, was physical therapy and home exercises, and the majority of dancers (64.3%) were able to return to full dance activity after injury.

Risk factors for small bowel bacterial overgrowth and diagnostic yield of duodenal aspirates in children with intestinal failure: a retrospective review.

BACKGROUND: Children with intestinal failure (IF) are at risk for small bowel bacterial overgrowth (SBBO) because of anatomical and other factors. We sought to identify risk factors for SBBO confirmed by quantitative duodenal culture. METHODS: A single-center retrospective record review of children who had undergone endoscopic evaluation for SBBO (defined as bacterial growth in duodenal fluid of >10(5) colony-forming unit per mL) was performed. RESULTS: We reviewed 57 children with median (25th-75th percentile) age 5.0 (2.0-9.2) years. Diagnoses included motility disorders (28%), necrotizing enterocolitis (16%), atresias (16%), gastroschisis (14%), and Hirschsprung disease (10.5%). Forty patients (70%) had confirmed SBBO. Univariate analysis showed no significant differences between patients with and without SBBO for the following variables: age, sex, diagnosis, presence of ileocecal valve, and antacid use. Patients receiving parenteral nutrition (PN) were more likely to have SBBO (70% vs 35%, P = .02). Multiple logistic regression analysis confirmed that PN administration was independently associated with SBBO (adjusted odds ratio, 5.1; adjusted 95% confidence interval, 1.4-18.3; P = .01). SBBO was not related to subsequent risk of catheter-related bloodstream infection (CRBSI). CONCLUSION: SBBO is strongly and independently associated with PN use. Larger prospective cohorts and more systematic sampling techniques are needed to better determine the relationship between SBBO and gastrointestinal function.

Pulmonary embolism detected by pulmonary MDCT angiography in older children and young adults: risk factor assessment.

OBJECTIVE: The purpose of this article is to determine the risk factors for pulmonary embolism (PE) among older children and young adults who underwent pulmonary CT angiography (CTA) for evaluation of clinically suspected PE. MATERIALS AND METHODS: We used our hospital information system to retrospectively identify all consecutive patients 19-25 years old who underwent pulmonary CTA for evaluation of clinically suspected PE between July 2004 and March 2011. Two experienced pediatric radiologists retrospectively and independently reviewed a series of 116 consecutive pulmonary CTA studies from this population. Each examination was reviewed for the presence of PE. Seven possible risk factors (immobilization, prior PE or deep venous thrombosis [DVT], cardiac disease, malignancy, hypercoagulable state, excess estrogen, and central venous line placement) were compared between patients with and without PE using univariate statistics, including Student t test and Pearson chi-square test. Multiple logistic regression modeling was used to identify independent risk factors for PE. Receiver operating characteristic curve analysis was applied to determine the optimal cutoff number of risk factors for predicting a pulmonary CTA result positive for PE. RESULTS: The study population consisted of 116 patients (34 men and 82 women; mean age, 20.7 ± 1.8 years; range, 18.6-25.4 years) who underwent a total of 116 pulmonary CTA studies. Sixteen (14%) of 116 patients were found to have PE on pulmonary CTA. The level of involvement of PE was segmental in 16 of 31 PEs (52%), lobar in eight (26%), subsegmental in five (16%), and main or central in two (6%). Three risk factors--immobilization (p < 0.001), history of prior PE or DVT (p = 0.001), and cardiac disease (p = 0.004)--were found to be significant independent risk factors for the presence of PE detected by pulmonary CTA. When two or more risk factors were used as the clinical threshold, the sensitivity for positive PE was 75% (12/16 patients) and the specificity was 99% (99/100 patients). CONCLUSION: The use of risk factor assessment as a first-line triage tool has the potential to guide more appropriate use of pulmonary CTA in this population, with potential associated reductions in radiation exposure and costs.

Hemodynamic changes during spinal anesthesia in premature infants with congenital heart disease undergoing inguinal hernia correction.

INTRODUCTION: There are conflicting reports on the effects of spinal anesthesia (SA) on hemodynamics. Data on the hemodynamic effects of SA in infants with congenital heart disease (CHD) are limited. METHODS: We reviewed our experience with 44 unsupplemented SA with 1 mg·kg(-1) of either hyperbaric tetracaine or bupivacaine in premature and former premature infants with noncyanotic CHD. Hemodynamics and oxyhemoglobin saturation (SpO(2)) were assessed. Neither preoperative fluid boluses nor atropine was administered to any of the infants. RESULTS: There was no significant change in systolic, diastolic, or mean blood pressures from pre-SA induction compared with end of surgery. Heart rate showed a small but systematic decline (mean change of 10 beats per minute, P < 0.01) but was within the normative range values for age. There was a small, but clinically insignificant increase in SpO(2) across the time course. Intraoperatively, two infants developed transient apneic spells. No infant developed postoperative apnea, oxygen desaturation, or bradycardia. CONCLUSIONS: The data suggest that SA with 1 mg·kg(-1) of either hyperbaric tetracaine or bupivacaine can be used safely as the sole anesthetic for inguinal hernia repair in infants with noncyanotic CHD even when fluid restricted and apparently causes minimal respiratory complications in these infants.

Resting energy expenditure after Fontan surgery in children with single-ventricle heart defects.

BACKGROUND: Data on resting energy expenditure (REE) and oxygen consumption (VO(2)) after pediatric cardiopulmonary bypass (CPB) will facilitate optimal nutrient prescription. METHODS: The authors measured continuous REE and VO(2), using an in-line indirect calorimetery (IC) in 30 consecutive children with single-ventricle physiology immediately after Fontan surgery. REE during steady state at 8 hours after surgery was compared with standard equation-estimated energy expenditure (EEE). Patients were classified into 3 groups: hypermetabolic (measured REE [MREE]/EEE ratio >1.2), hypometabolic (MREE/EEE ratio <0.8), and normometabolic (MREE/EEE ratio 0.8-1.2). Demographic, anthropometric, and perioperative clinical characteristics were examined for their correlation with metabolic status. RESULTS: In 26 of 30 patients with completed IC, mean REE at 8 hours after surgery was 57 ± 20 kcal/kg/d, and mean VO(2) was 110 ± 35 mL/min. Mean values of VO(2) and REE did not change within the first 24 hours after surgery. There was poor correlation between MREE at 8 hours and the EEE using the World Health Organization equation (r = 0.32, P = .11). Most patients (n = 19, 73%) were either normometabolic or hypometabolic. Lack of hypermetabolism was significantly associated with higher intraoperative serum lactate level and positive fluid balance compared with the rest of the group. CONCLUSIONS: The authors report a low prevalence of hypermetabolism in children with single-ventricle defects after Fontan surgery. Measured REE had poor correlation with equation-estimated energy expenditure in a majority of the cohort. The absence of increased energy expenditure after CPB will influence energy prescription in this group.

Respiratory, neuromuscular, and cardiovascular effects of neosaxitoxin in isoflurane-anesthetized sheep.

BACKGROUND: Neosaxitoxin (NeoSTX) is a potent site-1 sodium-channel blocker being developed as a local anesthetic. Doses of 100 µg have been used by local infiltration in anesthetized adult humans without adverse effect. We hypothesized that similar doses could cause significant respiratory, neuromuscular, and cardiovascular impairment and sought to test this hypothesis in sheep. METHODS: Procedures were approved by the Institutional Animal Care and Use Committee. In neuromuscular/respiratory experiments, 33 intubated, isoflurane-anesthetized sheep were randomized to 6 NeoSTX treatment groups: saline control, 1 µg/kg subcutaneous (SC), 1 µg/kg intravenous (IV), 2 µg/kg SC, 2 µg/kg SC with bupivacaine 0.25%, and 3 µg/kg SC. Primary outcome measures were doxapram-stimulated inspired volume (DSIV) and quantitative limb acceleration. In cardiovascular experiments, 8 sheep received escalating IV doses of NeoSTX (1, 2, and 3 µg), with hemodynamic and electrocardiographic measurements. Data were analyzed using repeated-measures analysis of variance with post hoc Bonferroni-corrected comparisons. RESULTS: NeoSTX 1 µg/kg IV and SC produced no significant reduction in DSIV or limb acceleration compared with baseline. NeoSTX 2 µg/kg SC produced clinically mild reduction in twitch and DSIV; animals recovered well postoperatively. Coadministration of bupivacaine did not worsen these effects. NeoSTX 3 µg/kg produced severe and prolonged impairment of DSIV and limb acceleration. Escalating IV doses of NeoSTX produced mild decrements in heart rate, systemic arterial pressure, and systemic vascular resistance; cardiac output was maintained. Transient interventricular conduction delay occurred without cardiac arrest or ventricular ectopy. CONCLUSIONS: In our sheep model, neuromuscular, respiratory, and cardiovascular effects of NeoSTX were dose dependent and mild using the dose range anticipated for clinical use.

Children suspected of having pulmonary embolism: multidetector CT pulmonary angiography--thromboembolic risk factors and implications for appropriate use.

PURPOSE: To evaluate thromboembolic risk factors for pulmonary embolism (PE) detected by using computed tomographic (CT) pulmonary angiography in children and to determine whether such information could be used for more appropriate use of CT pulmonary angiography in this patient population. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant retrospective study and waived the need for patient informed consent. Two hundred twenty-seven consecutive CT pulmonary angiography studies in 227 pediatric patients who underwent CT pulmonary angiography for clinically suspected PE at a single large pediatric referral hospital between July 2004 and March 2011 were evaluated. Age, sex, referral setting, and D-dimer result, as well as seven possible risk factors, were compared between patients with and those without PE. Multiple logistic regression modeling was used to identify the independent risk factors of PE. Receiver operating characteristic curve analysis was applied to determine the optimal cutoff number of risk factors for predicting a positive CT pulmonary angiography result for PE in children. RESULTS: Thirty-six (16%) of 227 CT pulmonary angiography studies were positive for PE. Five risk factors, including immobilization (P < .001), hypercoagulable state (P = .003), excess estrogen state (P = .002), indwelling central venous line (P < .001), and prior PE and/or deep venous thrombosis (P < .001), were found to be significant independent risk factors for PE. With use of two or more risk factors as the clinical threshold, the sensitivity of a positive PE result was 89% (32 of 36 patients), and the specificity was 94% (180 of 191 patients). CONCLUSION: It is unlikely for CT pulmonary angiography results to be positive for PE in children with no thromboembolic risk factors. The use of risk factor assessment as a first-line triage tool has the potential to guide more appropriate use of CT pulmonary angiography in children, with associated reductions in radiation exposure and costs.

Effects of age and platelet-rich plasma on ACL cell viability and collagen gene expression.

Platelet-rich plasma (PRP) has shown in vivo potential to stimulate anterior cruciate ligament (ACL) healing at early time points in large animal models. However, in animal models, the healing potential of the ACL is dependent on animal age. In this study, we hypothesized that there are age-dependent differences in ACL cell metabolism, collagen gene expression, and the ability of the cells to respond to growth factors in PRP. To test this hypothesis, ACL cells were obtained from skeletally immature, adolescent and adult pigs, and cultured in a collagen type I hydrogel with or without PRP for 14 days. When cultured in collagen-only hydrogel, ACL cells from adult pigs had a 19% lower apoptotic rate as compared to immature pigs (p = 0.001) and a 25% higher cellular metabolic activity as compared to adolescent pigs (p = 0.006). The addition of PRP to the collagen hydrogel resulted in a significantly increased cellular metabolic activity, reduced apoptotic rate, and stimulation of collagen production in the cells from the immature and adolescent animals (p < 0.05 for all comparisons) but had less effect on adult cells. These findings suggest that skeletal maturity may influence ACL cells' metabolic activity, apoptosis, collagen production, and response to PRP.

P wave duration and risk of longitudinal atrial fibrillation in persons ≥ 60 years old (from the Framingham Heart Study).

Long-term risk prediction is a priority for the prevention of atrial fibrillation (AF). P wave indices are electrocardiographic measurements describing atrial conduction. The role of P wave indices in the prospective determination of AF and mortality risk has had limited assessment. We quantified by digital caliper the P wave indices of maximum duration and dispersion in 1,550 Framingham Heart Study participants ≥ 60 years old (58% women) from single-channel electrocardiograms recorded from 1968 through 1971. We examined the association of selected P wave indices and long-term outcomes using Cox proportional hazards regression incorporating age, gender, body mass index, systolic blood pressure, treatment for hypertension, significant murmur, heart failure, and PR interval. Over a median follow-up of 15.8 years (range 0 to 38.7), 359 participants developed AF and 1,525 died. Multivariable-adjusted hazard ratios (HRs) per SD increase in maximum P wave duration were 1.15 (95% confidence interval [CI] 0.90 to 1.47, p = 0.27) for AF and 1.02 (95% CI 0.96 to 1.08, p = 0.18) for mortality. The upper 5% of P wave maximum duration had a multivariable-adjusted HR of 2.51 (95% CI 1.13 to 5.57, p = 0.024) for AF and an HR of 1.11 (95% CI 0.87 to 1.40, p = 0.20) for mortality. We found no significant associations between P wave dispersion with incidence of AF or mortality. In conclusion, maximum P wave duration at the upper fifth percentile was associated with long-term AF risk in an elderly community-based cohort. P wave duration is an electrocardiographic endophenotype for AF.