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BackgroundGuidelines for sinus of Valsalva (SOV)-thoracic aortic aneurysms in Marfan syndrome recommend size-based criteria for elective surgical repair. Biomechanics may provide a better prediction of dissection risk than diameter. Our aim was to determine magnitudes of wall stress in the aortic root of Marfan patients using finite element analyses.MethodsForty-six Marfan patients underwent patient-specific 3-dimensional SOV-thoracic aortic aneurysm geometry reconstruction using imaging data. Finite element analyses were performed to determine wall stress distributions at SOV, sinotubular junction (STJ), and ascending aorta (AscAo) at systole.ResultsPeak circumferential stresses were 432.8 ± 111 kPa, 408.1 ± 88.3 kPa, and 321.9 ± 83.8 kPa at the SOV, STJ, and AscAo, respectively, with significant differences between SOV and AscAo (P < 3.08E-07), and STJ and AscAo (P < 2.26E-06). Peak longitudinal wall stresses were 352 ± 73.9 kPa, 277.5 ± 89.5 kPa, and 200.6 ± 81 kPa at SOV, STJ, and AscAo, respectively, with significant differences between SOV and STJ (P < 6.01E-06), SOV and AscAo (P < 9.79E-13), and STJ and AscAo (P < 3.34E-07). Diameter was not correlated to wall stresses. Comparison of wall stresses in aneurysm

OBJECTIVE This post hoc analysis evaluated the efficacy of galcanezumab for the prevention of migraine in patients with and without comorbid anxiety and/or depression. BACKGROUND Patients with migraine have a higher risk of anxiety and/or depression. Given the high prevalence of psychiatric symptoms and their potential negative prognostic impact, determining the efficacy of migraine treatments in patients with these comorbidities is important. METHODS The results of 2 phase 3 episodic migraine studies of patients with 4-14 migraine headache days (MHD) per month were pooled. A third chronic migraine study, which was evaluated separately, enrolled patients with ≥15 headache days per month, of which ≥8 had migraine-like features. Patients in all 3 studies were randomized 2:1:1 to placebo, galcanezumab 120 mg, or galcanezumab 240 mg. The efficacy of galcanezumab on migraine was measured in subgroups of patients with anxiety and/or depression (current or past) and patients without. A repeated measures model was used to compare treatment groups within each subgroup and to test for consistency of treatment effect across the anxiety/depression subgroups (subgroup-by-treatment interaction) during the double-blind treatment phases. RESULTS Among 1773 intent-to-treat patients with episodic migraine, both doses of galcanezumab demonstrated statistically significant improvements relative to placebo in overall number of MHD for the subgroups of patients with anxiety and/or depression (mean change difference from placebo [95% CI]: -2.07 [-2.81, -1.33] for galcanezumab 120 mg [P

Orofacial clefts and their management impose a substantial burden on patients, on their families, and on the health system. Under the current standard of care, affected patients are subjected to a lifelong journey of corrective surgeries and multidisciplinary management to replace bone and soft tissues, as well as restore esthetics and physiologic functions while restoring self-esteem and psychological health. Hence, a better understanding of the dynamic interplay of molecular signaling pathways at critical phases of palate development is necessary to pioneer novel prenatal interventions. Such pathways include transforming growth factor–β ( Tgfβ), sonic hedgehog ( Shh), wingless-integrated site ( Wnt)/β-catenin, bone morphogenetic protein ( Bmp), and fibroblast growth factor ( Fgf) and its associated receptors, among others. Here, we summarize commonly used surgical methods used to correct cleft defects postnatally. We also review the advances made in prenatal diagnostics of clefts through imaging and genomics and the various in utero surgical corrections that have been attempted thus far. An overview of how key mediators of signaling that drive palatogenesis are emphasized in the context of the framework and rationale for the development and testing of therapeutics in animal model systems and in humans is provided. The pros and cons of in utero therapies that can potentially restore molecular homeostasis needed for the proper growth and fusion of palatal shelves are presented. The theme advanced throughout this review is the need to develop preclinical molecular therapies that could ultimately be translated into human trials that can correct orofacial clefts at earlier stages of development.

Gender inequality in science, medicine, and dentistry remains a central concern for the biomedical research workforce today. Although progress in areas of inclusivity and gender diversity was reported, growth has been slow. Women still face multiple challenges in reaching higher ranks and leadership positions while maintaining holistic success in these fields. Within dental research and academia, we might observe trends toward a more balanced pipeline. However, women continue to face barriers in seeking leadership roles and achieving economic equity and scholarship recognition. In an effort to evaluate the status of women in dental research and academia, the authors examined the role of the International Association for Dental Research (IADR), a global research organization, which has improved awareness on gender inequality. The goal of this article is to review five crucial issues of gender inequality in oral health research and academics—workforce pipeline, economic inequality, workplace harassment, gender bias in scholarly productivity, and work-life balance—and to discuss proactive steps that the IADR has taken to promote gender equality. Providing networking and training opportunities through effective mentoring and coaching for women researchers, the IADR has developed a robust pipeline of women leaders while promoting gender equality for women in dental academia through a culture shift. As knowledge gaps remained on the levels of conscious and unconscious bias and sexist culture affecting women advancement in academics, as well as the intersectionality of gender with race, gender identity, ability status, sexual orientation, and cultural backgrounds, the IADR has recognized that further research is warranted.

Introduction Early detection and treatment of anastomotic leak may mitigate its consequences. Within an enhanced recovery setting, the subtle signs of a leak can be more apparent. There are multiple treatment options for anastomotic leak following anterior resection. This study aimed to determine when leaks are diagnosed in enhanced recovery, and whether the choice of intervention affects outcomes. Materials and methods We conducted a retrospective study of a prospectively maintained database of complications of anterior resections for rectal cancer in a district general hospital in the UK. Data were extracted on day of leak diagnosis, length of stay, intensive care admission, mortality and ileostomy reversal rate. Statistical analysis was performed using Student’s t, Mann–Whitney U and chi square tests. Results A total of 323 patients underwent anterior resection for colorectal cancer between 1 January 2007 and 1 October 2015. The leak rate was 10.8% (35/323). Patients were diagnosed in hospital with leaks on median day 4 compared with day 11 for patients diagnosed with leaks after readmission from home (P < 0.001). Defunctioned patients diagnosed with a leak had a longer median length of stay (24 vs 18.0 days, P = 0.31) but were more frequently managed non-operatively (100% vs 19.0%, P < 0.001) and had a lower admission rate to intensive care (9.5% vs 42.9%, P = 0.02) than patients who were not defunctioned at time of resection. Overall mortality from anastomotic leak was 2.9% (1/35). Ileostomies were reversed in 73.5% of patients (25/34). Discussion Enhanced recovery enables early diagnosis of leaks following anterior resection. Defunctioning of patients with anastomotic leak lowers mortality.

Objectives aPL are present in between 20 and 30% of patients with SLE. They can cause vascular events (VE) or pregnancy morbidity. aCL and anti-beta-2-glycoprotein I (anti-β2GPI) are measured in clinical practice. Domain I (DI) of β2GPI is the main site for aPL binding. We investigated the prevalence of IgG anti-DI, aCL and anti-β2GPI antibodies in early SLE and their association with mortality and development of VE. Methods Samples from 501 patients with SLE that had been obtained and stored early during their disease were tested for IgG anti-DI, aCL and anti-β2GPI antibodies by ELISA. LA status and history of VE were obtained by reviewing medical records. Kaplan–Meier analysis was used to investigate mortality and occurrence of VE, comparing groups with and without aPL in early disease. Results Of 501 patients, 190 (38%) had at least one of these aPL, of whom 112 had anti-DI alone. Of 276 patients with complete vascular history, 83 had experienced VE. The 39 patients who were double or triple-ELISA-positive for any combination of the three aPL were more likely to have or develop lupus anticoagulant (P Conclusion IgG anti-DI antibodies were present in early serum samples from 29% of patients and were more common than IgG aCL or anti-β2GPI. There was some evidence suggesting that double or triple-ELISA-positivity for these antibodies identified a group with worse outcomes.

Clefts of the lip and/or palate are the most prevalent orofacial birth defects occurring in about 1:700 live human births worldwide. Early postnatal surgical interventions are extensive and staged to bring about optimal growth and fusion of palatal shelves. Severe cleft defects pose a challenge to correct with surgery alone, resulting in complications and sequelae requiring life-long, multidisciplinary care. Advances made in materials science innovation, including scaffold-based delivery systems for precision tissue engineering, now offer new avenues for stimulating bone formation at the site of surgical correction for palatal clefts. In this study, we review the present scientific literature on key developmental events that can go awry in palate development and the common surgical practices and challenges faced in correcting cleft defects. How key osteoinductive pathways implicated in palatogenesis inform the design and optimization of constructs for cleft palate correction is discussed within the context of translation to humans. Finally, we highlight new osteogenic agents and innovative delivery systems with the potential to be adopted in engineering-based therapeutic approaches for the correction of palatal defects. IMPACT STATEMENT: Tissue-engineered scaffolds supplemented with osteogenic growth factors have attractive, largely unexplored possibilities to modulate molecular signaling networks relevant to driving palatogenesis in the context of congenital anomalies (e.g., cleft palate). Constructs that address this need may obviate current use of autologous bone grafts, thereby avoiding donor-site morbidity and other regenerative challenges in patients afflicted with palatal clefts. Combinations of biomaterials and drug delivery of diverse regenerative cues and biologics are currently transforming strategies exploited by engineers, scientists, and clinicians for palatal cleft repair.

BACKGROUND: Acute appendicitis is the most common surgical emergency in children. Differentiation of acute appendicitis from conditions that do not require operative management can be challenging in children. This study aimed to identify the optimum risk prediction model to stratify acute appendicitis risk in children. METHODS: We did a rapid review to identify acute appendicitis risk prediction models. A prospective, multicentre cohort study was then done to evaluate performance of these models. Children (aged 5-15 years) presenting with acute right iliac fossa pain in the UK and Ireland were included. For each model, score cutoff thresholds were systematically varied to identify the best achievable specificity while maintaining a failure rate (ie, proportion of patients identified as low risk who had acute appendicitis) less than 5%. The normal appendicectomy rate was the proportion of resected appendixes found to be normal on histopathological examination. FINDINGS:15 risk prediction models were identified that could be assessed. The cohort study enrolled 1827 children from 139 centres, of whom 630 (34·5%) underwent appendicectomy. The normal appendicectomy rate was 15·9% (100 of 630 patients). The Shera score was the best performing model, with an area under the curve of 0·84 (95% CI 0·82-0·86). Applying score cutoffs of 3 points or lower for children aged 5-10 years and girls aged 11-15 years, and 2 points or lower for boys aged 11-15 years, the failure rate was 3·3% (95% CI 2·0-5·2; 18 of 539 patients), specificity was 44·3% (95% CI 41·4-47·2; 521 of 1176), and positive predictive value was 41·4% (38·5-44·4; 463 of 1118). Positive predictive value for the Shera score with a cutoff of 6 points or lower (72·6%, 67·4-77·4) was similar to that of ultrasound scan (75·0%, 65·3-83·1). INTERPRETATION: The Shera score has the potential to identify a large group of children at low risk of acute appendicitis who could be considered for early discharge. Risk scoring does not identify children who should proceed directly to surgery. Medium-risk and high-risk children should undergo routine preoperative ultrasound imaging by operators trained to assess for acute appendicitis, and MRI or low-dose CT if uncertainty remains. FUNDING: None.

To identify assessment tools and patient factors statistically associated with discharge destination in general medical inpatients. A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines. Four electronic databases were searched. Studies were eligible if they were a quantitative study design, had adult acute general medical inpatients and published in English. Outcomes of interest were tools or factors with statistical correlations with discharge destination (home, subacute or residential care). Articles were screened by two independent assessors. Data were extracted by one reviewer and independently checked by a second reviewer. Data were analysed/described descriptively. Twenty-three studies were included. Twenty-three tools and 44 factors were identified, which spanned Health Condition, Body Structure and Function, Activity, Participation, Environment and Personal concepts of the World Health Organisation International Classification of Function, Disability and Health (WHO ICF). The large number of tools and factors found and their distribution across several WHO ICF concepts exemplifies the complexities of predicting discharge. No single assessment tool that best predicts discharge destination was identified, but rather there were a variety of potential tools identified. Further research is needed to determine the psychometric properties of the identified assessment tools as well as additional predictors of subacute care (including rehabilitation). This is important as it may allow for timely clinical decision making. A priori, PROSPERO (CRD42017064209).IMPLICATIONS FOR REHABILITATIONThis systematic review identified a large number of assessment tools and patient factors associated with discharge destination (home, subacute and residential care) in general medical inpatients.All of the domains of the WHO ICF framework are associated with discharge destination and must be considered.Clinicians in the acute setting can use these findings to assist selection of assessment tools to identify patients likely to need rehabilitation or subacute care.Early identification of patients who are unable to return to their place of residence is essential as it allows for provision of early rehabilitation and subsequent discharge planning. This systematic review identified a large number of assessment tools and patient factors associated with discharge destination (home, subacute and residential care) in general medical inpatients. All of the domains of the WHO ICF framework are associated with discharge destination and must be considered. Clinicians in the acute setting can use these findings to assist selection of assessment tools to identify patients likely to need rehabilitation or subacute care. Early identification of patients who are unable to return to their place of residence is essential as it allows for provision of early rehabilitation and subsequent discharge planning.

Objective To identify an age at which initiation of whole nut into the pediatric diet could be considered safe, by evaluating the age distribution of children undergoing bronchoscopy with removal of nut or seed material from the airway. Method A retrospective chart review over a ten-year period identifying children age 0–18 that have undergone bronchoscopy with retrieval of airway foreign bodies. A statistical analysis of demographic data was carried out to identify age distribution of aspiration events. Results Sixty-four cases of foreign body aspiration were identified, of which 43 (67%) were of organic origin, specifically nuts. A Fisher’s exact test was carried out on the cumulative percentage of organic foreign body aspirations to identify the age distribution of nut aspiration events. A statistically significant decrease in organic foreign body aspirations occurred at approximately 36 months of age (p = 0.004). Conclusion Foreign body aspiration is a leading cause of accidental injury or death in children. Nut and other small organic foreign bodies account for a significant portion of accidental aspiration events, however, no guidelines exist regarding appropriate age of whole nut introduction into the diet. Our study suggests that 90% of pediatric nut aspiration events occur under the age of 36 months. We suggest supervised introduction of whole nuts between the ages of 3 and 4 years. Official guidelines regarding this should be considered by professional pediatric societies. Level of evidence 4

Background and purpose General medical patients often present to the hospital with medical, social, cognitive, and functional issues that may impact discharge destination. The aim of this study was to investigate the association between patient factors at hospital admission and discharge destination in general medical patients. Methods This was a prospective, single-site observational study conducted on the general medical wards at a tertiary hospital. Inpatients admitted to the general medical unit and referred to physical therapy were included. Patients admitted from residential care were excluded. Main outcome measures Data were collected a median of 2 days (interquartile range: 1-3) from hospital admission and included demographics, comorbidities (Charlson Comorbidity Index), premorbid physical function (Blaylock Risk Assessment Screening Score, BRASS), current function (de Morton Mobility Index, DEMMI and Alpha Functional Independence Measure, AlphaFIM), and cognition (Rowland Universal Dementia Assessment Scale, RUDAS). Results Between July 2016 and August 2017, 417 patients were recruited (53% female, median age: 81 years (interquartile range: 76-86). Of these, 245 patients were discharged directly home; 172 were not discharged home of whom 140 were discharged to a subacute temporary facility providing further opportunity for therapy and discharge planning. Patients discharged directly home had higher functional, mobility, and cognitive scores. Data were partitioned into training, validation, and test sets to provide unbiased estimates of sensitivity, specificity, receiver operating characteristic curve, and area under the curve. Models best associated with discharge were "DEMMI and toilet transfers" (sensitivity 82.1%, specificity 66.2%, area under the curve 83.8%, 95% confidence interval: 76.4-91.2) and "AlphaFIM and walking independence" (sensitivity: 66.7%, specificity: 83.1%, area under the curve: 81.5, 95% confidence interval: 73.2-89.7). Conclusion Two models were created that differentiated between discharge home and not home and had similar statistical measures of validity. Although the models require further validation, clinicians should consider whether identification of patients likely to be discharged home or not home is of greater relevance for their clinical setting.

Background Integration of three-dimensional (3D) printing and stereolithography into clinical practice is in its nascence, and concepts may be esoteric to the practicing neurosurgeon. Currently, creation of 3D printed implants involves recruitment of offsite third parties. We explored a range of 3D scanning and stereolithographic techniques to create patient-specific synthetic implants using an onsite, clinician-facilitated approach. Methods We simulated bilateral craniectomies in a single cadaveric specimen. We devised 3 methods of creating stereolithographically viable virtual models from removed bone. First, we used preoperative and postoperative computed tomography scanner–derived bony window models from which the flap was extracted. Second, we used an entry-level 3D light scanner to scan and render models of the individual bone pieces. Third, we used an arm-mounted, 3D laser scanner to create virtual models using a real-time approach. Results Flaps were printed from the computed tomography scanner and laser scanner models only in a ultraviolet-cured polymer. The light scanner did not produce suitable virtual models for printing. The computed tomography scanner–derived models required extensive postfabrication modification to fit the existing defects. The laser scanner models assumed good fit within the defects without any modification. Conclusions The methods presented varying levels of complexity in acquisition and model rendering. Each technique required hardware at varying in price points from $0 to approximately $100,000. The laser scanner models produced the best quality parts, which had near-perfect fit with the original defects. Potential neurosurgical applications of this technology are discussed.

Mutations in Janus kinase 2 (JAK2) are implicated in the pathogenesis of Philadelphia-chromosome negative myeloproliferative neoplasms, including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Gandotinib (LY2784544), a potent inhibitor of JAK2 activity, shows increased potency for the JAK2(V6l7F) mutation. The study had a standard 3 + 3 dose-escalation design to define the maximum-tolerated dose. Primary objectives were to determine safety, tolerability, and recommended oral daily dose of gandotinib for patients with JAK2(V617F)-positive myelofibrosis, essential thrombocythemia, or polycythemia vera. Secondary objectives included estimating pharmacokinetic parameters and documenting evidence of efficacy by measuring clinical improvement. Thirty-eight patients were enrolled and treated (31 myelofibrosis, 6 polycythemia vera, 1 essential thrombocythemia). The maximum-tolerated dose of gandotinib was 120 mg daily, based on dose-limiting toxicities of blood creatinine increase or hyperuricemia at higher doses. Maximum plasma concentration was reached 4 h after single and multiple doses, and mean half-life on day 1 was approximately 6 h. Most common treatment-emergent adverse events were diarrhea (55.3%) and nausea (42.1%), a majority of which were of grade 1 severity. Best response of clinical improvement was achieved by 29% of myelofibrosis patients. A ≥ 50% palpable spleen length reduction was observed at any time during therapy in 20/32 evaluable patients. Additionally, ≥ 50% reduction in the Total Symptom Myeloproliferative Neoplasm Symptom Assessment Form Score was seen in 11/21 (52%) and 6/14 patients (43%) receiving ≥ 120 mg at 12 and 24 weeks respectively. Gandotinib demonstrated an acceptable safety and tolerability profile, and findings at the maximum-tolerated dose of 120 mg supported further clinical testing. Clinicaltrials.gov identifier: NCT01134120.

Deep neural networks have gained immense popularity in the Big Data problem; however, the availability of training samples can be relatively limited in specific application domains, particularly medical imaging, and consequently leading to overfitting problems. This “Small Data” challenge may need a mindset that is entirely different from the existing Big Data paradigm. Here, under the small data scenarios, we examined whether the network structure has a substantial influence on the performance and whether the optimal structure is predominantly determined by sample size or data nature. To this end, we listed all possible combinations of layers given an upper bound of the VC-dimension to study how structural hyperparameters affected the performance. Our results showed that structural optimization improved accuracy by 27.99%, 16.44%, and 13.11% over random selection for a sample size of 100, 500, and 1,000 in the MNIST dataset, respectively, suggesting that the importance of the network structure increases as the sample size becomes smaller. Furthermore, the optimal network structure was mostly determined by the data nature (photographic, calligraphic, or medical images), and less affected by the sample size, suggesting that the optimal network structure is data-driven, not sample size driven. After network structure optimization, the convolutional neural network could achieve 91.13% accuracy with only 500 samples, 93.66% accuracy with only 1000 samples for the MNIST dataset and 94.10% accuracy with only 3300 samples for the Mitosis (microscopic) dataset. These results indicate the primary importance of the network structure and the nature of the data in facing the Small Data challenge.

With the number of small Unmanned Aircraft Systems (sUAS) in the national airspace projected to increase in the next few years, there is growing interest in a traffic management system capable of handling the demands of this aviation sector. It is expected that such a system will involve trajectory prediction, uncertainty propagation, and path planning algorithms. In this work, we use linear covariance propagation in combination with a quadratic programming-based collision detection algorithm to rapidly validate declared flight plans. Additionally, these algorithms are combined with a Dynamic, Informed RRT* algorithm, resulting in a computationally efficient algorithm for chance-constrained path planning. Detailed numerical examples for both fixed-wing and quadrotor sUAS models are presented., Comment: Submitted to Advanced Control for Applications

The need for precision landing of high mass payloads on Mars and the return of sensitive samples from other planetary bodies to specific locations on Earth is driving the development of an innovative NASA technology referred to as the Deployable Entry Vehicle (DEV). A DEV has the potential to deliver an equivalent science payload with a stowed diameter 3 to 4 times smaller than a traditional rigid capsule configuration. However, the DEV design does not easily lend itself to traditional methods of directional control. The NASA Space Technology Mission Directorate (STMD)’s Pterodactyl project is currently investigating the effectiveness of three different Guidance and Control (GC ii) determine a suitable TPS material; iii) produce TPS thickness estimations; and, iv) determine the final TPS mass estimation based on TPS thickness, vehicle control system, vehicle structure, and vehicle payload.

Background and aims An adolescent presenting with bilateral tibia and fibula amelia, single kidney, hip dysplasia and severe kyphoscoliosis with abdominal muscle weakness causing femoral hernia is an anaesthetic challenge. Methods An 18 year old girl, weighing 20 kg, height 80 cm, presented with left femoral hernia. Since birth she had bilateral tibial and fibular amelia, hip dysplasia, absent left kidney, external ear malformation, polydactyly and syndactyly. Presently she had severe kyphoscoliosis and mild restrictive lung disease with distorted anatomy of hip and surgical site. We avoided central neuraxial block in view of severe kyphoscoliosis, absence of lower limb with hip dysplasia and short stature. We planned general anesthesia and ultrasound guided TAP block. Patient was induced with inj Fentanyl 40mcg and inj Propofol 80 mg. Supreme LMA no. 3 was inserted. Muscle relaxant was avoided. Ultrasound guided TAP block was given with 0.25% Ropivacaine 20 ml on left side. Despite the anterior superior iliac spine being placed laterally and small in size, the internal oblique, external oblique and transversus abdominis appeared with similar thickness. Internal oblique was not larger than other two muscles. This could be attributed to her inability to walk and hip dysplasia. Procedure was uneventful. Results Good postoperative analgesia for 20 hrs with TAP block, decreasing the need of opioid consumption in the postoperative period. Conclusions Undiagnosed malformation syndrome put forth multisystem management challenges. Ultrasound guided block are a suitable aid in cases with malformation and distorted anatomy to facilitate surgical and postoperative analgesia.

Background: Melanotic schwannoma is a rare tumor with indeterminate biologic behavior and varying treatment recommendations. Methods: We report 2 cases of pigmented melanotic schwannoma of the head and neck and perform literature review. The pathologic and immunohistochemical characteristics of melanotic schwannoma are reviewed. Results: Two cases of melanotic schwannoma are presented. Both cases underwent surgical resection with one patient receiving adjuvant radiation therapy. Conclusions: Melanotic schwannoma is a rare nerve sheath tumor that is frequently mistaken for malignant melanoma. We describe 2 cases of pigmented melanotic schwannoma of the head and neck with different presentations and review the histopathological and immunohistochemical features.

Background Clinical diagnosis of Alzheimer disease (AD) is challenging, with a 70.9%–87.3% sensitivity and 44.3%–70.8% specificity, compared with autopsy diagnosis. Florbetapir F18 positron emission tomography (FBP-PET) estimates beta-amyloid plaque density antemortem. Methods Of 2052 patients (≥55 years old) clinically diagnosed with mild or moderate AD dementia from 2 solanezumab clinical trials, 390 opted to participate in a FBP-PET study addendum. We analyzed baseline prerandomization characteristics. Results A total of 22.4% had negative FBP-PET scans, whereas 72.5% of mild and 86.9% of moderate AD patients had positive results. No baseline clinical variable reliably differentiated negative from positive FBP-PET scan groups. Conclusions These data confirm the challenges of correctly diagnosing AD without using biomarkers. FBP-PET can aid AD dementia differential diagnosis by detecting amyloid pathology antemortem, even when the diagnosis of AD is made by expert clinicians.

The state-of-the-art in vehicle design decouples flight feasible trajectory generation from the optimization process of an entry spacecraft shape. The disadvantage to this decoupled process is seen when a particular aeroshell does not meet in-flight requirements when integrated into Guidance, Navigation, and Control simulations. It is postulated that the integration of a guidance algorithm into the design process will provide a real-time, rapid trajectory generation technique to enhance the robustness of vehicle design solutions. The potential benefit of this integration is a reduction in design cycles (possible cost savings) and increased accuracy in the aerothermal environment (possible mass savings). This work examines two aspects: 1) the performance of a reference tracking guidance algorithm for five different geometries with the same reference trajectory and 2) the potential of mass savings from improved aerothermal predictions. An Apollo Derived Guidance (ADG) algorithm is used in this study. The baseline geometry and five test case geometries were flown using the same baseline trajectory. The guided trajectory results are compared to separate trajectories determined in a vehicle optimization study conducted for NASA's Mars Entry, Descent, and Landing System Analysis. This study revealed several aspects regarding the potential gains and required developments for integrating a guidance algorithm into the vehicle optimization environment. First, the generation of flight feasible trajectories is only as good as the robustness of the guidance algorithm. The set of dispersed geometries modelled aerodynamic dispersions that ranged from +/-1% to +/-17% and a single extreme case was modelled where the aerodynamics were approximately 80% less than the baseline geometry. The ADG, as expected, was able to guide the vehicle into the aeroshell separation box at the target location for dispersions up to 17%, but failed for the 80% dispersion cases. Finally, the results revealed that including flight feasible trajectories for a set of dispersed geometries has the potential to save mass up to 430 kg.

BackgroundMachine learning (ML) is the application of specialized algorithms to datasets for trend delineation, categorization or prediction. ML techniques have been traditionally applied to large, highly-dimensional databases. Gliomas are a heterogeneous group of primary brain tumors, traditionally graded using histopathological features. Recently the World Health Organization proposed a novel grading system for gliomas incorporating molecular characteristics. We aimed to study whether ML could achieve accurate prognostication of 2-year mortality in a small, highly-dimensional database of glioma patients.MethodsWe applied three machine learning techniques: artificial neural networks (ANN), decision trees (DT), support vector machine (SVM), and classical logistic regression (LR) to a dataset consisting of 76 glioma patients of all grades. We compared the effect of applying the algorithms to the raw database, versus a database where only statistically significant features were included into the algorithmic inputs (feature selection).ResultsRaw input consisted of 21 variables, and achieved performance of (accuracy/AUC): 70.7%/0.70 for ANN, 68%/0.72 for SVM, 66.7%/0.64 for LR and 65%/0.70 for DT. Feature selected input consisted of 14 variables and achieved performance of 73.4%/0.75 for ANN, 73.3%/0.74 for SVM, 69.3%/0.73 for LR and 65.2%/0.63 for DT.ConclusionsWe demonstrate that these techniques can also be applied to small, yet highly-dimensional datasets. Our ML techniques achieved reasonable performance compared to similar studies in the literature. Though local databases may be small versus larger cancer repositories, we demonstrate that ML techniques can still be applied to their analysis, though traditional statistical methods are of similar benefit.

Deep neural networks have gained immense popularity in the Big Data problem; however, the availability of training samples can be relatively limited in certain application domains, particularly medical imaging, and consequently leading to overfitting problems. This “Small Data” challenge may need a mindset that is entirely different from the existing Big Data paradigm. Here, under the small data setting, we examined whether the network structure has a substantial influence on the performance and whether the optimal structure is predominantly determined by sample size or data nature. To this end, we listed all possible combinations of layers given an upper bound of the VC-dimension to study how structural hyperparameters affected the performance. Our results showed that structural optimization improved accuracy by 27.99%, 16.44%, and 13.11% over random selection for a sample size of 100, 500, and 1,000 in the MNIST dataset, respectively, suggesting that the importance of the network structure increases as the sample size becomes smaller. Furthermore, the optimal network structure was mostly determined by the data nature (photographic, calligraphic, or medical images), and less affected by the sample size, suggesting that the optimal network structure is data-driven, not sample size driven. After network structure optimization, the conventional convolutional neural network could achieve 91.13% in accuracy with only 500 samples, 93.66% in accuracy with only 1000 samples for the MNIST dataset and 94.10% in accuracy with only 3300 samples for the Mitosis (microscopic) dataset. These results indicate the primary importance of the network structure and the nature of the data in facing the Small Data challenge.

Objectives In light of current FDA guidelines on opioid use in children, we sought to determine the risk of post-tonsillectomy hemorrhage (PTH) in children who received ibuprofen with acetaminophen versus those who received narcotic with acetaminophen for postoperative pain control. Methods This was an IRB-approved retrospective chart review of patients at a tertiary-care pediatric center. The medical records of 449 children who received acetaminophen and ibuprofen following intracapsular tonsillectomy with or without adenoidectomy were reviewed (NSAID group) and compared with medical records of 1731 children who underwent intracapsular tonsillectomy and received acetaminophen with codeine or hydrocodone with acetaminophen postoperatively (narcotic group). Main outcome measure was the incidence of PTH requiring return to the operating room. Secondary outcome measures included incidence of primary PTH, secondary PTH, and postoperative evaluation in the emergency department or readmission for pain and/or dehydration. Results Incidence of PTH requiring return to the operating room was higher in the NSAID group (1.6%) compared with the narcotic group (0.5%), P = 0.01. Incidence of primary PTH was significantly higher in the NSAID group (2%) versus the narcotic group (0.12%), P P Conclusion Use of ibuprofen after intracapsular tonsillectomy in children is associated with statistically significant increase in PTH requiring return to the operating room, as well as an increase in overall rates of both primary and secondary PTH. Ibuprofen provides pain control that is at least equivalent to narcotic and is not associated with respiratory depression. Further study of ibuprofen use in the post-tonsillectomy patient is warranted.

Objectives3D scanning and stereolithographic printing technology becoming increasingly common, however its implementation into clinical practice is in its primacy. These technologies may be esoteric to the practicing neurosurgeon. We explored a range of 3D scanning and stereolithographic techniques to create patient-specific synthetic implants.MethodsWe simulated bilateral craniectomies from a single cadaveric specimen to create 3 methods of creating stereolithographically-viable virtual models. Firstly, we used ‘pre-and-post operative’ CT derived bony windows to create a virtual skull model, from which the flap was extracted. Secondly, we used an entry-level 3D light-scanner to scan and render models of the individual bone pieces. Thirdly, we used an arm-mounted, 3D laser-scanner to create virtual models using a real-time approach.ResultsFlaps were printed from the CT scanner and laser scanner models only, in a UV-cured polymer. The light scanner did not produce suitable virtual models for printing. The CT scanner derived models required extensive post-fabrication modification to fit the existing defects. The laser-scanner models assumed good fit within the defects without any modification.ConclusionsThe methods presented varying levels of complexity in acquisition and model rendering. Each technique required hardware at varying in price points from $0 to ∼$100,000. The laser-scanner models produced the best quality parts which bore near-perfect fit with the original defects. We discuss potential neurosurgical applications of this technology.

To date, surgical interventions are the only means by which craniofacial anomalies can be corrected so that function, esthetics, and the sense of well-being are restored in affected individuals. Unfortunately, for patients with cleft palate—one of the most common of congenital birth defects—treatment following surgery is prolonged over a lifetime and often involves multidisciplinary regimens. Hence, there is a need to understand the molecular pathways that control palatogenesis and to translate such information for the development of noninvasive therapies that can either prevent or correct cleft palates in humans. Here, we use the well-characterized model of the Pax9−/−mouse, which displays a consistent phenotype of a secondary cleft palate, to test a novel therapeutic. Specifically, we demonstrate that the controlled intravenous delivery of a novel mouse monoclonal antibody replacement therapy, which acts as an agonist for the ectodysplasin (Eda) pathway, can resolve cleft palate defects in Pax9−/−embryos in utero. Such pharmacological interventions did not reverse the arrest in tooth, thymus, and parathyroid gland development, suggesting that the relationship of Pax9 to the Eda/Edar pathway is both unique and essential for palatogenesis. Expression analyses and unbiased gene expression profiling studies offer a molecular explanation for the resolution of palatal defects, showing that Eda and Edar-related genes are expressed in normal palatal tissues and that the Eda/Edar signaling pathway is downstream of Pax9 in palatogenesis. Taken together, our data uncover a unique relationship between Pax9 and the Eda/Edar signaling pathway that can be further exploited for the development of noninvasive, safe, and effective therapies for the treatment of cleft palate conditions and other single-gene disorders affecting the craniofacial complex.

This paper details the adaptation of specific ‘knowledge production’ methods to implement a first of its kind, grassroots event that provokes a cultural change in how the NASA Ames civil servant community engages in the creation and selection of innovative ideas. Historically, selection of innovative proposals at NASA Ames Research Center is done at the highest levels of management, isolating the views and perspectives of the larger civil servant community. Additionally, NASA innovation programs are typically open to technical organizations and do not engage non-technical organizations to bring forward innovative processes/business practices. Finally, collaboration on innovative ideas and associated solutions tend to be isolated to organizational silos. In this environment, not all Ames employees feel empowered to innovate and opportunities for employee collaboration are limited. In order to address these issues, the ‘innovation contest’ method was adapted to create the NASA Ames Innovation Fair, a unique, grassroots innovation opportunity for the civil servant community. The Innovation Fair consisted of a physical event with a virtual component. The physical event provided innovators the opportunity to collaborate and pitch their innovations to the NASA Ames community. The civil servant community then voted for the projects that they viewed as innovative and would contribute to NASA's core mission, making this event a truly grassroots effort. The Innovation Fair website provided a location for additional knowledge sharing, discussion, and voting. On March 3rd, 2016, the ‘First Annual NASA Ames Innovation Fair’ was held with 49 innovators and more than 300 participants collaborating and/or voting for the best innovations. Based on the voting results, seven projects were awarded seed funding for projects ranging from innovative cost models to innovations in aerospace technology. Surveys of both innovators and Fair participants show the Innovation Fair was successful in fostering cross-organizational collaborations, soliciting participation of non-technical innovations, and increasing employee engagement in influencing the future of NASA Ames Research Center. The grassroots component of the Innovation Fair has been bench marked by the agency as a solid foundation for increasing employee engagement in the development of game changing aerospace technology and processes in support of NASA's mission.

Background The objective of the current study was to assess mean self-monitored blood glucose (SMBG), on day 6 of 6 days of continuous reservoir wear (6D), with insulin lispro (Lis) or insulin aspart (Asp). Methods Two 24-week, randomized trials were conducted in subjects with type 1 diabetes treated by continuous subcutaneous insulin infusion (CSII) for ≥6 months, with a mean total daily insulin dose capable of supporting 6 days of in-reservoir use. Study 1 had an open-label, six-sequence, three-treatment, three-period, cross-over design. Study 2 had a double-blind, two-sequence, two-treatment, two-period, cross-over design. The primary efficacy measure was the mean of Day 6, seven-point SMBG profiles for insulin lispro 6D (Lis6D) and insulin aspart 6D (Asp6D) treatment periods. Safety measures were also assessed. Results Lis did not achieve noninferiority (SMBG; margin = 0.6 mmol/L [10.8 mg/dL]) to Asp on Day 6 of reservoir wear in either Study (least-squares mean difference: Study 1 = 0.48 mmol/L [8.64 mg/dL]; 95% confidence interval [CI] [0.20, 0.76], Study 2 = 0.36 mmol/L [6.49 mg/dL]; 95% CI [0.06, 0.66]). Noninferiority was demonstrated for overall daily mean of SMBG values over days 1 to 6 of reservoir use during each treatment period. In the Lis treatment period, subjects reported a lower documented and total hypoglycemia rate per 30 days and a higher rate of non-explained hyperglycemia than in the Asp treatment period. Conclusion While the mean blood glucose on Day 6 of Lis6D did not meet non-inferiority, the overall daily mean blood glucose was not different, with a decreased rate of hypoglycemia with Lis.

In dentistry, the maintenance of a vital dental pulp is of paramount importance because teeth devitalized by root canal treatment may become more brittle and prone to structural failure over time. Advanced carious lesions can irreversibly damage the dental pulp by propagating a sustained inflammatory response throughout the tissue. Although the inflammatory response initially drives tissue repair, sustained inflammation has an enormously destructive effect on the vital pulp, eventually leading to total necrosis of the tissue and necessitating its removal. The implications of tooth devitalization have driven significant interest in the development of bioactive materials that facilitate the regeneration of damaged pulp tissues by harnessing the capacity of the dental pulp for self-repair. In considering the process by which pulpitis drives tissue destruction, it is clear that an important step in supporting the regeneration of pulpal tissues is the attenuation of inflammation. Macrophages, key mediators of the immune response, may play a critical role in the resolution of pulpitis because of their ability to switch to a proresolution phenotype. This process can be driven by the resolvins, a family of molecules derived from fatty acids that show great promise as therapeutic agents. In this review, we outline the importance of preserving the capacity of the dental pulp to self-repair through the rapid attenuation of inflammation. Potential treatment modalities, such as shifting macrophages to a proresolving phenotype with resolvins are described, and a range of materials known to support the regeneration of dental pulp are presented.

Introduction Midline Cervical Cleft (MCC) is a midline cervical congenital anomaly that manifests as a vertical cutaneous/subcutaneous defect with abnormal dermal elements as well as an underlying fibrous cord that extends from the sternum to the mentum of the mandible, which can lead to "wry neck" and hypoplastic mandible. The goal of surgical correction of MCC is to provide adequate healthy tissue coverage, as well as restore contour of the anterior neck. The primary treatment modality for midline cervical cleft is surgical. We describe a technique involving complete excision of the fibrous cord, and use of double z-plasty flap in order to create a tension-free closure and restore contour to the anterior neck. Methods Using a database search method, children with the clinical diagnosis of midline cervical cleft treated between 2006 and 2016 were identified at a pediatric tertiary care center. Chart review was completed to assess for age at surgery, follow up, results, and complications. Results 12 patients were identified in the Lurie Children's Hospital (LCH) database. 8 patients underwent complete cord excision by the seniorauthor using the double z-plasty (DZ) technique for closure, with no recurrences. 4 patients underwent linear closure by another surgeon, had persistent contracture, and underwent revision using the DZ technique by the senior author, with no recurrence. Average age of surgery was 9.5 months. Most common post op complication was hypertrophic scar (3/12). Recurrence was only seen in the linear closure cases (4/12). Conclusions Midline Cervical Cleft is a rare entity with less than 200 cases in the literature. We believe the double z-plasty closure and complete excision of the fibrous cord results in reproducible restoration of neck contour and prevents cord recurrence, and should be considered the standard method for surgical excision of MCC.

Implantable devices have improved the lives of many patients, but implant-associated infection remains a serious complication with significant morbidity and mortality. In recent years, the role of biofilm in the development of these infections has become increasingly recognized, and strategies to combat biofilm are beginning to proliferate in the literature. This review will explore how implant-associated infections have historically been treated, where the research currently stands, and the future trends of infection control.

This is a critical time in the history of the dental profession for it to fully embrace the responsibility to safeguard its reputation as a learned profession. In this golden era of scientific and technological advances, opportunities abound to create new diagnostics, preventions, treatments, and cures to improve oral health. Dental schools are the largest national resource entrusted with the responsibility to educate, train, and retain oral health researchers who can leverage such technologies and research opportunities that will benefit the profession at large as well as patients. This article reemphasizes the theme that research training and scholarship must be inextricably woven into the environment and culture in dental schools to ensure the future standing of the profession. An overview of the history of support provided by the National Institutes of Health and National Institute of Dental and Craniofacial Research for the training and career development of dentist-scientists is presented. In addition, new data on the outcomes of such investments are presented along with a comparison with other health professions. This overview underscores the need to expand the capacity of a well-trained cadre of oral health researchers through the reengineering of training programs. Such strategies will best prepare future graduates for team science, clinical trials, and translational research as well as other emerging opportunities. The urgent need for national organizations like the American Dental Association, American Dental Education Association, and American Association for Dental Research to create new alliances and novel initiatives to assist dental schools and universities in fulfilling their research mission is emphasized. To ignore such calls for action is to disavow a valuable legacy inherited by the dental profession. This article was written as part of the project "Advancing Dental Education in the 21st Century."

Enlargement of the ilioinguinal nerve at the external inguinal ring is observed in 34% of patients undergoing primary open inguinal herniorrhaphy; in 88% of patients it occurs at the fascial edge where the hernia mushrooms with abdominal pressure. Compression neuropathy occurs near many anatomical nerve constriction sites and is associated with enlargement of the peripheral nerve accompanied by sensory changes. In this prospective study, Carolina Comfort Scale (CCS) questionnaire data was collected for 35 primary hernia repairs. Each patient underwent primary inguinal herniorrhaphy that included ilioinguinal neurectomy. All nerves were sampled proximal to the external inguinal ring. Any nerves with grossly increased overall diameter to any degree distal to the external ring were additionally sampled in the thickened portions. A neuropathologist performed histologic evaluation of the H&E-stained cross sections. Paired comparison of proximal and distal nerves revealed a greater overall diameter and greater measured nerve-specific diameter in distal nerve segments. Nerves with increased overall diameter were also found to have a statistically significant positive correlation with four of eight pain measures. Additionally, increased nerve-specific diameter correlates with increased pain on four of eight pain values, but age effect on nerve diameter blunts this finding. Increased preoperative CCS pain values in primary open inguinal hernia are significantly correlated with gross enlargement of the overall diameter and nerve-specific diameter of the ilioinguinal nerve beyond the external inguinal ring. This is consistent with a compression neuropathy.

Managing trajectory separation of unmanned aircraft is critical to ensuring accessibility, efficiency, and safety in low altitude airspace. The concept of a geo-fence has emerged as a way to manage trajectory separation. A geo-fence consists of distance buffers that enclose individual trajectories to identify a ‘keep-in’ region and/or enclose areas that identify ‘keep-out’ regions. The ‘keep-in’ geo-fence size can be defined as a static number or calculated as a function of vehicle performance characteristics, state of the airspace, weather, and other unforeseen events such as emergency or disaster response. Given that the fleet of Unmanned Aircraft Systems (UAS) operating in low altitude airspace will be numerous and non-homogeneous, calculating a ‘keep-in’ geo-fence will need to balance operational safety and efficiency. A recently tested UAS Traffic Management (UTM) prototype used a geo-fence size of 30 meters, horizontally and vertically, for every operation submitted. The goal of this work is to determine the feasibility of a generalized, simple algorithm that calculates geo-fence sizes as a function of vehicle performance and potential wind disturbances. The resulting geo-fence size could be smaller or larger because the vehicle performance in the presence of wind is considered, thus leading to trajectory separation that is safe and efficient. In this paper, two simplified methods were developed to determine the feasibility of calculating a geo-fence as a function of vehicle parameters and wind information. The first method calculates the geo-fence using basic vehicle parameters and wind sensor data in a set of algebraic-geometric equations. The second method models a generic PID control system that uses a simplified set of equations of motion for the plant and uses gain scheduling to account for wind disturbances. It was found that the Algebraic-Geometric Geo-fence Algorithm provides geo-fence sizes of approximately 15 meters horizontally and 5 meters vertically, which is much smaller than the UTM static value of 30 meters. In the PID Controller Geo-fence Algorithm it was found that the geo-fence size is further reduced to less than 5 meters, horizontally and vertically. These results reveal that implementing geo-fence calculations provide UTM with the ability to schedule and separate operations based on geofences that are dynamic to vehicle capability and environment, which is more efficient than using a single static geo-fence.

The 4th Annual AADR Fall Focused Symposium (FFS), “Oral Health Disparities Research and the Future Face of America”, took place on November 3-4, 2011 in Washington, DC. The FFS strategy was developed by the AADR to help provide additional opportunities for members to engage in research discussions during the year by identifying specific research topics of interest among the 21 Scientific Groups and 4 Networks of the IADR and targeting a focused topic area for the FFS. The conference attracted an international group of approximately 120 registrants, including participants from Canada, India, Mexico, and China; 4 oral sessions and 32 poster presentations were offered.

Objective. This study was designed to describe burden of illness and treatment patterns, and to examine the patient, physician, and care factors associated with the treatment choices of individuals receiving new prescriptions for fibromyalgia (FM). Design. This is a baseline assessment of the Real-World Examination of Fibromyalgia: Longitudinal Evaluation of Costs and Treatments (REFLECTIONS), a prospective observational study. Baseline data (including a physician survey, a patient visit form, and computer-assisted telephone interviews) were collected from July 2008 through May 2010 in 58 care settings in the United States, including Puerto Rico. Results. Patients (N = 1,700) were mostly female (94.6%) and white (82.9%). Mean age was 50.4 years and mean duration of illness was 5.6 years. Mean Fibromyalgia Impact Questionnaire total score was 54.4 (range 0–80), and Brief Pain Inventory average pain severity level was 5.5 (range 0–10). Patients reported high annual health care use and numerous work limitations related to FM. Patients were taking 182 unique types of medications prescribed for FM, including duloxetine (26.8%), nonsteroidal anti-inflammatory drugs (26.6%), pregabalin (24.5%), opioids (24.2%), tramadol (15.3%), benzodiazepines (15.2%), cyclobenzaprine (12.9%), milnacipran (8.9%), and others. Most patients took more than one medication concurrently (77.8%). Type of current medications used was most strongly associated with medication history and physician specialty. Conclusions. Burden of illness was high for patients with FM, and treatment patterns were highly variable. Importantly, the treatments with the most evidence to support their use were not always the most frequently chosen.

The primary objective of this study is to review the efficacy of duloxetine in treating chronic pain using the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations for clinical significance across chronic pain states. These include pain intensity, patient ratings of overall improvement, physical functioning, and mental functioning. This review comprised the side-by-side analyses of 12 double-blind, placebo-controlled trials of duloxetine in patients with chronic pain (diabetic peripheral neuropathic pain, fibromyalgia, chronic pain due to osteoarthritis, and chronic low back pain). Patients received duloxetine (60 to 120 mg/day) or placebo. Average pain reduction was assessed over 3 months as the primary efficacy outcome. Other measures used were physical function and Patient Global Impression of Improvement. In 10 of the 12 studies, statistically significant greater pain reduction was observed for duloxetine- compared with placebo-treated patients. The response rates based on average pain reduction, improvement of physical function, and global impression were comparable across all 4 chronic pain states. Compared with patients on placebo, significantly more patients treated with duloxetine reported a moderately important pain reduction (≥30% reduction) in 9 of the 12 studies, a minimally important improvement in physical function in 8 of the 12 studies, and a moderately important to substantial improvement in Patient Global Impression of Improvement rating in 11 of the 12 studies. The analyses reported here show that duloxetine is efficacious in treating chronic pain as demonstrated by significant improvement in pain intensity, physical functioning, and patient ratings of overall improvement.

Introduction Recent successes in dental pulp engineering indicate that regenerative treatment strategies in endodontics are feasible. Clinically, revascularization procedures render completion of root formation in immature teeth. The generation of a pulp-like tissue after seeding of dental pulp stem cells into dentin discs or cylinders and transplantation in vivo is possible. In this experimental setup, which mimics the situation in the root canal, the pretreatment of dentin might influence cellular behavior at the cell-dentin interface. Thus, the objective of this study was to investigate whether dentin conditioning can determine cell fate. Methods Dental pulp stem cells (DPSCs) were seeded into a growth factor–laden peptide hydrogel, transferred into dentin cylinders, and transplanted subcutaneously into immunocompromised mice. Before cell seeding, dentin cylinders were either pretreated with sodium hypochloride (NaOCl) or conditioned with EDTA. The constructs were explanted after 6 weeks and subjected to histological and immunohistochemical analysis. Results In dentin treated with NaOCl, resorption lacunae were found at the cell-dentin interface created by multinucleated cells with clastic activity. After conditioning with EDTA, DPSCs adjacent to the dentin formed an intimate association with the surface, differentiated into odontoblasts-like cells that expressed dentin sialoprotein, and extended cellular processes into the dentinal tubules. A vascularized soft connective tissue similar to dental pulp was observed inside the dentin cylinder. Conclusions Dentin conditioning considerably influences DPSC fate when seeded in close proximity to dentin. This information might be critical for optimized strategic planning for future regenerative endodontic treatment.

In the early years of the new millennium, the National Institute of Dental and Craniofacial Research of the National Institutes of Health began funding Oral Health Research Education Grants using the R25 mechanism to promote the application of basic and clinical research findings to clinical training and to encourage students to pursue careers in oral health research. This report describes the impact of an R25 grant awarded to the Texas A&M Health Science Center’s Baylor College of Dentistry (BCD) on its curriculum and faculty development efforts. At BCD, the R25 grant supports a multipronged initiative that employs clinical research as a vehicle for acquainting both students and faculty with the tools of evidence-based dentistry (EBD). New coursework and experiences in all four years of the curriculum plus a variety of faculty development offerings are being used to achieve this goal. Progress on these fronts is reflected in a nascent EBD culture characterized by increasing participation and buy-in by students and faculty. The production of a new generation of dental graduates equipped with the EBD skill set as well as a growing nucleus of faculty members who can model the importance of evidence-based practice is of paramount importance for the future of dentistry.

Evaluate the efficacy and safety of duloxetine at doses up to 120 mg once daily in patients with fibromyalgia.This was a phase 3, 60-week study, which included an 8-week open-label period followed by a 52-week, randomized, double-blind period. Patients received duloxetine 30 mg daily for 1 week and duloxetine 60 mg daily for 7 weeks and were then randomized to receive either 60 or 120 mg daily (1:2 ratio).Enrolled patients (N=350, 95.7% female) exhibited moderate disease symptoms at study entry (Brief Pain Inventory average pain=6.7, Clinical Global Impression of Severity=4.1, and Patient's Global Impression of Severity=4.1). Significant pain reduction in patients was observed during the open-label study phase. This pain reduction continued during the 52-week double-blind study phase, as demonstrated by additional mean decreases in the Brief Pain Inventory average pain score within both duloxetine groups. The most common (or =15%) treatment-emergent adverse events (overall phase) were nausea, headache, insomnia, dizziness, constipation, and dry mouth. Seventy-four (21.1%) patients reported adverse events as a reason for discontinuation [most common (1%) were insomnia, vomiting, diarrhea, dizziness, and nausea]. The mean change (SD) in sitting systolic blood pressure (mm Hg) was -0.1 (14.4), in sitting diastolic blood pressure was -0.2 (9.6), in sitting pulse rate was 1.9 (10.4) bpm, and in weight was 0.7 (4.3) kg.The profile of duloxetine for the long-term treatment of fibromyalgia was consistent with that seen in other indications for which the drug is currently marketed.

Amy S Chappell1, Laurence A Bradley2, Curtis Wiltse1, Michael J Detke1,3,4, Deborah N D’Souza1, Michael Spaeth51Lilly Research Laboratories, Indianapolis, IN, USA; 2University of Alabama at Birmingham, Birmingham, Alabama, USA; 3Indiana University School of Medicine, Indianapolis, IN, USA; 4Harvard Medical School, Boston, MA, USA; 5Practice for Internal Medicine/Rheumatology, Graefelfing, GermanyObjective: Assess the efficacy of duloxetine 60/120 mg (N = 162) once daily compared with placebo (N = 168) in the treatment of patients with fibromyalgia, during six months of treatment.Methods: This was a phase-III, randomized, double-blind, placebo-controlled, parallel-group study assessing the efficacy and safety of duloxetine.Results: There were no significant differences between treatment groups on the co-primary efficacy outcome measures, change in the Brief Pain Inventory (BPI) average pain severity from baseline to endpoint (P = 0.053) and the Patient’s Global Impressions of Improvement (PGI-I) at endpoint (P = 0.073). Duloxetine-treated patients improved significantly more than placebo-treated patients on the Fibromyalgia Impact Questionnaire pain score, BPI least pain score and average interference score, Clinical Global Impressions of Severity scale, area under the curve of pain relief, Multidimensional Fatigue Inventory mental fatigue dimension, Beck Depression Inventory-II total score, and 36-item Short Form Health Survey mental component summary and mental health score. Nausea was the most common treatment-emergent adverse event in the duloxetine group. Overall discontinuation rates were similar between groups.Conclusions: Although duloxetine 60/120 mg/day failed to demonstrate significant improvement over placebo on the co-primary outcome measures, in this supportive study, duloxetine demonstrated significant improvement compared with placebo on numerous secondary measures.Keywords: fibromyalgia, duloxetine, placebo, double-blind, trial, pain

Objective: Review nonclinical and clinical trial data for hepatic effects of duloxetine. Methods: Review studies of toxicology, metabolism, mitochondrial effects, and clinical trials. Results: Nonclinical studies revealed no treatment-related transaminase elevations and no effects of duloxetine on mitochondrial beta-oxidation in rat hepatocytes. In patients with a normal baseline alanine transaminase (ALT), duloxetine was associated with elevated transaminases > 3X ULN in about 1% of patients. ALT and aspartate transaminase values peaked at 8 weeks, alkaline phosphatase steadily increased to maximum value at Week 52 and mean total bilirubin values were not increased. Hepatic-related treatment-emergent adverse events were uncommon. Seven of 23,000 duloxetine- and 2/6000 placebo-treated patients met criteria for modified Hys rule (significant elevation of both ALT and total bilirubin) but were complicated by contributing factors such as excessive alcohol consumption (n=3), gall stones, common bile duct calculus, hepatitis C, and liver adenocarcinoma (n=1 each). Conclusions: Duloxetine has an effect on the liver, manifested by transient, self-limiting transaminase elevations. Rare events characterized as hepatocellular injury, cholestatic injury, or mixed type of hepatic injury have been reported. The pattern of liver effects was different from that in laboratory animals.

To assess the efficacy (in particular, in pain, functional impairment, and quality of life) and safety and tolerability (incidence of adverse events, discontinuation rates, changes in laboratory findings, and vital signs) of duloxetine in female patients with fibromyalgia.Data were pooled from two placebo-controlled clinical trials of similar design (randomized, 12-week, and double-blind), comparing duloxetine 60 mg a day (q.d.) or 60 mg twice daily (b.i.d.) (n = 326) with placebo (n = 212), in women who met the American College of Rheumatology criteria for primary fibromyalgia.Compared with the patients receiving placebo, duloxetine-treated female patients demonstrated a significantly greater improvement in the Brief Pain Inventory (BPI) average pain severity score and in the Fibromyalgia Impact Questionnaire (FIQ) total score, beginning at week 1 and continuing through week 12 (p0.001). Duloxetine was superior to placebo on all efficacy measures, including mean tender point threshold, Clinical Global Impression of Severity, Patient Global Impression of Improvement, and average interference from pain scores. The duloxetine-treated group was superior to placebo on all quality of life and functional measures, including each domain of the Medical Outcomes Study Short Form-36 (SF-36). A direct treatment effect of duloxetine on pain reduction was demonstrated and shown to be independent of secondary improvement in mood (based on BPI average pain score). Significantly more duloxetine-treated patients reported treatment-emergent adverse events (296 [90.8%] duloxetine-treated and 165 [77.8%] placebo-treated, p0.001). Rates of serious adverse events were similar between duloxetine-treated and placebo-treated patients.The pooled results of these studies demonstrate that duloxetine is a safe and efficacious treatment for both the pain and functional impairment associated with fibromyalgia in female patients, while significantly improving quality of life.

Objective. To assess the effectiveness of duloxetine, compared with placebo, on patient-reported health outcomes over a 12-week period, in the management of diabetic peripheral neuropathic pain (DPNP). Methods. The results were pooled from three 12-week multicenter, double-blind studies. In study 1 (N = 457), patients with DPNP were randomly assigned to treatment with duloxetine 20 mg once daily (QD), 60 mg QD, 60 mg twice daily (BID), or placebo. In studies 2 (N = 334) and 3 (N = 348), patients with DPNP were randomly assigned to treatment with duloxetine 60 mg QD, 60 mg BID, or placebo. Patient-reported functional outcomes were measured by the Short Form 36 (SF-36), the interference portion of the Brief Pain Inventory (BPI), and EuroQol 5D Health Questionnaire (EQ-5D). Results for all functional outcomes from the intent-to-treat and completer populations are discussed. Results. In the SF-36 health survey and the BPI interference, duloxetine 60 mg QD and 60 mg BID were significantly superior to placebo in all the domains (P ≤ 0.03). In the analysis of the EQ-5D, duloxetine 60 mg QD (P = 0.004) and 60 mg BID (P

Background: Serotonin (5-HT) and norepinephrine (NE) are involved in pain modulation via descending inhibitory pathways in the brain and spinal cord. Objective: To assess the efficacy of duloxetine, a dual reuptake inhibitor of 5-HT and NE, on the reduction of pain severity, as well as secondary outcome measures in patients with diabetic peripheral neuropathic pain (DPNP). Methods: In this double-blind study, patients with DPNP and without comorbid depression were randomly assigned to treatment with duloxetine 60 mg once daily (QD), duloxetine 60 mg twice daily (BID), or placebo for 12 weeks. The primary outcome measure was the weekly mean score of 24-hour average pain severity on the 11-point Likert scale. Secondary measures and health outcome measures were also assessed. Results: Duloxetine 60 mg QD and 60 mg BID demonstrated improvement in the management of DPNP and showed rapid onset of action, with separation from placebo beginning at week 1 on the 24-hour average pain severity score. For all secondary measures for pain (except allodynia), mean changes showed an advantage of duloxetine over placebo, with no significant difference between 60 mg QD and 60 mg BID. Clinical Global Impression of Severity and Patient’s Global Impression of Improvement evaluation demonstrated greater improvement on duloxetine- vs placebo-treated patients. Duloxetine showed no notable interference on diabetic controls, and both doses were safely administered. Conclusions: This study confirms previous findings that duloxetine at 60 mg QD and 60 mg BID is effective and safe in the management of diabetic peripheral neuropathic pain.