bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the abuse potential of pitolisant, a selective H3-receptor antagonist/inverse agonist, for the treatment of adult patients with narcolepsy with or without cataplexy
Authors: Setnik Beatrice , McDonnell Michael , Mills Catherine , Scart-Grès Catherine , Robert Philippe , Dayno Jeffrey M , Schwartz Jean-Charles
Published: October 2019

Objectives

To evaluate the human abuse potential of pitolisant, a selective histamine 3 (H3)-receptor antagonist/inverse agonist recently approved by the US Food and Drug Administration for the treatment of excessive daytime sleepiness in adult patients with narcolepsy.

Methods

Nondependent, recreational stimulant users able to distinguish phentermine HCl 60 mg from placebo in a drug discrimination test were randomized in a four-period, double-blind, crossover design to receive single doses of pitolisant 35.6 mg (therapeutic dose), pitolisant 213.6 mg (supratherapeutic dose), phentermine HCl 60 mg, and placebo. The primary endpoint was maximum effect (Emax) on the 100-point Drug Liking (“at this moment”) visual analog scale.

Results

In 38 study completers (73.7% male; 65.8% white; mean age, 33.3 years), mean Drug Liking Emax was significantly greater for phentermine versus pitolisant 35.6 mg (mean difference, 21.4; p < 0.0001) and pitolisant 213.6 mg (mean difference, 19.7; p < 0.0001). Drug Liking Emax was similar for pitolisant (both doses) and placebo. Similarly, for key secondary measures of Overall Drug Liking and willingness to Take Drug Again, mean Emax scores were significantly greater for phentermine versus pitolisant (both doses) and similar for pitolisant (both doses) versus placebo. The incidence of adverse events was 82.1% after phentermine HCl 60 mg, 72.5% after pitolisant 213.6 mg, 47.5% after pitolisant 35.6 mg, and 48.8% after placebo administration.

Conclusions

In this study, pitolisant demonstrated significantly lower potential for abuse compared with phentermine and an overall profile similar to placebo; this suggests a low risk of abuse for pitolisant.

Clinical Trial Registration

ClinicalTrials.gov NCT03152123. Determination of the abuse potential of pitolisant in healthy, nondependent recreational stimulant users. https://clinicaltrials.gov/ct2/show/NCT03152123.
Methylation‐dependent transcriptional repression of RUNX3 by KCNQ1OT1 regulates mouse cardiac microvascular endothelial cell viability and inflammatory response following myocardial infarction
Authors: Wang Yanbin , Yang Xudong , Jiang An , Wang Wei , Li Jian , Wen Junmin
Published: October 2019

Myocardial infarction (MI) is a major contributor to death and disability throughout the world. Increasing evidence shows that long noncoding RNAs (lncRNAs) are involved in the progression of MI. Here, we hypothesized that lncRNA potassium voltage‐gated channel subfamily q member 1 overlapping transcript 1 (KCNQ1OT1) could affect the development of MI via regulation of Runt‐related transcription factor (RUNX)3 by methylation. Initially, by ligation of the left anterior descending coronary artery, an acute MI (AMI) mouse model was established to collect the cardiac microvascular endothelial cells (CMECs), which revealed a high KCNQ1OT1 expression and a low RUNX3 expression with its high methylation. After that, KCNQ1OT1 knockdown or RUNX3 overexpression were transduced into the CMECs in order to detect their role in CMEC proliferation, apoptosis, and inflammatory response. Moreover, we assessed their interaction with the inflammatory Notch pathway, by determining the expression of Jagged 1, Hey1, Hes1, Notch intracellular domain, and Notch1. It was observed that after KCNQ1OT1 knockdown, the proliferation of AMI‐CMECs was promoted, whereas their apoptosis was inhibited, accompanied by reduced level of inflammatory factors. These trends could also be achieved by RUNX3 overexpression via the Notch pathway. Finally, the regulation of DNA methyltransferase (DNMT)1‐dependent methylation in RUNX3 by KCNQ1OT1 was determined, suggesting that KCNQ1OT1 could result in down‐regulated RUNX3 expression through promoted RUNX3 methylation caused by recruiting DNMT1. Overall, this study demonstrates that KCNQ1OT1 silencing inhibits RUNX3 methylation, thereby offering protection against CMEC injury and inflammatory response in AMI, which may serve as a promising target for the disease treatment.—Wang Y., Yang X., Jiang A., Wang W., Li, J., Wen, J. Methylation‐dependent transcriptional repression of RUNX3 by KCNQ1OT1 regulates mouse cardiac microvascular endothelial cell viability and inflammatory response following myocardial infarction. FASEB J. 33, 13145–13160 (2019). www.fasebj.org
Abnormal lacuno‐canalicular network and negative correlation between serum osteocalcin and Cobb angle indicate abnormal osteocyte function in adolescent idiopathic scoliosis
Authors: Chen Huanxiong , Zhang Jiajun , Wang Yujia , Cheuk Ka‐Yee , Hung Alec L. H. , Lam Tsz‐Ping , Qiu Yong , Feng Jian Q. , Lee Wayne Y. W. , Cheng Jack C. Y.
Published: October 2019

Adolescent idiopathic scoliosis (AIS) is a prevalent spinal deformity occurring during peripubertal growth period that affects 1‐4% of adolescents globally without clear etiopathogenetic mechanism. Low bone mineral density is an independent and significant prognostic factor for curve progression. Currently, the cause underlying low bone mass in AIS remains elusive. Osteocytes play an important role in bone metabolism and mineral homeostasis, but its role in AIS has not been studied. In the present study, iliac bone tissues were harvested from 21 patients with AIS (mean age of 14.3 ± 2.20 yr old) with a mean Cobb angle of 55.6 ± 10.61° and 13 non‐AIS controls (mean age of 16.5 ± 4.79 yr old) intraoperatively. Acid‐etched scanning electron microscopy (SEM) images of AIS demonstrated abnormal osteocytes that were more rounded and cobblestone‐like in shape and were aligned in irregular clusters with shorter and disorganized canaliculi. Further quantitative analysis with FITC‐Imaris technique showed a significant reduction in the canalicular number and length as well as an increase in lacunar volume and area in AIS. SEM with energy‐dispersive X‐ray spectroscopy analysis demonstrated a lower calcium‐to‐phosphorus ratio at the perilacunar/canalicular region. Moreover, microindentaion results revealed lower values of Vickers hardness and elastic modulus in AIS when compared with controls. In addition, in the parallel study of 99 AIS (27 with severe Cobb angle of 65.8 ± 14.1° and 72 with mild Cobb angle of 26.6 ± 9.1°) with different curve severity, the serum osteocalcin level was found to be significantly and negatively associated with the Cobb angle. In summary, the findings in this series of studies demonstrated the potential link of abnormal osteocyte lacuno‐canalicular network structure and function to the observed abnormal bone mineralization in AIS, which may shed light on etiopathogenesis of AIS.—Chen, H., Zhang, J., Wang, Y., Cheuk, K.‐Y., Hung, A. L. H., Lam, T.‐P., Qiu, Y., Feng, J. Q., Lee, W. Y. W., Cheng, J. C. Y. Abnormal lacuno‐canalicular network and negative correlation between serum osteocalcin and Cobb angle indicate abnormal osteocyte function in adolescent idiopathic scoliosis. FASEB J. 33, 13882‐13892 (2019). www.fasebj.org
A Bolus Dose of Ketamine Reduces the Amplitude of the Transcranial Electrical Motor-evoked Potential: A Randomized, Double-blinded, Placebo-controlled Study
Authors: Furutani Kenta , Deguchi Hiroyuki , Matsuhashi Mari , Mitsuma Yusuke , Kamiya Yoshinori , Baba Hiroshi
Published: October 2019

Background:

A low-dose bolus or infusion of ketamine does not affect transcranial electrical motor-evoked potential (MEP) amplitude, but a dose ≥1 mg/kg may reduce MEP amplitude. We conducted a randomized, double-blinded, placebo-controlled study to evaluate the effect of ketamine (1 mg/kg) on transcranial electrical MEP.

Methods:

Twenty female patients (aged 12 to 18 y) with adolescent idiopathic scoliosis scheduled to undergo posterior spinal fusion were randomly allocated to receive ketamine or saline. General anesthesia was induced and maintained with continuous infusions of propofol and remifentanil. MEP was elicited by supramaximal transcranial electrical stimulation. MEP recordings were obtained at baseline and then at 2, 4, 6, 8, and 10 minutes after administration of ketamine (1 mg/kg) or saline (0.1 ml/kg). The primary endpoint was the minimum relative MEP amplitude (peak-to-peak amplitude, % of baseline value) recorded from the left tibialis anterior muscle. The baseline amplitude recorded before test drug administration was defined as 100%.

Results:

Medians (interquartile range) minimum MEP amplitudes in the left tibialis anterior muscle in the ketamine and saline groups were 26% (9% to 34%) and 87% (55% to 103%) of the baseline value, respectively (P<0.001). MEP amplitudes in other muscles were significantly reduced by ketamine. The suppressive effect of ketamine lasted for at least 10 minutes in each muscle.

Conclusion:

A 1-mg/kg bolus dose of ketamine can reduce MEP amplitude. Anesthesiologists should consider the dosage and timing of intravenous ketamine administration during MEP monitoring.
A Novel Low-Cost Surgical Simulation Tool for Pinning Supracondylar Humerus Fractures
Authors: Urwin John W. , Trionfo Arianna , Storey Eileen P. , Brusalis Christopher M. , Gajewski Christopher , Lawrence John Todd R.
Published: October 2019

Background:

Simulation-based training is one way to improve basic competence for surgical trainees and thus improve patient safety. Closed reduction and percutaneous pinning of a supracondylar humerus fracture is a common procedure that encompasses many basic orthopaedic skills and has been identified as a residency milestone. Despite this, no quantitative tools exist to help learners attain this basic skill. This study seeks to validate a quantitative, low-cost simulation-based training tool for teaching orthopaedic surgery trainees the fundamentals of fracture stabilization with pins.

Methods:

Two low-cost models were developed with simulated cancellous bone blocks and cortical bone sheets: a pinning agility tool to teach pin placement and redirection, and a low-cost construct stability tool to replicate pinning. A high-cost construct stability tool was cut using a pediatric supracondylar humerus model to simulate pinning a real fracture. Construct stability was assessed by adding weight until ∼1.6 mm of displacement was observed. Participants were tested naively on all 3 models and then completed a training session using only the low-cost models. Performance following training was then assessed and compared with fellowship-trained pediatric orthopaedic surgeons. Participants also rated their preintervention and postintervention confidence, skill, and knowledgeability.

Results:

A total of 18 novice trainees participated (10 PGY1 and PGY2 orthopaedic surgery residents and 8 medical student members of the orthopaedic surgery interest club), whereas the reference group consisted of 7 orthopaedic surgery attendings. The subjects significantly improved their scores on both the low-cost (P=0.002) and high-cost (P<0.001) construct stability tools after the training with only the low-cost tools. Compared with the attending benchmark, trainee scores improved on the high-fidelity model from 31% preintervention to 86% postintervention and their pinning times decreased by 38%. Trainees reported increased knowledge, skill, and confidence after the intervention (P<0.001).

Conclusions:

A novel, low-cost simulation model and training session for supracondylar humerus fracture pinning resulted in improved performance in stabilizing a supracondylar humerus model and increased trainee knowledgeability, confidence, and skill.

Level of Evidence:

Level II—economic.
Phase I Study of IGF-Methotrexate Conjugate in the Treatment of Advanced Tumors Expressing IGF-1R
Authors: Venepalli Neeta K. , Emmadi Rajyasree , Danciu Oana C. , Chowdhery Rozina , Cabay Robert J. , Gaitonde Sujata , Aardsma Nathan , Kothari Rajul , Liu Li C. , Fischer James H. , Zaidi Ayesha , Russell Meredith J. , Dudek Arkadiusz Z.
Published: October 2019

Objectives:

Insulin-like growth factor-methotrexate (IGF-MTX) is a conjugate of methotrexate and 765IGF, a variant of IGF-1 with high affinity for insulin-like growth factor type 1 receptor. The study aim was to determine the maximum tolerated dose of IGF-MTX in refractory solid organ and hematologic malignancies expressing insulin-like growth factor type 1 receptor.

Materials and Methods:

This phase I trial used a modified toxicity probability interval design with 5 cohort dose levels, and expansion cohort at maximum tolerated dose. IGF-MTX was given intravenously over 90 minutes on days 1, 8, and 15 of a 28-day cycle.

Results:

A total of 17 patients were enrolled. The highest tolerated dose tested was 0.80 µEq/kg with dose-limiting toxicity of grade 3 hypoglycemia. Drug-related grade 3 and 4 toxicities included abdominal pain (26%), hypoglycemia (10%), and hypotension (10%). Of the 15 evaluable for response, 3 patients (20%) had stable disease, including the patient with Hodgkin lymphoma with stable disease for 12 cycles of therapy. IGF-MTX concentrations declined rapidly, with half-lives of 5.2 to 14 minutes for the initial distribution phase and 6.5 to 7.5 hours for the terminal elimination phase. Higher IGF-R1 expression did not correlate with better outcome.

Conclusions:

IGF-MTX is well tolerated. IGF-MTX pharmacokinetics suggest rapid cellular uptake. The activity of IGF-MTX in Hodgkin lymphoma should be explored.
Associations between fine particulate matter, extreme heat events, and congenital heart defects
Authors: Stingone Jeanette A. , Luben Thomas J. , Sheridan Scott C. , Langlois Peter H. , Shaw Gary M. , Reefhuis Jennita , Romitti Paul A. , Feldkamp Marcia L. , Nembhard Wendy N. , Browne Marilyn L. , Lin Shao
Published: October 2019

Background:

Previous research reports associations between air pollution measured during pregnancy and the occurrence of congenital heart defects (CHDs) in offspring. The objective of this research was to assess if exposure to extreme heat events (EHEs) during pregnancy may modify this association.

Methods:

The study population consisted of 4,033 controls and 2,632 cases with dates of delivery between 1999 and 2007 who participated in the National Birth Defects Prevention Study, a multi-site case–control study in the United States. Daily data from the closest stationary fine particulate matter (PM2.5) monitor within 50 km from the maternal residence were averaged across weeks 3–8 post-conception. EHEs were defined as maximum ambient temperature in the upper 95th percentile for at least 2 consecutive days or the upper 90th percentile for 3 consecutive days. Logistic regression models were adjusted for maternal age, ethnicity, education, and average humidity. Relative excess risks due to interaction (RERI) were calculated.

Results:

Compared with women with low PM2.5 exposure and no exposure to an EHE, the odds of a ventricular septal defect in offspring associated with high PM2.5 exposure was elevated only among women who experienced an EHE (odds ratio [OR] 2.14 95% confidence interval [CI] 1.19, 3.38 vs. OR 0.97 95% CI 0.49, 1.95; RERI 0.82 95% CI −0.39, 2.17). The majority of observed associations and interactions for other heart defects were null and/or inconclusive due to lack of precision.

Conclusions:

This study provides limited evidence that EHEs may modify the association between prenatal exposure to PM2.5 and CHD occurrence.
Population Pharmacokinetics of Levobupivacaine During Transversus Abdominis Plane Block in Children
Authors: Vincent Marc , Mathieu Olivier , Nolain Patrick , Menacé Cecilia , Khier Sonia
Published: October 2019

Background:

Levobupivacaine is commonly used during transversus abdominis plane (TAP) block in pediatric patients. However, the dosing regimen is still empirical, and the pharmacokinetic properties of levobupivacaine are not considered. Here, the pharmacokinetics of levobupivacaine during an ultrasound-guided TAP block were evaluated to optimize dosing regimen, regarding the between-subject variability (BSV) and the volume of levobupivacaine injected.

Method:

The clinical trial (prospective, randomized, double-blind study protocol) was conducted in 40 children aged 1–5 years, who were scheduled for inguinal surgery. Each patient received 0.4 mg/kg of levobupivacaine with a volume of local anesthesia solution adjusted to 0.2 mL/kg of 0.2% or 0.4 mL/kg of 0.1% levobupivacaine. Blood samples were collected at 5, 15, 20, 25, 30, 45, 60, and 75 minutes after the block injection. The population pharmacokinetic analysis was performed using the NONMEM software.

Results:

From the pharmacokinetic parameters obtained, median Cmax, tmax,, and area under the concentration versus time curve were 0.315 mg/L, 17 minutes, and 41 mg/L·min−1, respectively. BSV of clearance was explained by weight. At the dose regimen of 0.4 mg/kg, none of the infants showed signs of toxicity, but in 13 patients, TAP block failed. After analysis, BSV for absorption rate constant, distribution volume, and clearance were 81%, 47%, and 41%, respectively. Residual unexplained variability was estimated to be 14%.

Conclusions:

For improved efficiency in the pediatric population, the dose of levobupivacaine should be greater than 0.4 mg/kg. Children's weight should be considered to anticipate any risk of toxicity.
Localized Retinal Nerve Fiber Layer Defect Location Among Red-free Fundus Photographs, En Face Structural Images, and Cirrus HD-OCT Maps
Authors: Park Ji-Hye , Yoo Chungkwon , Kim Yong Yeon
Published: October 2019

Precis:

Although the localized retinal nerve fiber layer (RNFL) defects in the en face structural images showed excellent topographic correlation with those in red-free photographs, the RNFL defect was frequently misidentified by the optical coherence tomography (OCT) deviation map.

Purpose:

The purpose of this study was to compare the location of localized RNFL defects using red-free fundus photographs, OCT en face structural images, and OCT RNFL deviation and thickness maps.

Methods:

We investigated the agreement of angular locations of localized RNFL defects. Seventy localized RNFL defects were selected in red-free photographs (red-free defect). En face images and OCT deviation and thickness maps were overlaid on the corresponding red-free photographs. The proximal/distal angular locations and angular width of the red-free defects were compared with those of en face structural images (en face defect) and OCT RNFL deviation (deviation map defect) and thickness maps (thickness map defect).

Results:

Among 70 eyes with red-free defects, 13 (18.6%), 1 (1.4%), and 0 (0%) defects were misidentified by the OCT deviation map, thickness map, and en face image, respectively. There were no significant differences among red-free defects, en face defects, and OCT thickness map defects in the angular width and proximal/distal angular locations. The angular widths were significantly greater in OCT RNFL deviation maps compared with those of other imaging modalities. The correlation coefficients of angular width and locations between the red-free defect and en face defect were significantly higher than those between the red-free defect and OCT map defects (all, P<0.001).

Conclusions:

Localized RNFL defects detected in red-free photographs showed the highest topographic correlation with defects detected in OCT en face images. En face structural images may aid in identifying the localized RNFL defects in glaucomatous eyes.
Increasing Rates of Pediatric Empyema and Disease Severity With Predominance of Serotype 3 S. pneumonia
Authors: Haggie Stuart , Fitzgerald Dominic A. , Pandit Chetan , Selvadurai Hiran , Robinson Paul , Gunasekera Hasantha , Britton Philip
Published: October 2019

Background:

The impact of universal 13-valent pneumococcal conjugate vaccine immunization on pediatric empyema rates and pathogens in Australia is not known. We aimed to describe empyema epidemiology, clinical characteristics and treatment during an 8-year period.

Methods:

A retrospective study between 2011 and 2018 of empyema cases admitted to a large pediatric referral hospital, for management with either pleural drainage and fibrinolytics or surgical intervention.

Results:

There were 195 cases in 8 years. Empyema incidence and ICU admission rates significantly increased during the study with a peak incidence of 7.1/1000 medical admissions in 2016 (χ2 for trend of incidence 37.8, P < 0.001 and for ICU admissions 15.3, P < 0.001). S. pneumoniae was the most common pathogen (75/195, 39%) with serotype 3 the most detected (27/75: 27%). S. pyogenes compared with S. pneumoniae had significantly fewer days of fever before admission (3.9 vs. 6.4, mean difference 2.4, 95% CI: 0.84–4.08, P = 0.003) and higher proportion requiring direct ICU admission (6/75; 8% vs. 7/15; 47%, P < 0.001). Compared with S. pneumoniae, cases with no pathogen detected by culture or PCR had fewer days of fever post intervention (4.4 vs. 7.4 days, mean difference 2.7 days, P = 0.002). S. aureus occurred more commonly in infants (10/25; 40% vs. 1/75; 1%, P < 0.001) and children of indigenous background (5/25; 20% vs. 1/75; 1%, P < 0.001) compared with S. pneumoniae.

Conclusions:

We report increasing rates of pediatric empyema with higher proportions requiring ICU treatment. The most common pathogens detected were S. pneumoniae, S. aureus and S. pyogenes. Despite high 13-valent pneumococcal conjugate vaccine coverage, serotype 3 was the most common S. pneumoniae serotype identified.
Experimentally induced spinal nociceptive sensitization increases with migraine frequency: a single-blind controlled study
Authors: De Icco Roberto , Perrotta Armando , Grillo Valentina , Cosentino Giuseppe , Sances Grazia , Sandrini Giorgio , Tassorelli Cristina
Published: October 2019

The nitric-oxide donor nitroglycerin (NTG) administration induces a facilitation of nociceptive pathways in episodic migraine. This study aims to test the hypothesis that induced spinal sensitization could be more pronounced in patients affected by high-frequency migraine (HF-MIG) with respect to low-frequency migraine (LF-MIG). We enrolled 28 patients with LF-MIG (1-5 migraine days/month), 19 patients with HF-MIG (6-14 migraine days/month), and 21 healthy controls (HCs). Spinal sensitization was evaluated with the neurophysiological recording of the temporal summation threshold (TST) of the nociceptive withdrawal reflex at the lower limb. Temporal summation threshold was recorded at baseline and 30, 60, and 120 minutes after NTG administration (0.9 mg sublingual). Spinal sensitization was detected in LF-MIG at 60 (P = 0.010) and 120 minutes (P = 0.001) and in HF-MIG at 30 (P = 0.008), 60 (P = 0.001), and 120 minutes (P = 0.001) after NTG administration. Temporal summation threshold did not change in HC (P = 0.899). Moreover, TST reduction was more pronounced in HF-MIG with respect to LF-MIG (P = 0.002). The percentage of patients who developed a migraine-like headache after NTG was comparable in the 2 migraine groups (LF-MIG: 53.6%, HF-MIG: 52.6%, P = 0.284), whereas no subjects in the HC group developed a delayed-specific headache. Notably, the latency of headache onset was significantly shorter in the HF-MIG group when compared with the LF-MIG group (P = 0.015). Our data demonstrate a direct relationship between migraine frequency and both neurophysiological and clinical parameters, to suggest an increasing derangement of the nociceptive system control as the disease progresses, probably as a result of the interaction of genetic and environmental factors.
Culture Cell Block Controls as a Tool to the Biomolecular Diagnosis of Infectious Diseases
Authors: José Tadeu de Araujo Leonardo , Salas-Gómez David , Midori Kimura Lidia , Fernandes Possatto Takahashi Juliana , de Souza Barrel Joana , Rollin Dominique C. , Mariotti Guerra Juliana
Published: October 2019

The cell block (CB) technique has allowed easy obtainment of samples such as cellular and culture suspensions, to perform specific molecular tests such as immunohistochemistry and in situ hybridization. It has been improved along time, accuracy, and quality of the diagnoses, however, the cost of a commercial gel matrix for the preparation of CB is high and not suitable depending on the situation. The objective of this study is to test agarose as an alternative to the commercial gel matrix in the preparation of Aspergillus fumigatus’ CB.
Thrombotic Hemangioma With Organizing/Anastomosing Features
Authors: Liau Jau-Yu , Lee Jen-Chieh , Tsai Jia-Huei , Chen Chih-Chi , Wang Ying-Hao , Chung Yung-Chuan
Published: October 2019

In this study, we aimed to present the clinicopathologic and molecular features of a distinct group of hemangioma with GNA mutations that exhibited prominent thrombosis and organization changes with florid intravascular endothelial cell proliferation that we provisionally termed “thrombotic hemangioma with organizing/anastomosing features.” Twenty-six cases were included. No sex predilection was seen (male:female=13:13). Patients’ age ranged from 17 to 89 years (median: 51 y). All but 1 occurred in the skin whereas the remaining tumor involved the neck soft tissue. Remarkably, the majority (18) occurred in the lower abdominal/inguinal regions. Histologically, thrombotic hemangioma with organizing/anastomosing features were circumscribed tumors composed of variably sized and congested thin-walled vessels. The most striking features were prominent thrombosis and organization with florid intravascular endothelial cell proliferation. The proliferating endothelial cells exhibit a streaming pattern with focal anastomosing–like feature resembling anastomosing hemangioma. The stroma was sclerotic or hyalinized but could also be myxoid/edematous. Other features included vessels with nuclear hobnailing and perivascular hyalinization, cherry hemangioma–like component, cavernous-like or sinusoidal hemangioma–like areas, Masson hemangioma–like feature, and spindle cell fascicular pattern. Mitotic activity was usually low and nuclei were bland but 2 tumors exhibited moderate nuclear atypia and higher mitotic activity. Extramedullary hematopoiesis and hyaline globules were not identified. Genetically, by Sanger sequencing and MassARRAY analysis, mutually exclusive GNAQ, GNA11, and GNA14 exon 5 mutations were identified in 15, 5, and 2 tumors, respectively, with a combined mutation rate of 85% (22/26). In conclusion, we described a distinct group of hemangioma and expanded the clinicopathologic features of GNA-mutated hemangiomas.
Immunohistochemistry for PRAME in the Distinction of Nodal Nevi From Metastatic Melanoma
Authors: Lezcano Cecilia , Pulitzer Melissa , Moy Andrea P. , Hollmann Travis J. , Jungbluth Achim A. , Busam Klaus J.
Published: October 2019

The distinction of metastatic melanoma from melanocytic nevi in lymph nodes can on occasion be difficult. As diffuse immunohistochemical (IHC) PRAME (PReferentially expressed Antigen in MElanoma) expression is detected in the majority of primary and metastatic melanomas, but rarely in nevi, we reasoned that PRAME could be a useful adjunct marker for the diagnosis of melanocytes in lymph nodes. In this study, we examined 45 nodal melanocytic deposits comprising 30 nodal nevi and 15 melanoma metastases. The latter were diagnostically not straightforward because they either coexisted with nodal nevi or were present in perinodal fibrous tissue. All nodal nevi (30/30) were negative for PRAME, whereas all melanoma metastases (15/15) were diffusely positive for PRAME IHC. We additionally report the novel use of a PRAME/Melan A dual-label immunostain. Our results show that PRAME IHC may be useful in the assessment of diagnostically challenging nodal melanocytic deposits, such as intraparenchymal nodal nevi, metastases confined to the capsular fibrous tissue, or in the setting of small metastases coexisting with a nodal nevus in the same lymph node.
Extremity Mobilization After Split-Thickness Skin Graft Application
Authors: Retrouvey Helene , Adibfar Alexander , Shahrokhi Shahriar
Published: October 2019

Purpose

To determine the current postoperative mobilization care practice patterns of burn surgeons after split-thickness skin grafting and to assess potential inconsistencies in management strategies.

Methods

A cross-sectional study of active burn surgeons was conducted with an online questionnaire (SurveyMonkey) comprising 7 demographic and 22 mobilization-related questions.

Results

Seventy-three (22%) of the 337 members of the American Burn Association mailing list consented to participate in the study, of whom 71 completed the demographic questions and 59 completed the mobilization-related questions. The majority of respondents had more than 10 years of burn care experience (68%) and practiced in an American Burn Association–verified center (70%). Standardized postoperative autograft mobilization protocols were used by 68% of respondents. Most (66%) never or rarely immobilized the upper extremity without joint involvement. When the elbow or wrist was involved, 73% always or very often immobilized. Similarly, 63% never or rarely immobilized the lower extremity without joint involvement. Most immobilized when the knee (70%) or ankle (63%) was involved. Immobilization duration was most commonly 3 or 5 days. Most respondents (71%) reported following Nedelec and colleagues' recommendation that “early postoperative ambulation protocol should be initiated immediately after lower extremity grafting,” although there was practice variability.

Conclusions

Our findings reveal that the majority of survey respondents do not immobilize the extremities after autograft without joint involvement. When grafts cross major joints, most surgeons immobilize for 3 or 5 days. Despite some practice variability, surveyed burn surgeons' current lower extremity ambulation practices generally align with the 2012 guidelines of Nedelec et al.
Current Trends in Unilateral Cleft Lip Care
Authors: Roberts John M. , Jacobs Aaron , Morrow Brad , Hauck Randy , Samson Thomas D.
Published: October 2019

Background

The care of unilateral cleft lip (UCL) patients is extremely variable. Historical benchmarks for perioperative and intraoperative choices by cleft surgeons were produced by Sitzman et al (Plast Reconstr Surg. 2008;121:261e–270e) in 2005. However, emerging data and cleft lip repair methods around this period were not captured by this study. The aim of this study was to update the current practice patterns of cleft lip surgeons.

Methods

An electronic survey was distributed to surgeons in the American Cleft Palate Association. Demographic data about the surgeon were collected as well as their choices regarding perioperative and intraoperative cleft lip care.

Results

Eighty-six surgeons responded to the survey. Nearly 40% of surgeons have changed their technique for UCL repair with Fisher anatomical subunit repair gaining significant popularity. Nasoalveolar molding is also being used more frequently (41% vs 22%). At the time of the cleft lip repair, closure of the nasal floor is occurring in 83.1% of patients and primary cleft rhinoplasty is being performed routinely 57% of the time.

Conclusions

Over the last 10 years, there has been an increase in the use of modified rotation advancement repairs and Fisher anatomic subunit approximation technique for treatment of UCL. There continues to be a lack of evidence regarding superiority of specific repair techniques or the benefits of adjunct procedures, which results in varying practice patterns. Educating all cleft surgeons on practices that are well supported is important to improve care to cleft patients.
Nasolabial Flap Based on the Upper Lateral Lip Subunit for Large Involuted Infantile Hemangiomas of the Upper Lip
Authors: Gao Wei , Jin Yunbo , Lin Xiaoxi
Published: October 2019

Background

Large involuted upper lip infantile hemangioma is a challenge for plastic surgeon because of high visibility of disfigurement. To achieve an optimal reconstruction with matched color and texture, nasolabial flap based on the upper lateral lip subunit is used for the upper lip reconstruction.

Methods

Records of 8 patients who underwent upper lip reconstruction from 2014 to 2018 at Shanghai Ninth People's Hospital were reviewed. After flap design according to the contralateral upper lip subunit, nasolabial flap was dissected and rotated to the defect. The donor site was subsequently closed by extensive undermining cheek skin tissue. The incisions were hidden in the border of lateral upper lip subunit.

Results

There were a few deformities observed, including scar hypertrophy (4/8), alar flaring (2/8), and lower lid bulking (1/8). Five patients received following trimming procedures because of residual scars or deformity. All the patients were satisfied with the postoperative results. No obvious complications were observed.

Conclusions

The nasolabial flap based on the upper lateral lip subunit is a safe, effective, and reliable technique for correction of severe upper lip defect caused by large involuted infantile hemangioma. Although subsequent trimming procedures are required in some complicated cases, satisfactory results can still be achieved.
The Application of Multilayer Direct Closure With a Longitudinal Relaxing Incision in Urethrocutaneous Fistula Repair
Authors: Chen Wen , Ma Ning , Wang Weixin , Ju Mengran
Published: October 2019

The simple closure of a urethrocutaneous fistula is technically easy, but direct suture tension is associated with a higher urethral fistula recurrence rate. We describe a multilayer direct closure with a longitudinal relaxing incision in urethrocutaneous fistula repair, avoiding the tension associated with the direct suturing of the surgical skin wound. From March 2015 to January 2018, 46 urethrocutaneous fistulas in 34 patients were repaired at the Hypospadias Center of our hospital. During the operations, after the urethral fistula closure, a longitudinal penile skin incision was created 0.5 to 1.5 cm from the edge of the surgical wound. The penile skin wound was closed, and the longitudinal penile skin incision made during the operation was used as a relaxing incision to reduce the skin tension of the closed fistula area. The urethral fistula repairs were successful, and no signs of infection or poor healing were present at the closure sites of the penile skin wounds. The relaxing incisions gradually healed within 7 to 21 days after operation, and the residual scars were soft and did not significantly differ in color from normal skin. The key to increasing the success rate of urethrocutaneous fistula repair is creating a longitudinal relaxing penile skin incision. The technique aims to avoid the direct suture tension of the penile skin wound, thereby providing a favorable environment for the normal healing of the urethral fistula suture site.
Extensive Post-Traumatic Surgical Emphysema Exacerbated by Cocaine Insufflation
Authors: Shah Nirmal , Shafi Ahad , Benech Rodolfo , Campbell Duncan
Published: October 2019

Surgical emphysema (SE) is characterized by air in the soft tissues causing a crackling sensation on palpation. In oral and maxillofacial surgery, it might occur using conventional air-driven dental hand pieces, as a complication of trauma and with cocaine insufflation.

The subcutaneous air may travel through tissue planes causing cervicofacial emphysema, pneumothorax, and pneumomediastinum. It may carry bacteria and potentially lead to cellulitis or necrotizing fasciitis.

The SE is usually a self-limiting entity requiring analgesia, close observation of the airway, occasionally prophylactic antibiotics, and rarely steroids. Although, the consensus on antibiotic and corticosteroid therapy is unclear.

Here presented an unusual and extensive presentation of surgical emphysema. A 29 years old male presented with emphysema following a left orbital-zygomatic complex fracture and following intranasal cocaine insufflation. It extended from the temple to the parotid region, down into the neck and into the mediastinum. No surgical intervention was required. The patient was discharged after 24 hours of observation with a week-long course of co-amoxiclav antibiotics and no corticosteroids administration.

Typical instructions following facial bone fractures are to avoid nose blowing because of the risk of SE, however, avoidance of drug habits is rarely considered. This case report highlights the importance of tailored advice to this particular patient cohort.
Applied Deep Learning in Plastic Surgery: Classifying Rhinoplasty With a Mobile App
Authors: Borsting Emily , DeSimone Robert , Ascha Mustafa , Ascha Mona
Published: October 2019

Background:

Advances in deep learning (DL) have been transformative in computer vision and natural language processing, as well as in healthcare. The authors present a novel application of DL to plastic surgery. Here, the authors describe and demonstrate the mobile deployment of a deep neural network that predicts rhinoplasty status, assess model accuracy compared to surgeons, and describe future directions for such applications in plastic surgery.

Methods:

A deep convolutional neural network (“RhinoNet”) was developed to classify rhinoplasty images using only pixels and rhinoplasty status labels (“before”/“after”) as inputs. RhinoNet was trained using a dataset of 22,686 before and after photos which were collected from publicly available sites. Network classification was compared to that of plastic surgery attendings and residents on 2269 previously-unseen test-set images.

Results:

RhinoNet correctly predicted rhinoplasty status in 85% of the test-set images. Sensitivity and specificity of model predictions were 0.840 (0.79–0.89) and 0.826 (0.77–0.88), respectively; the corresponding values for expert consensus predictions were 0.814 (0.76–0.87) and 0.867 (0.82–0.91). RhinoNet and humans performed with effectively equivalent accuracy in this classification task.

Conclusion:

The authors describe the development of DL applications to identify the presence of superficial surgical procedures solely from images and labels. DL is especially well suited for unstructured, high-fidelity visual and auditory data that does not lend itself to classical statistical analysis, and may be deployed as mobile applications for potentially unbridled use, so the authors expect DL to play a key role in many areas of plastic surgery.
Surgical Smoke Evacuators Reduce the Risk of Fires From Alcohol-Based Skin Preparations
Authors: Carmichael Heather , Samuels Jason M. , Wikiel Krzysztof J. , Robinson Thomas N. , Barnett Carlton C. , Jones Teresa S. , Jones Edward L.
Published: October 2019

Surgical smoke evacuators may reduce the concentration of alcohol vapors from skin preparations at the site of electrosurgical device activation, decreasing operating room fire risk. Our aim was to compare the incidence of flames with and without smoke evacuation in a porcine ex vivo model. A monopolar device was activated after application of either 70% isopropyl alcohol/2% chlorhexidine gluconate (CHG-IPA) or 74% isopropyl alcohol/0.7% iodine povacrylex (iodine-IPA) skin preparations. No suction was compared with standard wall suction and 2 monopolar devices with built-in smoke evacuators. Flames were generated in 60% of CHG-IPA and 47% of iodine-IPA tests without suction. Wall suction did not significantly reduce fires (CHG-IPA 43% vs. 60%, P=0.30; iodine-IPA 57% vs. 47%, P=0.61). Use of both smoke evacuation devices reduced fires for CHG-IPA (17% vs. 60%, P=0.001 and 20% vs. 60%, P=0.004) but not for iodine-IPA. Smoke evacuation devices reduce fire risk when used with a chlorhexidine-alcohol skin preparation.
On the origin of degeneracy in the genetic code
Authors: Gonzalez D. L. , Giannerini S. , Rosa R.
Published: October 2019

The degeneracy of amino acid coding is one of the most crucial and enigmatic aspects of the genetic code. Different theories about the origin of the genetic code have been developed. However, to date, there is no comprehensive hypothesis on the mechanism that might have generated the degeneracy as we observe it. Here, we provide a new theory that explains the origin of the degeneracy based only on symmetry principles. The approach allows one to describe exactly the degeneracy of the early code (progenitor of the genetic code of LUCA, the last universal common ancestor) which is hypothesized to have the same degeneracy as the present vertebrate mitochondrial genetic code. The theory is based upon the tessera code, that fits as the progenitor of the early code. Moreover, we describe in detail the possible evolutionary transitions implied by our theory. The approach is supported by a unified mathematical framework that accounts for the degeneracy properties of both nuclear and mitochondrial genetic codes. Our work provides a new perspective to the understanding of the origin of the genetic code and the roles of symmetry principles in the organization of genetic information.
Protein three-dimensional structures at the origin of life
Authors: Milner-White E. James
Published: October 2019

Proteins are relatively easy to synthesize, compared to nucleic acids and it is likely that there existed a stage prior to the RNA world which can be called the protein world. Some of the three-dimensional (3D) peptide structures in these proteins have, we argue, been conserved since then and may constitute the oldest biological relics in existence. We focus on 3D peptide motifs consisting of up to eight or so amino acid residues. The best known of these is the ‘nest’, a three- to seven-residue protein motif, which has the function of binding anionic atoms or groups of atoms. Ten per cent of amino acids in typical proteins belong to a nest, so it is a common motif. A five-residue nest is found as part of the well-known P-loop that is a recurring feature of many ATP or GTP-binding proteins and it has the function of binding the phosphate part of these ligands. A synthetic hexapeptide, ser–gly–ala–gly–lys–thr, designed to resemble the P-loop, has been shown to bind inorganic phosphate. Another type of nest binds iron–sulfur centres. A range of other simple motifs occur with various intriguing 3D structures; others bind cations or form channels that transport potassium ions; other peptides form catalytically active haem-like or sheet structures with certain transition metals. Amyloid peptides are also discussed. It now seems that the earliest polypeptides were far from being functionless stretches, and had many of the properties, both binding and catalytic, that might be expected to encourage and stabilize simple life forms in the hydrothermal vents of ocean depths.
Probing complexity: thermodynamics and computational mechanics approaches to origins studies
Authors: Bartlett Stuart J. , Beckett Patrick
Published: October 2019

This paper proposes new avenues for origins research that apply modern concepts from stochastic thermodynamics, information thermodynamics and complexity science. Most approaches to the emergence of life prioritize certain compounds, reaction pathways, environments or phenomena. What they all have in common is the objective of reaching a state that is recognizably alive, usually positing the need for an evolutionary process. As with life itself, this correlates with a growth in the complexity of the system over time. Complexity often takes the form of an intuition or a proxy for a phenomenon that defies complete understanding. However, recent progress in several theoretical fields allows the rigorous computation of complexity. We thus propose that measurement and control of the complexity and information content of origins-relevant systems can provide novel insights that are absent in other approaches. Since we have no guarantee that the earliest forms of life (or alien life) used the same materials and processes as extant life, an appeal to complexity and information processing provides a more objective and agnostic approach to the search for life's beginnings. This paper gives an accessible overview of the three relevant branches of modern thermodynamics. These frameworks are not commonly applied in origins studies, but are ideally suited to the analysis of such non-equilibrium systems. We present proposals for the application of these concepts in both theoretical and experimental origins settings.
Catalysts, autocatalysis and the origin of metabolism
Authors: Preiner Martina , Xavier Joana C. , Vieira Andrey do Nascimento , Kleinermanns Karl , Allen John F. , Martin William F.
Published: October 2019

If life on Earth started out in geochemical environments like hydrothermal vents, then it started out from gasses like CO
2
, N
2
and H
2
. Anaerobic autotrophs still live from these gasses today, and they still inhabit the Earth's crust. In the search for connections between abiotic processes in ancient geological systems and biotic processes in biological systems, it becomes evident that chemical activation (catalysis) of these gasses and a constant source of energy are key. The H
2
–CO
2
redox reaction provides a constant source of energy and anabolic inputs, because the equilibrium lies on the side of reduced carbon compounds. Identifying geochemical catalysts that activate these gasses en route to nitrogenous organic compounds and small autocatalytic networks will be an important step towards understanding prebiotic chemistry that operates only on the basis of chemical energy, without input from solar radiation. So, if life arose in the dark depths of hydrothermal vents, then understanding reactions and catalysts that operate under such conditions is crucial for understanding origins.
Towards a differential diagnosis of cochlear synaptopathy and outer-hair-cell deficits in mixed sensorineural hearing loss pathologies
Authors: Vasilkov Viacheslav , Verhulst Sarah
Published: October 2019

Damage to the auditory periphery is more widespread than predicted by the gold-standard clinical audiogram. Noise exposure, ototoxicity and aging can destroy cochlear inner-hair-cell afferent synapses and result in a degraded subcortical representation of sound while leaving hearing thresholds unaffected. Damaged afferent synapses, i.e. cochlear synaptopathy, can be quantified using histology, but a differential diagnosis in living humans is difficult: histology cannot be applied and existing auditory evoked potential (AEP) metrics for synaptopathy become insensitive when other sensorineural hearing impairments co-exist (e.g., outer-hair-cell damage associated with elevated hearing thresholds). To develop a non-invasive diagnostic method which quantifies synaptopathy in humans and animals with normal or elevated hearing thresholds, we employ a computational model approach in combination with human AEP and psychoacoustics. We propose the use of a sensorineural hearing loss (SNHL) map which comprises two relative AEP-based metrics to quantify the respective degrees of synaptopathy and OHC damage and evaluate to which degree our predictions of AEP alterations can explain individual data-points in recorded SNHL maps from male and female listeners with normal or elevated audiometric thresholds. We conclude that SNHL maps can offer a more precise diagnostic tool than existing AEP methods for individual assessment of the synaptopathy and OHC-damage aspect of sensorineural hearing loss.

Significance Statement

Hearing loss ranks fourth in global causes for disability and risk factors include noise exposure, ototoxicity and aging. The most vulnerable parts of the cochlea are the inner-hair-cell afferent synapses and their damage (cochlear synaptopathy) results in a degraded subcortical representation of sound. While synaptopathy can be estimated reliably using histology, it cannot be quantified this way in living humans. Secondly, other co-existing sensorineural hearing deficits (e.g., outer-hair-cell damage) can complicate a differential diagnosis. To quantify synaptopathy in humans and animals with normal or elevated hearing thresholds, we adopt a theoretical and interdisciplinary approach. Sensitive diagnostic metrics for synaptopathy are crucial to assess its prevalence in humans, study its impact on sound perception and yield effective hearing restoration strategies.