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Abstract Background Noise-induced hearing loss (NIHL) is the most prevalent form of acquired hearing loss and affects about 40 million US adults. Among the suggested therapeutics tested in rodents, suberoylanilide hydroxamic acid (SAHA) has been shown to be otoprotective from NIHL; however, these results were limited to male mice. Methods Here we tested the effect of SAHA on the hearing of 10-week-old B6CBAF1/J mice of both sexes, which were exposed to 2 h of octave-band noise (101 dB SPL centered at 11.3 kHz). Hearing was assessed by measuring auditory brainstem responses (ABR) at 8, 16, 24, and 32 kHz, 1 week before, as well as at 24 h and 15–21 days following exposure (baseline, compound threshold shift (CTS) and permanent threshold shift (PTS), respectively), followed by histologic analyses. Results We found significant differences in the CTS and PTS of the control (vehicle injected) mice to noise, where females had a significantly smaller CTS at 16 and 24 kHz (p

Abstract Background Small-diameter, myelinated axons are selectively susceptible to dysfunction in several inflammatory PNS and CNS diseases, resulting in pain and degeneration, but the mechanism is not known. Methods We used in vivo confocal microscopy to compare the effects of inflammation in experimental autoimmune neuritis (EAN), a model of Guillain-Barré syndrome (GBS), on mitochondrial function and transport in large- and small-diameter axons. We have compared mitochondrial function and transport in vivo in (i) healthy axons, (ii) axons affected by experimental autoimmune neuritis, and (iii) axons in which mitochondria were focally damaged by laser induced photo-toxicity. Results Mitochondria affected by inflammation or laser damage became depolarized, fragmented, and immobile. Importantly, the loss of functional mitochondria was accompanied by an increase in the number of mitochondria transported towards, and into, the damaged area, perhaps compensating for loss of ATP and allowing buffering of the likely excessive Ca2+ concentration. In large-diameter axons, healthy mitochondria were found to move into the damaged area bypassing the dysfunctional mitochondria, re-populating the damaged segment of the axon. However, in small-diameter axons, the depolarized mitochondria appeared to “plug” the axon, obstructing, sometimes completely, the incoming (mainly anterograde) transport of mitochondria. Over time (~ 2 h), the transported, functional mitochondria accumulated at the obstruction, and the distal part of the small-diameter axons became depleted of functional mitochondria. Conclusions The data show that neuroinflammation, in common with photo-toxic damage, induces depolarization and fragmentation of axonal mitochondria, which remain immobile at the site of damage. The damaged, immobile mitochondria can “plug” myelinated, small-diameter axons so that successful mitochondrial transport is prevented, depleting the distal axon of functioning mitochondria. Our observations may explain the selective vulnerability of small-diameter axons to dysfunction and degeneration in a number of neurodegenerative and neuroinflammatory disorders.

The Prostate Urine Risk (PUR) biomarker is a four-group classifier for predicting outcome in patients prior to biopsy and for men on active surveillance. The four categories correspond to the probabilities of the presence of normal tissue (PUR-1), D’Amico low-risk (PUR-2), intermediate-risk (PUR-3), and high-risk (PUR-4) prostate cancer. In the current study we investigate how the PUR-4 status is linked to Gleason grade, prostate volume, and tumor volume as assessed from biopsy (n = 215) and prostatectomy (n = 9) samples. For biopsy data PUR-4 status alone was linked to Gleason Grade group (GG) (Spearman’s, ρ = 0.58, p < 0.001 trend). To assess the impact of tumor volume each GG was dichotomized into Small and Large volume cancers relative to median volume. For GG1 (Gleason Pattern 3 + 3) cancers volume had no impact on PUR-4 status. In contrast for GG2 (3 + 4) and GG3 (4 + 3) cancers PUR-4 levels increased in large volume cancers with statistical significance observed for GG2 (p = 0.005; Games-Howell). These data indicated that PUR-4 status is linked to the presence of Gleason Pattern 4. To test this observation tumor burden and Gleason Pattern were assessed in nine surgically removed and sectioned prostates allowing reconstruction of 3D maps. PUR-4 was not correlated with Gleason Pattern 3 amount, total tumor volume or prostate size. A strong correlation was observed between amount of Gleason Pattern 4 tumor and PUR-4 signature (r = 0.71, p = 0.034, Pearson’s). These observations shed light on the biological significance of the PUR biomarker and support its use as a non-invasive means of assessing the presence of clinically significant prostate cancer.

This study compared outcomes of two surgical methods for patients diagnosed with active condylar hyperplasia type 1. Group 1 (n = 12) was treated with orthognathic surgery only, while group 2 (n = 42) was treated with high condylectomies, articular disc repositioning, and orthognathic surgery. There was no statistically significant difference between the two groups for maximum incisal opening, lateral excursions, and subjective jaw function before surgery. Group 2 showed more active presurgical mandibular growth (P < 0.05). At long-term follow up, no differences were found in lateral excursions and subjective jaw function. Group 2 showed a greater increase in maximum incisal opening (P < 0.01) and stability (P < 0.05) at long-term follow-up. All of the patients in group 1 grew back into skeletal and occlusal Class III relationships requiring secondary intervention, whereas all patients in group 2 remained stable in a Class I skeletal and occlusal relationship. Thus, patients with active condylar hyperplasia treated with high condylectomy, articular disc repositioning, and orthognathic surgery had stable, predictable outcomes compared with those treated with orthognathic surgery only. The high condylectomy effectively arrests disproportionate mandibular growth while maintaining normal jaw function. [ABSTRACT FROM AUTHOR]

This study evaluated 1) the efficacy of packing autologous fat grafts around temporomandibular joint (TMJ) total joint prosthetic reconstructions to prevent fibrosis and heterotopic bone formation and 2) the effects on postsurgical joint mobility and jaw function. One hundred fifteen patients (5 males and 110 females) underwent TMJ reconstruction with total joint prostheses and simultaneous fat grafts (88 bilateral and 27 unilateral) for a total of 203 joints. The abdominal fat grafts were packed around the articulating portion of the joint prostheses after the fossa and mandibular components were stabilized. Patients were divided into two groups: group 1 (n = 76 joints) received Christensen total joint prostheses, and group 2 (n = 127 joints) received TMJ Concepts total joint prostheses. Clinical and radiographic assessments were performed before surgery, immediately after surgery, and at long-term follow-up. In group 1, maximal incisal opening (MIO) increased 3.5 mm, lateral excursions (LE) decreased 0.2 mm, and jaw function improved 1.9 levels. In group 2, MIO increased 6.8 mm, LE decreased 1.4 mm, and jaw function improved 2.4 levels. The improvement for MIO and patient perception of jaw function in both groups was statistically significant; no significant difference was found for LE. There was no radiographic or clinical evidence of heterotopic calcifications or limitation of mobility secondary to fibrosis in either group. Twenty-five Christensen prostheses (33%) were removed because of device failure and/or metal hypersensitivity; no fibrosis or heterotopic bone formation was seen at surgical removal. Four TMJ Concepts prostheses (3%) were removed because of metal hypersensitivity. In all instances, removal of the prostheses was unrelated to the autologous fat grafting. Ten patients (8.7%) developed complications involving the fat donor site: two patients (1.8%) developed abdominal cysts requiring surgery, and eight patients (6.9%) developed seroma formation requiring aspiration. Autologous fat transplantation is a useful adjunct to prosthetic TMJ reconstruction to minimize the occurrence of excessive joint fibrosis and heterotopic calcification, consequently providing improved range of motion and jaw function. [ABSTRACT FROM AUTHOR]

The World Health Organization's ICF shifts the focus of health from functional ability to improved capacity for living with the consequences of conditions such as a stroke. Reintegration into the family and community are seen as a measure of health. Seventeen couples in which one partner has had a stroke and were at least 6 months post discharge from a health facility took part in a project to develop a multidisciplinary family centered community stroke program. Participants self-reported their involvement in individual and community leisure pursuits and completed the Leisure Diagnostic Battery (LDB; Witt & Ellis, 1989) at pre- and post-treatment and 8-month follow-up to evaluate the Therapeutic Recreation Services component of this program. Participants were found to have increases in their perception of opportunities for leisure and the actual amount of involvement they had in community programs. Spouses' perception of the leisure competence of the individual who has had a stroke also increased. [ABSTRACT FROM AUTHOR]

Intraluminal pulmonary vein stenosis is a disease with significant morbidity and mortality, though recent progress has been made using multimodal therapy with antiproliferative agents. The aim of this study was to evaluate the association between aspiration and poor treatment response in patients with intraluminal pulmonary vein stenosis. A retrospective, single-center cohort analysis was performed of patients treated with a combination of imatinib mesylate and multimodal anatomic relief between March 2009 and November 2019. Analysis focused on 2-ventricle patients due to small numbers and clinical heterogeneity of single ventricle patients. Among the 84 patients included, 15 had single ventricle physiology and 69 had 2-ventricle physiology. Among the 2-ventricle group, multivariable analysis revealed that patients with clinical aspiration had nearly five times higher odds of poor treatment response than patients without aspiration (OR 4.85, 95% CI [1.37, 17.2], p = 0.014). Furthermore, male patients had higher odds of poor treatment response than their female counterparts (OR 3.67, 95% CI [1.04, 12.9], p = 0.043). Aspiration is a novel, potentially modifiable risk factor for poor treatment response in pediatric multi-vessel intraluminal pulmonary vein stenosis in patients with 2-ventricle physiology.

Purpose: To evaluate extravascular findings on thoracic MDCT angiography in secondary pulmonary vein stenosis (PVS) due to total anomalous pulmonary venous connection (TAPVC) repair in children. Materials and Methods: All patients aged ≤18 years with a known diagnosis of secondary PVS after TAPVC repair, confirmed by echocardiography, conventional angiography, and/or surgery, who underwent thoracic MDCT angiography studies between July 2008 and April 2021 were included. Two pediatric radiologists independently examined MDCT angiography studies for the presence of extravascular thoracic abnormalities in the lung, pleura, and mediastinum. The location and distribution of each abnormality (in relation to the location of PVS) were also evaluated. Interobserver agreement between the two independent pediatric radiology reviewers was studied using kappa statistics. Results: The study group consisted of 20 consecutive pediatric patients (17 males, 3 females) with secondary PVS due to TAPVC repair. Age ranged from 2 months to 8 years (mean, 16.1 months). In children with secondary PVS due to TAPVC repair, the characteristic extravascular thoracic MDCT angiography findings were ground-glass opacity (19/20; 95%), septal thickening (7/20; 35%), pleural thickening (17/20; 85%), and a poorly defined, mildly heterogeneously enhancing, non-calcified soft tissue mass (17/20; 85%) which followed the contours of affected pulmonary veins outside the lung. There was excellent interobserver kappa agreement between two independent reviewers for detecting extravascular abnormalities on thoracic MDCT angiography studies (k = 0.99). Conclusion: Our study characterizes the extravascular thoracic MDCT angiography findings in secondary pediatric PVS due to TAPVC repair. In the lungs and pleura, ground-glass opacity, interlobular septal thickening, and pleural thickening are common findings. Importantly, the presence of a mildly heterogeneously enhancing, non-calcified mediastinal soft tissue mass in the distribution of the PVS is a novel characteristic thoracic MDCT angiography finding seen in pediatric secondary PVS due to TAPVC repair.

Pulmonary vein stenosis is a serious condition characterized by restriction or blockage due to fibrotic tissue ingrowth that develops in the pulmonary veins of infants or children. It is often progressive and can lead to severe pulmonary hypertension and death. Efforts to halt or reverse disease progression include surgery and catheter-based balloon dilation and stent implantation. Its cause and mechanism of progression are unknown. In this pilot study, we propose and explore the hypothesis that elevated wall shear stress at discrete pulmonary venous sites triggers stenosis. To assess this theory, we retrospectively analyzed cardiac catheterization, lung scan, and X-ray computed tomography data to estimate wall shear stress in the pulmonary veins at multiple time points during disease progression in two patients. Results are consistent with the existence of a level of elevated wall shear stress above which the disease is progressive and below which progression is halted. The analysis also suggests the possibility of predicting the target lumen size necessary in a given vein to reduce wall shear stress to normal levels and remove the trigger for stenosis progression.

BACKGROUND: After perinatal asphyxia, predicting which infants will develop significant hypoxic-ischemic encephalopathy and neonatal seizures remains a difficult task. High-risk markers (Apgar score, acidosis, nucleated red blood cells, and resuscitation) have been used to predict neonatal seizures with varying success. The '3 strikes' of Apgar score of <5 at 5 minutes, pH <7.00, and need for intubation have been cited as having a positive predictive value of 80%. We examined whether the predictive values of these markers would be increased if early continuous electroencephalographic monitoring allowed us to accurately identify all neonatal seizures and to grade the encephalopathy. METHOD: We recruited term infants with perinatal asphyxia. Continuous video electroencephalography was commenced soon after birth and continued for 24 to 72 hours. The abilities of high-risk markers to predict electroencephalographic seizures, background electroencephalographic activity, and Sarnat grade were examined. RESULTS: Forty-nine infants were suitable for analysis. Electrographic seizures occurred in 11 of the 49 infants. Encephalopathy was scored by using Sarnat grade (6, severe; 18, moderate; 25, mild) and electroencephalographic findings (4 inactive, 4 major abnormalities, 16 moderate abnormalities, and 25 normal/mildly abnormal). Apgar score of <5 at 5 minutes, pH <7.0, and the need for intubation had positive predictive values for neonatal seizures of 18%, 16%, and 21%, respectively. Combining these markers gave a positive predictive value of 25% and a negative predictive value of 77%. Substituting base deficit or lactate for pH in the 3-strikes model did not improve its predictive value. Apgar score of <5 at 5 minutes, nucleated red blood cells, and a base deficit less than -15 mEq/L showed some association with Sarnat grade. Only 5-minute Apgar score was significantly associated with both Sarnat grade and electroencephalographic grade. CONCLUSION: After perinatal asphyxia, neither the condition at birth nor the degree of metabolic acidosis reliably predict neonatal seizures. [ABSTRACT FROM AUTHOR]

Outlet glaciers undergo rapid spatial and temporal changes in flow velocity during calving events. Observing such changes requires both high temporal and high spatial resolution methods, something now possible with terrestrial radar interferometry. While a single such radar provides line-of-sight velocity, two radars define both components of the horizontal flow field. To assess the feasibility of obtaining the two-dimensional (2-D) flow field, we deployed two terrestrial radar interferometers at Jakobshavn Isbrae, a major outlet glacier on Greenland's west coast, in the summer of 2012. Here, we develop and demonstrate a method to combine the line-of-sight velocity data from two synchronized radars to produce a 2-D velocity field from a single (3 min) interferogram. Results are compared with the more traditional feature-tracking data obtained from the same radar, averaged over a longer period. We demonstrate the potential and limitations of this new dual-radar approach for obtaining high spatial and temporal resolution 2-D velocity fields at outlet glaciers.

Abstract Background All typically developing children are born with flexible flat feet, progressively developing a medial longitudinal arch during the first decade of their lives. Whilst the child’s foot is expected to be flat, there is currently no consensus as to how flat this foot should be. Furthermore, whilst feet are observed to decrease in flatness with increasing age, it is not known how flat they should be at each age increment. The objective of this systematic review is to define the postural characteristics of the ‘typically’ developing paediatric foot. Methods The PRISMA protocol was applied to compare all data currently published describing the typical development of the paediatric foot. The Epidemiological Appraisal Instrument (EAI) was used to assess the risk of bias of the included studies. Results Thirty four epidemiological papers pertaining to the development of the paediatric foot were graphically compared. Sixteen different foot posture assessments were identified of which footprint based measures were the most reported outcome. Conclusion Firstly, the use of the term normal in relation to foot posture is misleading in the categorisation of the paediatric foot, as indeed a flat foot posture is a normal finding at specific ages. Secondly, the foot posture of the developing child is indeed age dependent and has been shown to change over time. Thirdly, no firm conclusion could be reached as to which age the foot posture of children ceases to develop further, as no two foot measures are comparable, therefore future research needs to consider the development of consensus recommendations as to the measurement of the paediatric foot, using valid and reliable assessment tools.

We assess ice loss and velocity changes between 1985 and 2014 of three tidewater and five-land terminating glaciers in Godthåbsfjord (Nuup Kangerlua), Greenland. Glacier thinning accounted for 43.8 ± 0.2 km3 of ice loss, equivalent to 0.10 mm eustatic sea-level rise. An additional 3.5 ± 0.3 km3 was lost to the calving retreats of Kangiata Nunaata Sermia (KNS) and Narsap Sermia (NS), two tidewater glaciers that exhibited asynchronous behavior over the study period. KNS has retreated 22 km from its Little Ice Age (LIA) maximum (1761 AD), of which 0.8 km since 1985. KNS has stabilized in shallow water, but seasonally advects a 2 km long floating tongue. In contrast, NS began retreating from its LIA moraine in 2004–06 (0.6 km), re-stabilized, then retreated 3.3 km during 2010–14 into an over-deepened basin. Velocities at KNS ranged 5–6 km a−1, while at NS they increased from 1.5 to 5.5 km a−1 between 2004 and 2014. We present comprehensive analyses of glacier thinning, runoff, surface mass balance, ocean conditions, submarine melting, bed topography, ice mélange and conclude that the 2010–14 NS retreat was triggered by a combination of factors but primarily by an increase in submarine melting.

Several studies in sub-Saharan Africa have reported that HIV prevalence in young women is higher than in young men. We used data from Kenya HIV sentinel surveillance conducted from 1990 to 2001 among sexually transmitted disease (STD) patients (15-49 years old) to investigate consistency of gender differentials over time and their risk factors. Of the 15,889 STD patients, the HIV prevalence ranged from 16.0% in 1990 to 41.8% in 1997. The odds ratios (ORs) of HIV infection for women compared to men decreased by age; women 15-24 years were nearly twice as likely as men of the same ages to be HIV infected (OR 1.7 [1.5-2.0]), but risk in those >44 years was almost equal (OR 0.8 [95% CI 0.7-1.2]). The odds of HIV infection for women compared to men were twice in unmarried patients (OR 2.1 [95% CI 1.8-2.3]). This association persisted after controlling for age groups or marital status, residence, level of education, and presence of STD syndromes. This pattern had been consistent over 12 years. Adolescent women with symptoms of STDs should be a focus for the HIV/STD intervention programmes because of their high risk for HIV. [ABSTRACT FROM AUTHOR]

Medication-induced cutaneous hyperpigmentation has variable clinical presentations and is dependent on the specific drug involved. Most commonly, an attentive patient observes such changes early in the course; when missed by the patient, such changes are usually noted by an observant clinician. Clinical diagnosis can be challenging if the patient is on multiple medications because other causes must be excluded. This condition occurs via multiple mechanisms. Frequently, the pigmentary change is reversible with discontinuation of the drug. Causative medications include nonsteroidal; anti-inflammatory agents, antimalarials, antibiotics, psychotropics, amiodarone, and chemotherapeutic agents. The; antimicrobials responsible for hyperpigmentation are antimalarials, tetracyclines, tigecycline, dapsone, rifampicin, and antiretrovirals such as zidovudine. Sunlight exposure can worsen the pigmentation seen with some of the above antimicrobials (e.g., dapsone). Here, we describe an older adult white woman presenting with acute cutaneous; hyperpigmentation of the bilateral lower extremities while on levofloxacin therapy. Hyperpigmentation resolved after cessation of the agent. Our case highlights this unique acute presentation after only a few days of oral levofloxacin.

Category: Bunion Introduction/Purpose: Over 130 techniques have been described for the treatment of hallux valgus, ranging from bunionectomies, osteotomies, and arthrodesis. Modern attempts at bunion correction with less invasive joint sparing approaches, such as suture-button techniques, have introduced additional complications like second metatarsal fracture. Suture fixation techniques have evolved in an attempt to avoid these complications. We present our results, with up to 26 months of radiographic follow up including initial correction and complications, with a novel device which utilizes a 3D printed titanium plate on the lateral cortex of the second metatarsal without bony violation, and reduces the 1-2 intermetatarsal angle using suture tape passed through drill holes in the first metatarsal with PEEK interference screw fixation. Methods: This study includes 33 feet in 31 patients. A single board certified and fellowship trained orthopedic foot and ankle surgeon performed all operations over the course of 18 months at a single institution. He utilized a dual incision approach and followed previously described surgical technique for the application of the device. We retrospectively reviewed radiographs including pre-operative AP, lateral, and oblique images, along with another set at the two and six week post operative periods, and another at the last available follow up visit. Using standard technique we measured the 1-2 intermetatarsal angle (IMA), as well as the hallux valgus angle (HVA), which were used as the primary outcomes. Chart review was performed to determine patient satisfaction with the outcome. All secondary procedures and complications were recorded based on the chart review and radiographs. Results: Average radiographic follow up was 15 months. The average initial HVA was 31.4º and IMA was 16.0º. Two-week average HVA was 11.3º and IMA was 7.1º. At six weeks, weight-bearing radiographs showed an average HVA 14.5º and IMA 8.2º. Final radiographic measurements, accounting for either the latest available image or the final image prior to revision, showed average HVA of 24.3º and IMA of 13.7º. Six patients had revision for recurrence or fracture. One underwent removal of symptomatic hardware. Seventeen patients had at least mild radiographic recurrence, without revision. Two patients had an intraoperative fracture of the first metatarsal, and one had an intraoperative fracture of the second metatarsal shaft. There were no infections or wound healing issues. Conclusion: Although this device allows a minimally invasive hallux valgus correction, and provides a powerful initial correction with little bony manipulation, results presented in this study suggest a high rate of radiographic recurrence, and relatively high rates of intra-operative complication, post-operative complication, and revision surgery. We found that more severe deformity had a higher rate of recurrence, suggesting it may be more beneficial in mild deformity, but even in many of these patients we found recurrence and other complications. As a result, this technique has since been abandoned at our local institution with the last procedure being performed in 2016.

Human milk oligosaccharides are important components of breast milk. We evaluated feeding tolerance of the human milk oligosaccharide 2′-fucosyllactose (2′FL) in a 100% whey, partially hydrolyzed infant formula with the probiotic Bifidobacterium animalis ssp lactis strain Bb12 ( B lactis ; Test) as compared with the same formula without 2′FL (Control) in a randomized controlled trial of healthy infants enrolled at 2 weeks of age (±5 days). After 6 weeks of feeding the assigned formula, the primary outcome of tolerance was assessed using the Infant Gastrointestinal Symptom Questionnaire. Stooling, vomiting, spit-up, crying, and fussing were compared between groups. Seventy-nine infants were enrolled and 63 completed the study per protocol (30 Test, 33 Control). Infant Gastrointestinal Symptom Questionnaire scores were similar between groups (Test 20.9 ± 4.8, Control 20.7 ± 4.3, P = .82). Partially hydrolyzed infant formula with 2′FL and B lactis is tolerated well, as confirmed by a validated multi-symptom index.

A nurse practitioner’s experience in managing children with intraluminal pulmonary vein stenosis. A case study of a 3-year-old patient with multi–vessel intraluminal pulmonary vein stenosis.

Pulmonary vein stenosis (PVS) is an extremely challenging clinical problem in congenital heart disease. It has traditionally required multimodal therapy given its complex underlying pathophysiology. As with other modalities, surgical therapy has undergone tremendous evolution since the 1950s. These evolving strategies have been based upon an improved understanding of the substrates that cause PVS and recurrent vein obstruction. More recent anatomic-based surgical strategies have focused on the pulmonary vein course, and how adjacent mediastinal structures can create a fulcrum effect on the pulmonary veins as they pass from the lung parenchyma to the left atrium. The consequent angulation of pulmonary veins creates altered wall shear stress and likely serves as a nidus for recurrent PVS. Encouraging early results suggest that eliminating pulmonary vein angulation and shortening/straightening the pulmonary vein course may prove effective in surgically managing PVS.

Purpose: To retrospectively investigate the extravascular thoracic MDCT angiography findings of pulmonary vein stenosis (PVS) in children with a cardiac septal defect. Materials and Methods: Pediatric patients (age ≤ 18 years) with cardiac septal defect and PVS, confirmed by echocardiogram and/or conventional angiography, who underwent thoracic MDCT angiography studies from April 2009 to April 2021 were included. Two pediatric radiologists independently evaluated thoracic MDCT angiography studies for the presence of extravascular thoracic abnormalities in: (1) lung and airway (ground-glass opacity (GGO), consolidation, pulmonary nodule, mass, cyst, septal thickening, fibrosis, and bronchiectasis); (2) pleura (pleural thickening, pleural effusion, and pneumothorax); and (3) mediastinum (mass and lymphadenopathy). Interobserver agreement between the two independent pediatric radiology reviewers was evaluated with kappa statistics. Results: The final study group consisted of 20 thoracic MDCT angiography studies from 20 consecutive individual pediatric patients (13 males (65%) and 7 females (35%); mean age: 7.5 months; SD: 12.7; range: 2 days to 7 months) with cardiac septal defect and PVS. The characteristic extravascular thoracic MDCT angiography findings were GGO (18/20; 90%), septal thickening (9/20; 45%), pleural thickening (16/20; 80%), and ill-defined, mildly heterogeneously enhancing, non-calcified soft tissue mass (9/20; 45%) following the contours of PVS in the mediastinum. There was a high interobserver kappa agreement between two independent reviewers for detecting extravascular abnormalities on thoracic MDCT angiography studies (k = 0.99). Conclusion: PVS in children with a cardiac septal defect has a characteristic extravascular thoracic MDCT angiography finding. In the lungs and pleura, GGO, septal thickening, and pleural thickening are frequently seen in children with cardiac septal defect and PVS. In the mediastinum, a mildly heterogeneously enhancing, non-calcified soft tissue mass in the distribution of PVS in the mediastinum is seen in close to half of the pediatric patients with cardiac septal defect and PVS.

(1) Pulmonary vein stenosis (PVS) can be a severe, progressive disease with lung involvement. We aimed to characterize findings by computed tomography (CT) and identify factors associated with death; (2) Veins and lung segments were classified into five locations: right upper, middle, and lower; and left upper and lower. Severity of vein stenosis (0–4 = no disease–atresia) and lung segments (0–3 = unaffected–severe) were scored. A PVS severity score (sum of all veins + 2 if bilateral disease; maximum = 22) and a total lung severity score (sum of all lung segments; maximum = 15) were reported; (3) Of 43 CT examinations (median age 21 months), 63% had bilateral disease. There was 30% mortality by 4 years after CT. Individual-vein PVS severity was associated with its corresponding lung segment severity (p < 0.001). By univariate analysis, PVS severity score >11, lung cysts, and total lung severity score >6 had higher hazard of death; and perihilar induration had lower hazard of death; (4) Multiple CT-derived variables of PVS severity and lung disease have prognostic significance. PVS severity correlates with lung disease severity.

The purpose of this study was to determine what patient and pulmonary vein characteristics at the diagnosis of intraluminal pulmonary vein stenosis (PVS) are predictive of individual vein outcomes. A retrospective, single-center, cohort sub-analysis of individual pulmonary veins of patients enrolled in the clinical trial NCT00891527 using imatinib mesylate +/− bevacizumab as adjunct therapy for the treatment of multi-vessel pediatric PVS between March 2009 and December 2014 was performed. The 72-week outcomes of the individual veins are reported. Among the 48 enrolled patients, 46 patients and 182 pulmonary veins were included in the study. Multivariable analysis demonstrated that patients with veins without distal disease at baseline (odds ratio, OR 3.69, 95% confidence interval, CI [1.52, 8.94], p = 0.004), location other than left upper vein (OR 2.58, 95% CI [1.07, 6.19], p = 0.034), or veins in patients ≥ 1 y/o (OR 5.59, 95% CI [1.81, 17.3], p = 0.003) were at higher odds of having minimal disease at the end of the study. Veins in patients who received a higher percentage of eligible drug doses required fewer reinterventions (IRR 0.76, 95% CI [0.68, 0.85], p < 0.001). The success of a multi-modal treatment approach to aggressive PVS depends on the vein location, disease severity, and drug dose intensity.

Preliminary intravascular ultrasound (IVUS) images of suspected pediatric intraluminal pulmonary vein stenosis (PVS) demonstrate wall thickening. It is unclear how the IVUS-delineated constituents of wall thickening correlate with the histology. We analyzed six postmortem formalin-fixed heart/lung specimens and four live patients with PVS as well as control pulmonary veins using IVUS and light microscopic examination. In PVS veins, IVUS demonstrated wall thickening with up to two layers of variable echogenicity, often with indistinct borders. Histologically, the veins showed fibroblastic proliferation with areas rich in myxoid matrix as well as areas with abundant collagen and elastic fibers. Discrete vein layers were obscured by scarring and elastic degeneration. A lower reflective periluminal layer by IVUS corresponded with hyperplasia of myofibroblast-like cells in abundant myxoid matrix. The hyper-reflective layer by IVUS extended to the outer edge of the vessel and corresponded to a less myxoid area with more collagen, smooth muscle and elastic fibers. The outer less reflective edge of the IVUS image correlated with a gradual transition into adventitia. Normal veins had a thin wall, correlating with histologically normal cellular and extracellular components, without intimal proliferation. IVUS may provide further understanding of the anatomy and mechanisms of pediatric pulmonary vein obstruction.

Background: Surgical and transcatheter bioprosthetic valves (BPVs) in the pulmonary position in patients with congenital heart disease may ultimately fail and undergo transcatheter reintervention. Angiographic assessment of the mechanism of BPV failure has not been previously described. Aims: The aim of this study was to determine the mode of BPV failure (stenosis/regurgitation) requiring transcatheter reintervention and to describe the angiographic characteristics of the failed BPVs and report the types and efficacy of reinterventions. Materials and Methods: This is a retrospective single-center review of consecutive patients who previously underwent pulmonary BPV placement. (surgical or transcatheter) and subsequently underwent percutaneous reintervention from 2005 to 2014. Results: Fifty-five patients with surgical. (41) and transcutaneous pulmonary valve. (TPV) (14) implantation of BPVs underwent 66 catheter reinterventions. The surgically implanted valves underwent fifty reinterventions for indications including 16 for stenosis, seven for regurgitation, and 27 for both, predominantly associated with leaflet immobility, calcification, and thickening. Among TPVs, pulmonary stenosis. (PS) was the exclusive failure mode, mainly due to loss of stent integrity. (10) and endocarditis. (4). Following reintervention, there was a reduction of right ventricular outflow tract gradient from 43 ± 16 mmHg to 16 ± 10. mmHg (P < 0.001) and RVp/AO ratio from 0.8 ± 0.2 to 0.5 ± 0.2 (P < 0.001). Reintervention with TPV placement was performed in 45. (82%) patients. (34 surgical, 11 transcatheter) with no significant postintervention regurgitation or paravalvular leak. Conclusion: Failing surgically implanted BPVs demonstrate leaflet calcification, thickness, and immobility leading to PS and/or regurgitation while the mechanism of TPV failure in the short- to mid-term is stenosis, mainly from loss of stent integrity. This can be effectively treated with a catheter.based approach, predominantly with the valve-in-valve technique.

Abstract Sexual dimorphism evolves when selection favors different phenotypic optima between the sexes. Such sexually antagonistic selection creates intralocus sexual conflict when traits are genetically correlated between the sexes and have sex‐specific optima. Brown anoles are highly sexually dimorphic: Males are on average 30% longer than females and 150% heavier in our study population. Viability selection on body size is known to be sexually antagonistic, and directional selection favors large male size whereas stabilizing selection constrains females to remain small. We build on previous studies of viability selection by measuring sexually antagonistic selection using reproductive components of fitness over three generations in a natural population of brown anoles. We estimated the number of offspring produced by an individual that survived to sexual maturity (termed RSV), a measure of individual fitness that includes aspects of both individual reproductive success and offspring survival. We found directional selection on male body size, consistent with previous studies of viability selection. However, selection on female body size varied among years, and included periods of positive directional selection, quadratic stabilizing selection, and no selection. Selection acts differently in the sexes based on both survival and reproduction and sexual conflict appears to be a persistent force in this species.

Antibodies that block the Wnt inhibitors sclerostin and DKK- 1 enhance bone formation and fracture repair. Here the authors show these monospecific antibodies induce compensatory mechanisms that limit efficacy, and have designed a sclerostin/DKK-1 bispecific antibody that promotes superior fracture repair in rodents and bone formation in primates.

We conducted a study to determine whether patients born with Trisomy 21 and left-to-right shunts who develop pulmonary vein stenosis (PVS) have a longer exposure to shunt physiology compared to those who do not develop PVS. We included patients seen at Boston Children’s Hospital between 15 August 2006 and 31 August 2017 born with Trisomy 21 and left-to-right shunts who developed PVS within 24 months of age. We conducted a retrospective 3:1 matched case–control study. The primary predictor was length of exposure to shunt as defined as date of birth to the first echocardiogram showing mild or no shunt. Case patients with PVS were more likely to have a longer exposure to shunt than patients in the control group (6 vs. 3 months, p-value 0.002). Additionally, PVS patients were also more likely to have their initial repair ≥ 4 months of age (81% vs. 42%, p-value 0.003) and have a gestational age ≤ 35 weeks (48% vs. 13%, p-value 0.003). Time exposed to shunts may be an important modifiable risk factor for PVS in patients with Trisomy 21.

Allosteric antagonism by bitopic ligands, as reported for many receptors, is a distinct modulatory mechanism. Although several bitopic A2A adenosine receptor (A2AAR) ligand classes were reported as pharmacological tools, their receptor binding and functional antagonism patterns, i.e., allosteric or competitive, were not well characterized. Therefore, here we systematically characterized A2AAR binding and functional antagonism of two distinct antagonist chemical classes. i.e., fluorescent conjugates of xanthine amine congener (XAC) and SCH442416. Bitopic ligands were potent, weak, competitive or allosteric, based on the combination of pharmacophore, linker and fluorophore. Among antagonists tested, XAC, XAC245, XAC488, SCH442416, MRS7352 showed Ki binding values consistent with KB values from functional antagonism. Interestingly, MRS7396, XAC-X-BY630 (XAC630) and 5-(N,N-hexamethylene)amiloride (HMA) were 9–100 times weaker in displacing fluorescent MRS7416 binding than radioligand binding. XAC245, XAC630, MRS7396, MRS7416 and MRS7322 behaved as allosteric A2AAR antagonists, whereas XAC488 and MRS7395 antagonized competitively. Schild analysis showed antagonism slopes of 0.42 and 0.47 for MRS7396 and XAC630, respectively. Allosteric antagonists HMA and MRS7396 were more potent in displacing [3H]ZM241385 binding than MRS7416 binding. Sodium site D52N mutation increased and decreased affinity of HMA and MRS7396, respectively, suggesting possible preference for different A2AAR conformations. The allosteric binding properties of some bitopic ligands were rationalized and analyzed using the Hall two-state allosteric model. Thus, fluorophore tethering to an orthosteric ligand is not neutral pharmacologically and may confer unexpected properties to the conjugate.

Access to therapeutic oxygen remains a challenge in the effort to reduce pneumonia mortality among children in low- and middle-income countries. The use of oxygen concentrators is common, but their effectiveness in delivering uninterrupted oxygen is gated by reliability of the power grid. Often cylinders are employed to provide continuous coverage, but these can present other logistical challenges. In this study, we examined the use of a novel, low-pressure oxygen storage system to capture excess oxygen from a concentrator to be delivered to patients during an outage. A prototype was built and tested in a non-clinical trial in Jinja, Uganda. The trial was carried out at Jinja Regional Referral Hospital over a 75-day period. The flow rate of the unit was adjusted once per week between 0.5 and 5 liters per minute. Over the trial period, 1284 power failure episodes with a mean duration of 3.1 minutes (range 0.08 to 1720 minutes) were recorded. The low-pressure system was able to deliver oxygen over 56% of the 4,295 power outage minutes and cover over 99% of power outage events over the course of the study. These results demonstrate the technical feasibility of a method to extend oxygen availability and provide a basis for clinical trials.

Background: Musculoskeletal disorders are common medical problems encountered by physicians and affected 126.6 million Americans in 2012. Musculoskeletal education has inadequate in United States medical schools. Objective: To determine the musculoskeletal competency of third year medical students. Methods: A cross-sectional 25-question nationally validated musculoskeletal competency exam was given to the third year medical students. A survey was given to second and third year medical students to assess students’ level of interest in musculoskeletal medicine and their feedback regarding the curriculum. Results: The mean score of the competency exam was 69.0%. There was 48/107 (44.9%) students’ who reached the minimum passing score of 70%. Free-response feedback from both classes featured themes of more hands-on learning, a longer clinical block, and more small-group learning sessions. Conclusions: Third year medical students scored relatively well on the exam. Student feedback suggests the 2-week musculoskeletal block is useful and relevant to their future careers.

Epilepsy is among the most common serious disabling disorders of the brain, and the global burden of epilepsy exerts a tremendous cost to society. Most people with epilepsy have acquired forms of the disorder, and the development of antiepileptogenic interventions could potentially prevent or cure epilepsy in many of them. However, the discovery of potential antiepileptogenic treatments and clinical validation would require a means to identify populations of patients at very high risk for epilepsy after a potential epileptogenic insult, to know when to treat and to document prevention or cure. A fundamental challenge in discovering biomarkers of epileptogenesis is that this process is likely multifactorial and crosses multiple modalities. Investigators must have access to a large number of high quality, well-curated data points and study subjects for biomarker signals to be detectable above the noise inherent in complex phenomena, such as epileptogenesis, traumatic brain injury (TBI), and conditions of data collection. Additionally, data generating and collecting sites are spread worldwide among different laboratories, clinical sites, heterogeneous data types, formats, and across multi-center preclinical trials. Before the data can even be analyzed, these data must be standardized. The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) is a multi-center project with the overarching goal that epileptogenesis after TBI can be prevented with specific treatments. The identification of relevant biomarkers and performance of rigorous preclinical trials will permit the future design and performance of economically feasible full-scale clinical trials of antiepileptogenic therapies. We have been analyzing human data collected from UCLA and rat data collected from the University of Eastern Finland, both centers collecting data for EpiBioS4Rx, to identify biomarkers of epileptogenesis. Big data techniques and rigorous analysis are brought to longitudinal data collected from humans and an animal model of TBI, epilepsy, and their interaction. The prolonged continuous data streams of intracranial, cortical surface, and scalp EEG from humans and an animal model of epilepsy span months. By applying our innovative mathematical tools via supervised and unsupervised learning methods, we are able to subject a robust dataset to recently pioneered data analysis tools and visualize multivariable interactions with novel graphical methods.

Category: Other Introduction/Purpose: Evaluation and management of osteochondral lesions of the talus (OLTs) often warrant advanced imaging studies such as CT and/or MRI. While MRI has its advantages in determining the degree of cartilage damage, stability of the fragment and edema, CT imaging is better delineates the osseous anatomy and extent of the lesion. The latter imaging modality offers increasing acuity and resolution in characterizing the complex osteochondral landscape via three-dimensional (3D) reconstructions. It is possible that orthopedic surgeons may overestimate the size and misinterpret the morphology of OLT from conventional MRI and CT thereby influencing treatment strategies. The purpose of this study is to determine the utility of a novel means to estimate the true-volume of OLTs using 3D reconstructed images and volume analysis. Methods: After IRB approval, an institutional radiology database was queried for patients with OLTs and compatible CT scans between 2011 and 2016. Fourteen patients were found to have OLT compatible with the software used to approximate true-volumes of 3D reconstructed images. 3D reconstructions were created using Mimics software (Materialise, Belgium). From the 14 reconstructed OLTs, 5 were randomly selected for evaluation. 10 orthopedic surgeons independently estimated the volume of these 5 OLTs via standard CT scans. Then 3D reconstructions were made and true-volume (TV) analysis measurements of each OLT were generated. The percent change in volumes from CT were compared to TVs determined from 3D reconstructive analysis. Results: On average the volume calculated by conventional CT scanner grossly overestimated the actual size of the OLTs. The volume calculated on conventional CT scanner overestimated the size of OLTs compared to the 3D TV reconstructed analysis by 285-864%. Conclusion: Our results show that conventional measurements of OLTS with CT grossly overestimates the size of the lesion by up to 8-times the actual lesion size. This overestimation of volumes of the lesion can drastically change surgical planning and may lead to unnecessary costs associated with specific surgical treatments. With the use of our newly defined model for volume measurement in OLTs, we can more accurately predict the exact size of the OLT. This can better guide surgeons to choices both the correct cartilage restoring procedure as well as the need for bone grafting.

Category: Ankle Arthritis Introduction/Purpose: Total ankle arthroplasty (TAA) has evolved over the past decades with later generation implants being associated with improved instrumentation and hardware. There have been multiple reports of the “learning curve” associated with total ankle arthroplasty. These report higher complication rates during the initial procedures performed by an inexperienced surgeon. To our knowledge, there is no comparison of the 2nd generation and 3 rd generation implant learning curves. Methods: The clinical outcomes of the first 15 cases (8/2002-4/2005) of a 2nd generation fixed bearing prosthesis (Agility Total Ankle System) and the first 15 cases (6/2007-3/2009) of a 3 rd generation fixed bearing prosthesis (Salto Talaris® TotalAnkle Prosthesis) performed by a single surgeon were retrospectively reviewed to determine complication incidence. The initial cases with each system were also independently reviewed to determine if there was a significant learning curve in regards to complications. Reoperation, infection, gutter impingement, fracture, persistent pain, and periprosthetic cyst formation were included for comparison of complication rates. Results: The overall complication rates for the Agility were 54.9% (28/51) and 35.7% (25/70) for Salto Talaris. There was no significant difference in reoperation rates when comparing the first 15 Agility cases (8/15, 53%) to the remainder of Agility cases (11/36, 30.6%) p=0.2. The initial 15 Salto Talaris cases also demonstrated no significant difference in reoperation rates (1/15, 8%) when compared to the remaining Salto Talaris replacements (7/55, 12.7%) p=1. Reoperation rates were higher in the initial 15 Agility cases (8/15, 53%) compared to the initial 15 Salto cases (1/15, 8%) p=0.01. There was no significant difference in infection, hardware failure, and medial malleolus fracture rates for any of the groups. Conclusion: While this series demonstrated no significant learning curve for each individual total ankle system, there was a significantly higher reoperation rate in the initial cases for the 2nd generation TAA when compared to the initial cases of the 3 rd generation implants. This could be attributed to improved instrumentation and hardware and/or surgeon experience.

Category: Bunion Introduction/Purpose: Foot and ankle surgery is unique in that both orthopedic surgeons and podiatrists perform many of the same procedures. Very little data exists comparing the two groups for treatment trends and potential complications for acquired hallux valgus deformity. The Truven Health MarketScan® Commercial Claims and Encounters database offers a breadth of information for comparing commercially available health insurance claims. The MarketScan® database was utilized to gain understanding in treatment trends between podiatrists and orthopedic surgeons. Methods: MarketScan® database was used to retrospectively search from 2005-2014 for cases involving a diagnosis of hallux valgus (ICD-9 735.0) that included procedural codes for distal metatarsal osteotomy (CPT 28296), double osteotomy (CPT 28299), and first tarsometatarsal arthrodesis (CPT 28297). The procedures were then divided into the provider groups of podiatry (PO) or orthopedic surgery (OS) to compare the trends in treatment options. Additionally, hospital admission within 3 months, reoperation, and pain medication prescriptions were tracked for the separate groups and for the individual procedures within those groups. Results: From 2005-2014, 206409 patients were identified for comparison. Podiatrists performed 87.5% of hallux valgus corrective procedures with significantly different (p

Category: Ankle Introduction/Purpose: Tibiotalocalcaneal (TTC) fusion with a nail is an effective salvage procedure for several foot and ankle pathologies, but it is associated with a relatively high complication rate and often performed on patients with multiple medical comorbidities. There is a paucity of literature that aids in predicting outcomes for patients undergoing TTC fusion with a nail. Methods: Clinical and radiographic outcomes for 82 patients from 2012-2016 who underwent TTC fusion with intramedullary nailing were retrospectively evaluated. Postoperative complications of nonunion, infection, reoperation, and hardware failure were included for comparison. Patient dependent variables and surgeon dependent variables were evaluated for association with these postoperative complications. Results: The overall complication rate for TTC fusion with a nail was 47/82 (57.3%). Diabetes (p=.049), diabetic neuropathy (p=.031), ASA classification (p=.005), and Charcot neuropathy (p=.003) were associated with nonunion of either the tibiotalar or subtalar joints in 29/82 (35.3%) patients. Diabetic neuropathy was associated with need for reoperation (p=.016) in 21/82 (25.6%) patients. Diabetic neuropathy (p=.022) and HbA1C >7.5 (p=.047) was associated with hardware failure in 13/82 (15.9%) patients. The odds ratio (OR) for diabetic neuropathy was 2.99 (p=0.038) for nonunion in the tibiotalar or subtalar joints, 3.46 (p=0.021) for re-operation, and 4.11 (p=0.035) for hardware failure. High ASA classification had an odds ratio of 3.93 (p=0.006) for nonunion in the tibiotalar or subtalar joints. Conclusion: Patients with diabetic neuropathy, Charcot neuropathy, elevated HbA1C, and higher ASA classification demonstrated a higher complication rate in patients undergoing TTC fusion with a nail.

In animals, color signals that convey information about quality are often associated with costs linked to the expression of coloration and may therefore be honest signals of sender quality. Honest indicators are often seen in sexual signals that are used by males to advertise quality to females. Carotenoid and pterin pigments are responsible for yellow, orange, and red coloration in a variety of taxa, but can also serve important roles as antioxidants by reducing free radicals in the body. In this study, we test the effects of a novel full-bodied orange color phenotype of the brown anole, Anolis sagrei, on mate choice, physiology, and survival. We found no evidence that lizards expressing the orange phenotype were preferred by females. Additionally, they did not differ in immune function, running endurance, or maximum sprint speed from lizards that did not express the novel phenotype. Pigment extractions revealed that orange body coloration resulted from pterin pigments and not carotenoids. Visual models suggest that the orange phenotype is less conspicuous to bird predators than the brown phenotype and may provide an adaptive explanation for the persistence of this trait. Given its small, yet positive effect on fitness, we expect the orange color phenotype to increase in frequency in subsequent decades.

One of the major mechanisms driving the evolution of all organisms is genomic rearrangement. In hyperthermophilic Archaea of the order Thermococcales, large chromosomal inversions occur so frequently that even closely related genomes are difficult to align. Clearly not resulting from the native homologous recombination machinery, the causative agent of these inversions has remained elusive. We present a model in which genomic inversions are catalyzed by the integrase enzyme encoded by a family of mobile genetic elements. We characterized the integrase from Thermococcus nautili plasmid pTN3 and showed that besides canonical site-specific reactions, it catalyzes low sequence specificity recombination reactions with the same outcome as homologous recombination events on DNA segments as short as 104bp both in vitro and in vivo, in contrast to other known tyrosine recombinases. Through serial culturing, we showed that the integrase-mediated divergence of T. nautili strains occurs at an astonishing rate, with at least four large-scale genomic inversions appearing within 60 generations. Our results and the ubiquitous distribution of pTN3-like integrated elements suggest that a major mechanism of evolution of an entire order of Archaea results from the activity of a selfish mobile genetic element.