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Ultraviolet radiation (UVR) exposure is the primary modifiable risk factor for melanoma. Wearable UVR sensors provide a means of quantifying UVR exposure objectively and with a lower burden than self-report measures used in most research. The purpose of this study was to evaluate the relationship between detected UVR exposure and reported sunburn occurrence. In this study, a UVR monitoring device was worn by 97 parent–child dyads during waking hours for 14 days to measure instantaneous and accumulated UVR exposure. The results showed that the participants’ total UVR exposure was associated with reported sunburn after adjusting for Fitzpatrick skin type and geographic location. It was observed that one standard erythemal dose (SED) increase in the participants’ daily total UVR exposure was associated with reported sunburn (an odds ratio (OR) of 1.26 with a 95% CI of 1.13 and 1.41, and p < 0.001 for parents and an OR of 1.28 with a 95% CI of 1.12 and 1.47, and p < 0.001 for children). A one-SED increase in the participants’ UVR exposure from 10 am to 4 pm was also associated with reported sunburn (an OR of 1.31 with a 95% CI of 1.15 and 1.49, and p < 0.001 for parents and an OR of 1.33 with a 95% CI of 1.12 and 1.59, and p = 0.001 for children). We found that elevated UVR exposure recordings measured by the UVR sensor were associated with reported sunburn occurrence. Future directions for wearable UVR sensors may include their use as an intervention tool to support in-the-moment sunburn prevention.

AIM: To identify instrument holding archetypes used by experienced surgeons in order to develop a universal language and set of validated techniques that can be utilized in manual small incision cataract surgery (MSICS) curricula. METHODS: Experienced cataract surgeons performed five MSICS steps (scleral incision, scleral tunnel, side port, corneal tunnel, and capsulorhexis) in a wet lab to record surgeon hand positions. Images and videos were taken during each step to identify validated hand position archetypes. RESULTS: For each MSICS step, one or two major archetypes and key modifying variables were observed, including tripod for scleral incision, tripod-thumb bottom for scleral tunnel, underhand-index to thumb grip for side port, index-contact tripod for corneal entry, and tripod-forceps for capsulorhexis. Key differences were noted in thumb placement and number of fingers supporting the instrument, and modifying variables included index finger curvature and amount of flexion. CONCLUSION: Identification of optimal hand positions and development of a formal nomenclature has the potential to help trainees adopt hand positions in an informed manner, influence instrument design, and improve surgical outcomes.

The auditory brainstem implant (ABI) was originally developed to provide rehabilitation of retrocochlear deafness caused by neurofibromatosis type 2 (NF2). Recent studies of the ABI have investigated outcomes in non-NF2 cohorts, such as patients with cochlear nerve aplasia or cochlear ossification and more recently, intractable tinnitus. New technologies that improve the ABI-neural tissue interface are being explored as means to improve performance and decrease side effects. Innovative discoveries in optogenetics and bioengineering present opportunities to continually evolve this technology into the future, enhancing spatial selectivity of neuronal activation in the cochlear nucleus and preventing side effects through reduction in activation of non-target neuronal circuitry. These advances will improve surgical planning and ultimately improve patients’ audiological capabilities. ABI research has rapidly increased in the 21st century and applications of this technology are likely to continually evolve. Herein, we aim to characterize ongoing clinical, basic science, and bioengineering advances in ABIs and discuss future directions of this technology.

BACKGROUND: Ocular neovascularization is a hallmark of retinal diseases including neovascular age-related macular degeneration and diabetic retinopathy, two leading causes of blindness in adults. Neovascularization is driven by the interaction of soluble vascular endothelial growth factor (VEGF) ligands with transmembrane VEGF receptors (VEGFR), and inhibition of the VEGF pathway has shown tremendous clinical promise. However, anti-VEGF therapies require invasive intravitreal injections at frequent intervals and high doses, and many patients show incomplete responses to current drugs due to the lack of sustained VEGF signaling suppression. METHODS: We synthesized insights from structural biology with molecular engineering technologies to engineer an anti-VEGF antagonist protein. Starting from the clinically approved decoy receptor protein aflibercept, we strategically designed a yeast-displayed mutagenic library of variants and isolated clones with superior VEGF affinity compared to the clinical drug. Our lead engineered protein was expressed in the choroidal space of rat eyes via nonviral gene delivery. RESULTS: Using a structure-informed directed evolution approach, we identified multiple promising anti-VEGF antagonist proteins with improved target affinity. Improvements were primarily mediated through reduction in dissociation rate, and structurally significant convergent sequence mutations were identified. Nonviral gene transfer of our engineered antagonist protein demonstrated robust and durable expression in the choroid of treated rats one month post-injection. CONCLUSIONS: We engineered a novel anti-VEGF protein as a new weapon against retinal diseases and demonstrated safe and noninvasive ocular delivery in rats. Furthermore, our structure-guided design approach presents a general strategy for discovery of targeted protein drugs for a vast array of applications. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12195-020-00641-0) contains supplementary material, which is available to authorized users.

The promotion of axonal regeneration is required for functional recovery from stroke and various neuronal injuries. However, axonal regeneration is inhibited by diverse axonal growth inhibitors, such as Nogo-A. Nogo-66, a C-terminal domain of Nogo-A, binds to the Nogo-A receptor 1 (NgR1) and induces the collapse of growth cones and inhibits neurite outgrowth. NgR1 is also a receptor for additional axonal growth inhibitors, suggesting it is an important target for the prevention of axonal growth inhibition. By using the indirect immunofluorescence method, we show for the first time that a cell-permeable cAMP analog (dibutyryl-cAMP) induced a rapid decrease in the cell surface expression of NgR1 in Neuroscreen-1 (NS-1) cells. The biotinylation method revealed that cAMP indeed induced internalization of NgR1 within minutes. Other intracellular cAMP-elevating agents, such as forskolin, which directly activates adenylyl cyclase, and rolipram, which inhibits cyclic nucleotide phosphodiesterase, also induced this process. This internalization was found to be reversible and influenced by intracellular levels of cAMP. Using selective activators and inhibitors of protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac), we found that NgR1 internalization is independent of PKA, but dependent on Epac. The decrease in cell surface expression of NgR1 desensitized NS-1 cells to Nogo-66-induced growth cone collapse. Therefore, it is likely that besides axonal growth inhibitors affecting neurons, neurons themselves also self-regulate their sensitivity to axonal growth inhibitors, as influenced by intracellular cAMP/Epac. This normal cellular regulatory mechanism may be pharmacologically exploited to overcome axonal growth inhibitors, and enhance functional recovery after stroke and neuronal injuries.

Understanding the mechanisms of neural stimulation is necessary to improve the management of sensory disorders. Neurons can be artificially stimulated using electrical current, or with newer stimulation modalities, including optogenetics. Electrical stimulation forms the basis for all neuroprosthetic devices that are used clinically. Off-target stimulation and poor implant performance remain concerns for patients with electrically based neuroprosthetic devices. Optogenetic techniques may improve cranial nerve stimulation strategies used by various neuroprostheses and result in better patient outcomes. This article reviews the fundamentals of neural stimulation and provides an overview of recent major advancements in light-based neuromodulation."

The use of non-invasive ventilation (NIV) devices such as continuous positive airway pressure and bi-level positive airway pressure machines have been associated with an increased incidence of dry eye disease (DED). To understand how the use of these ventilation masks impacts the eyes, a review of the pathophysiology of DED and an evaluation of recent studies investigating the effects of NIV use on the severity and incidence of this condition were performed. It was found that the use of face masks associated with the ventilation devices exhibited a positive correlation to the incidence and severity of numerous ocular pathologies. However, the benefits of non-invasive mechanical ventilation are undeniable in treating conditions such as obstructive sleep apnea, chronic obstructive pulmonary disease, and respiratory failure; therefore, proper education, behavioral modifications, and treatment can help reduce or prevent the adverse effects that NIV have on the eyes.

Background Emerging UV radiation (UVR) monitoring devices may present an opportunity to integrate such technology into skin cancer prevention interventions. However, little is known about the effects of using a wearable UVR monitor on adults’ and children’s sun protection–related behaviors and attitudes (eg, cancer worry and perceived risk). Understanding the potential role of reactivity and seasonal effects will help inform the use of objective monitors in the context of skin cancer prevention research, including intervention studies. Objective The aim of this study is to examine the potential reactivity associated with a wearable personal UVR monitor, specifically the effects associated with reported sun-protective behaviors and skin cancer–related attitudes, which are often the targets of skin cancer preventive interventions. Methods Child-parent dyads (n=97 dyads) were asked to wear a UVR monitoring device during waking hours for 2 weeks. Participants were asked to sync the device daily with a smartphone app that stored the UVR exposure data. Participants were blinded to their UVR exposure data during the 2-week period; thus, the smartphone app provided no feedback to the participants on their UVR exposure. Participants completed self-report questionnaires assessing sun-protective behaviors, sunburn, tanning, skin self-examination, skin cancer–related knowledge, perceived risk, cancer worry, response efficacy, and intentions to change behaviors over the 2-week period. Linear regressions were conducted to investigate changes in the outcomes over time and to account for the role of the season of study participation. Results Regression results revealed that there was a significant decrease over time for several sun protection outcomes in children, including time spent outdoors on weekends (P=.02) and weekdays (P=.008), sunscreen use (P=.03), reapplication (P Conclusions The findings from this study suggest that daily use of a UVR monitoring device over a 2-week period may result in changes in certain sun-protective behaviors. These results highlight the importance of identifying and addressing potential reactivity to UVR monitoring devices, especially in the context of skin cancer preventive intervention research. Ultimately, objectively assessed UVR exposure could be integrated into the outcome assessment for future testing of skin cancer prevention interventions.

The purpose of this study was to present the successful management and outcomes in a series of 6 cases of culture-positive nontuberculous mycobacterial keratitis after clear corneal incision phacoemulsification surgery.This is a case series of 6 consecutive eyes that presented at the Cornea Division at an academic institution, diagnosed with culture-positive nontuberculous mycobacterial keratitis after phacoemulsification surgery.Six eyes of 5 patients were included. The mean interval from cataract surgery to presentation was 7.7 weeks. All cases presented with intrastromal abscesses adjacent to corneal incisions, and 2 had scleral extension of the infection. Isolated organisms were Mycobacterium abscessus (n = 4), Mycobacterium chelonae (n = 1), and Mycobacterium mucogenicum (n = 1). All cases were treated with topical amikacin 8 mg/mL for 10.5 weeks on average. All cases received either oral clarithromycin at 500 mg twice-daily dosage or oral azithromycin at 500 mg daily. Two patients with scleral abscesses underwent surgical debridement with amniotic membrane grafts. All 6 eyes achieved infection resolution and good visual recovery, with the final visual acuity ranging from 20/20 to 20/60. None of the patients experienced recurrence of infection.Prompt medical treatment with combined topical and oral therapy can lead to infection resolution and favorable visual recovery. Early surgical intervention can ensure good outcomes in cases of scleral extension.

Hearing loss is the most common neurosensory impairment worldwide. While conductive hearing loss can be managed by surgery, the management of sensorineural hearing loss (SNHL), related to the damage of sensory cells of the inner ear is more challenging to manage medically. Many causes of SNHL such as sudden idiopathic SNHL, Meniere's disease, noise-induced hearing loss, autoimmune hearing loss or hearing loss from exposure to ototoxic substances can benefit from delivery of otoprotective drugs to the inner ear. However, systemic drug delivery through oral, intravenous and intramuscular methods leads to undesirable side effects due to the inner ear's limited blood supply and the relatively poor penetration of the blood-inner ear barrier (BLB). Therefore, there has been an increased interest for the targeted drug delivery to the inner ear using nanoparticles. Drug delivery through nanoparticles offers several advantages including drug stabilization for controlled release and surface modification for specific targeting. Understanding the biocompatibility of nanoparticles with cochlea and developing novel non-invasive delivery methods will promote the translation of nanoparticle-mediated drug delivery for auditory disorders from bench to bedside.

Mesenchymal stem cell (MSC) therapy is an emerging treatment modality for various human diseases. Although induced pluripotent stem cells have been explored for the restoration of hearing, the potential of MSCs as a therapeutic strategy for various cochlear insults is not precisely known. MSCs possess anti-inflammatory, anti-apoptotic and neuroprotective properties, making them an attractive target for the treatment of inner ear disorders such as hair cell damage in response to inflammation. Most of the previous studies have used immunosuppression or the complex surgical techniques to deliver stem cells into the cochlea. However, no information is available regarding the biocompatibility and safety of MSCs in the inner ear in immunocompetent cochlea. The aim of the present study was to determine the effect of non-surgical administration of rodent bone marrow derived MSCs (BM-MSCs) through transtympanic delivery on the cochlear function and to assess any adverse effects on the auditory system employing a rat model without immunosuppression. We observed that the transtympanic administration of BM-MSCs has no significant effect on the hearing thresholds as determined by auditory brainstem response and distortion product otoacoustic emissions. Histopathological examination revealed no recruitment of inflammatory leukocytes and edema in the cochlea of BM-MSCs administrated rats. The results of this study suggest that transtympanic administration of BM-MSCs is safe and can be explored in providing otoprotection against cochlear insults. Anat Rec, 303:487-493, 2020. © 2019 American Association for Anatomy.

BACKGROUND: Melanoma is the deadliest form of skin cancer. Screening can aid in early disease detection, when treatment is more effective. Although there are currently no consensus guidelines regarding skin screening for pediatric populations with elevated familial risk for melanoma, at-risk children with the help of their parents and healthcare providers, may implement skin self-exams. Healthcare providers may also recommend screening practices for these children. The goal of the current study was to describe current screening behaviors and provider recommendation for screening among children of melanoma survivors. METHODS: Parents of children with a family history of melanoma completed a questionnaire that included items on children’s screening frequency, thoroughness, and who performed the screening. RESULTS: Seventy-four percent of parents reported that their children (mean age=9.0 years, SD=4.8) had engaged in parent-assisted skin self-exams (SSE) in the past six months. Only 12% of parents reported that children received SSEs once per month (the recommended frequency for adult melanoma survivors). In open-ended responses, parents reported that healthcare providers had provided recommendations around how to conduct SSEs, but most parents did not report receiving information on recommended SSE frequency. Twenty-six percent of parents (n=18) reported that children had received a skin exam by a healthcare provider in the past six months. CONCLUSIONS: The majority of children with a family history of melanoma are reportedly engaging in skin exams despite the lack of guidelines on screening in this population. Future melanoma preventive interventions should consider providing families guidance about implementing screening with their children.

BACKGROUND Emerging UV radiation (UVR) monitoring devices may present an opportunity to integrate such technology into skin cancer prevention interventions. However, little is known about the effects of using a wearable UVR monitor on adults’ and children’s sun protection–related behaviors and attitudes (eg, cancer worry and perceived risk). Understanding the potential role of reactivity and seasonal effects will help inform the use of objective monitors in the context of skin cancer prevention research, including intervention studies. OBJECTIVE The aim of this study is to examine the potential reactivity associated with a wearable personal UVR monitor, specifically the effects associated with reported sun-protective behaviors and skin cancer–related attitudes, which are often the targets of skin cancer preventive interventions. METHODS Child-parent dyads (n=97 dyads) were asked to wear a UVR monitoring device during waking hours for 2 weeks. Participants were asked to sync the device daily with a smartphone app that stored the UVR exposure data. Participants were blinded to their UVR exposure data during the 2-week period; thus, the smartphone app provided no feedback to the participants on their UVR exposure. Participants completed self-report questionnaires assessing sun-protective behaviors, sunburn, tanning, skin self-examination, skin cancer–related knowledge, perceived risk, cancer worry, response efficacy, and intentions to change behaviors over the 2-week period. Linear regressions were conducted to investigate changes in the outcomes over time and to account for the role of the season of study participation. RESULTS Regression results revealed that there was a significant decrease over time for several sun protection outcomes in children, including time spent outdoors on weekends (P=.02) and weekdays (P=.008), sunscreen use (P=.03), reapplication (PPPPP=.01), intentions to change sun-protective behaviors (P=.02), and intentional (P=.008) and unintentional tanning (P=.01) for participants who participated in the fall versus the summer. CONCLUSIONS The findings from this study suggest that daily use of a UVR monitoring device over a 2-week period may result in changes in certain sun-protective behaviors. These results highlight the importance of identifying and addressing potential reactivity to UVR monitoring devices, especially in the context of skin cancer preventive intervention research. Ultimately, objectively assessed UVR exposure could be integrated into the outcome assessment for future testing of skin cancer prevention interventions. CLINICALTRIAL

OBJECTIVES:Mobile apps are suggested for supporting home monitoring and reducing emergency department (ED) visits and hospitalizations for children with medical complexity (CMC). None have been implemented. We sought to assess the MyChildCMC app (1) feasibility for CMC home monitoring, (2) ability to detect early deteriorations before ED and hospital admissions, and (3) preliminary impact.METHODS:Parents of CMC (aged 1–21 years) admitted to a children’s hospital were randomly assigned to MyChildCMC or usual care. MyChildCMC subjects recorded their child’s vital signs and symptoms daily for 3 months postdischarge and received real-time feedback. Feasibility measures included parent’s enrollment, retention, and engagement. The preliminary impact was determined by using quality of life, parent satisfaction with care, and subsequent ED and hospital admissions and hospital days.RESULTS:A total of 62 parents and CMC were invited to participate: 50 enrolled (80.6% enrollment rate) and were randomly assigned to MyChildCMC (n = 24) or usual care (n = 26). Retention at 1 and 3 months was 80% and 74%, and engagement was 68.3% and 62.6%. Run-chart shifts in vital signs were common findings preceding admissions. The satisfaction score was 26.9 in the MyChildCMC group and 24.1 in the control group (P = .035). No quality of life or subsequent admission differences occurred between groups. The 3-month hospital days (pre-post enrollment) decreased from 9.25 to 4.54 days (rate ratio = 0.49; 95% confidence interval = 0.39–0.62; P < .001) in the MyChildCMC group and increased from 1.08 to 2.46 days (rate ratio = 2.29; 95% confidence interval = 1.47–3.56; P < .001) in the control group.CONCLUSIONS:MyChildCMC was feasible and appears effective, with the potential to detect early deteriorations in health for timely interventions that might avoid ED and hospitalizations. A larger and definitive study of MyChildCMC’s impact and sustainability is needed.

Cochlear implants (CIs) are neuroprosthetic devices that can provide hearing to deaf people

Background In the United States, melanoma is the fifth most common type of cancer. Reducing UV radiation (UVR) exposure is essential for the prevention of melanoma. The assessment of individual-level UVR exposure using wearable technology is a promising method to monitor and reduce UVR exposure. However, the feasibility and acceptability of using wearable UVR monitoring devices have not been assessed. Objective This study aimed to assess the feasibility and acceptability of using a commercially available UVR monitoring wearable device in adults and children. Methods We recruited families (1 parent and 1 child) to test a new, commercially available UVR monitoring device (namely, Shade). Participants wore Shade for 2 weeks and completed questionnaires assessing the feasibility and acceptability of wearing the device. Qualitative analyses were conducted to summarize participants’ open-ended responses regarding device feasibility. Results A total of 194 individuals (97 adults and 97 children) participated in this study. The participating children were aged, on average, 12.7 years. Overall, adults and children reported moderate satisfaction with wearing Shade. The feasibility of the use of Shade was adequate, with 73% (65/89) of adults and 61% (54/89) of children reporting that they wore the device “all of the time they were outside.” Through open-ended responses, participants reported that the device was easy to use, was compact, and increased their awareness about their exposure to UVR. Conclusions Adults and children can feasibly use a wearable UVR monitoring device, and the use of the device was acceptable to participants. The device could be integrated into melanoma preventive interventions to increase individuals’ and families’ awareness of UVR exposure and to facilitate the use of recommended melanoma preventive strategies.

Ultraviolet radiation (UVR) exposure is a primary risk factor for the development of melanoma. However, adults and adolescents often do not engage in preventive behaviors to reduce UVR exposure. Rural residents may be at higher risk for melanoma due to lower use of sun protection strategies, which increases their overall UVR exposure compared to those who live in urban areas. The purpose of this study was to evaluate differences in UVR exposure between rural and urban residents in a geographic area with high incidence of melanoma. Children (aged 8-17 years) and adults (≥18 years) from rural and urban areas of Utah were asked to wear a UVR monitoring device for 14 days. The sample included 97 children and 97 adults. Data was collected from June to October 2018. Non-parametric Mann-Whitney tests and quantile regression were used to compare UVR exposure levels between urban and rural participants, separately for adults and children. For adults, rural residence significantly increased total UVR dose ( β: 24.6; 95% CI: 3.75, 42.74) and the UVR dose during peak UVR hours among participants with the highest UVR doses (β: 16.3; 95% CI: 17.4, 24.63). Rural children exhibited significantly higher UVR doses for peak UVR hours for the entire study period (β: 4.14; 95% CI: 0.83, 7.46) and on weekdays (β: 0.39; 95% CI: 0.05, 0.73). The findings from this study indicate that rural residents may receive higher levels of UVR exposure than urban residents, and that prevention efforts could be tailored to address these geographical differences.

Recent advancements in stem cell therapy have led to an increased interest within the auditory community in exploring the potential of mesenchymal stem cells (MSCs) in the treatment of inner ear disorders. However, the biocompatibility of MSCs with the inner ear, especially when delivered non-surgically and in the immunocompetent cochlea, is not completely understood. In this study, we determined the effect of intratympanic administration of rodent bone marrow MSCs (BM-MSCs) on the inner ear in an immunocompetent rat model. The administration of MSCs did not lead to the generation of any oxidative stress in the rat inner ear. There was no significant production of proinflammatory cytokines, tumor necrosis factor (TNF)-&alpha, interleukin (IL)-1&beta, IL-6 and IL-12, due to BM-MSCs administration into the rat cochlea. BM-MSCs do not activate caspase 3 pathway, which plays a central role in sensory cell damage. Additionally, transferase dUTP nick end labeling (TUNEL) staining determined that there was no significant cell death associated with the administration of BM-MSCs. The results of the present study suggest that trans-tympanic administration of BM-MSCs does not result in oxidative stress or inflammatory response in the immunocompetent rat cochlea.

Objectives The behavior of advanced cutaneous squamous cell carcinoma of the head and neck (HNcSCC) remains poorly understood, with highly variable risk factors and a paucity of data for adjuvant treatment. The objective of our study was to review the oncologic outcomes of patients with high-risk HNcSCC treated with surgery and to identify risk factors for treatment failure. Study design Retrospective cohort study. Methods Retrospective review of patients treated for HNcSCC with definitive surgery involving at least parotidectomy and neck dissection at a tertiary care academic center from 2011 to 2017 was conducted. The primary outcome was disease-free survival (DFS). Results One-hundred four patients with a median age of 68 years (range = 42-91 years) were reviewed. Twenty-one patients were treated with surgery alone, 45 patients underwent adjuvant radiotherapy (RT), and 38 patients underwent adjuvant chemoradiotherapy (CRT). The 2-year DFS for patients treated with surgery, surgery + RT, and surgery + CRT were 71%, 65%, and 58%, respectively, with no significant difference between the groups (P = .70). On multivariate analyses, tumor size (P = .006) and perineural invasion (PNI, P = .04) independently predicted recurrence. The addition of chemotherapy did not appear to improve DFS, neither for those patients with extranodal extension and/or positive margins (P = .93) nor for the entire cohort (P = .43). Conclusions Advanced HNcSCC has a high recurrence rate despite adjuvant treatment. Tumor size >2 cm was a strong independent risk factor for recurrence. Out of the traditional mucosal HNcSCC risk factors, PNI was most strongly associated with worse DFS. There was no observed survival benefit to the addition of chemotherapy. Level of evidence 4. Laryngoscope, 131:E136-E143, 2021.

Recovery of stroke and neuronal injuries requires the promotion of axonal regeneration from the remaining neurons. However, axonal regeneration is inhibited by diverse axonal growth inhibitors, such as Nogo-A. C-terminal domain of Nogo-A, Nogo-66 binds to the Nogo-A receptor 1 (NgR1) and induces the collapse of growth cones and inhibition of neurite outgrowth. NgR1 is also a receptor for additional axonal growth inhibitors. In this study, by using indirect immunofluorescence and biotinylation method, we have found that a cell-permeable cAMP analog (dibutyryl-cAMP) and other intracellular cAMP-elevating agents, such as forskolin, which directly activates adenylyl cyclase, and rolipram, which inhibits cyclic nucleotide phosphodiesterase, all induced rapid internalization of the cell surface NgR1 in Neuroscreen-1 (NS-1) cells. This endocytosis of NgR1 is lipid raft mediated. These cAMP-elevating agents induced a reversible distribution of NgR1 between the cell surface and intracellular compartment; NgR1 distributed to the cell surface at low levels of cAMP and distributed to an intracellular compartment at high levels of cAMP. Using pharmacological activators and inhibitors of protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac), we found that NgR1 internalization is independent of PKA but dependent on Epac. There is a correlation between the decrease in cell surface expression of NgR1 decreased sensitivity of NS-1 cells to Nogo-66-induced growth cone collapse. Therefore, besides axonal growth inhibitors affecting neurons, neurons by themselves self-regulate their own sensitivity to extracellular cues such as axonal growth inhibitors. This normal cellular regulatory mechanism may be therapeutically applied to overcome axonal growth inhibitors and enhance functional recovery after stroke and neuronal injuries.

In patients with anticipated challenges to compliance with refractive amblyopia management after pediatric cataract surgery, primary intraocular lens (IOL) implantation after lensectomy has become the preferred alternative to aphakia ever since the Infant Aphakia Treatment Study (IATS) demonstrated that was an acceptable decision (The Infant Aphakia Treatment Study Group, JAMA Ophthalmol 132:676–682, 2014). However, there can be a variable degree of myopic shift after pseudophakia that can result in significant anisometropia while the child is still within amblyogenic age. As the focus in pediatric cataract surgery has shifted more toward optimizing refractive outcomes given advances in surgical technology, IOL exchange has become a widely accepted option for managing severe anisometropia and associated intolerable aniseikonia in pseudophakic children. Utilizing an illustrative case, the preoperative, intraoperative, and postoperative considerations for IOL exchange in pediatric cases are discussed in detail within this chapter. A step-by-step guide to extracting the primary IOL and implanting a new IOL (planned sulcus placement with optic capture) is explained.

Understanding the mechanisms of neural stimulation is necessary to improve the management of sensory disorders. Neurons can be artificially stimulated using electrical current, or with newer stimulation modalities, including optogenetics. Electrical stimulation forms the basis for all neuroprosthetic devices that are used clinically. Off-target stimulation and poor implant performance remain concerns for patients with electrically based neuroprosthetic devices. Optogenetic techniques may improve cranial nerve stimulation strategies used by various neuroprostheses and result in better patient outcomes. This article reviews the fundamentals of neural stimulation and provides an overview of recent major advancements in light-based neuromodulation."

OBJECTIVES To translate and validate the Zurich Chronic Middle Ear Inventory (ZCMEI-21) for the English language in order to provide an English instrument to assess health-related quality of life in chronic otitis media (COM). DESIGN Pilot translation study including cognitive debriefings, prospective multicenter cross-sectional psychometric validation study. SETTING Four tertiary referral centers in three different English-speaking countries (United Kingdom, United States of America and Australia). PARTICIPANTS Adult patients suffering from COM. MAIN OUTCOME MEASURES The English translation of the ZCMEI-21 (ZCMEI-21-E) and the five-level version of the EQ-5D questionnaire. The EQ-5D, which constitutes a generic measure of health-related quality of life, consists of a descriptive system score and a visual analogue scale. Statistical outcomes included single item descriptive statistics, internal consistency (Cronbach's α) as an indicator of reliability, as well as construct validity. RESULTS A total of 124 patients suffering from COM were included. The mean age was 50.1 years (SD 16.9 years) and 72 (58.1%) were males. The Cronbach's α of the ZCMEI-21-E was 0.91, suggesting an excellent internal consistency. The Spearman's correlation coefficient of the ZCMEI-21-E total score was 0.55 (p < 0.0001) for convergent construct validity with EQ-5D descriptive system score and 0.57 (p < 0.0001) with the EQ-5D visual analogue scale. CONCLUSIONS The ZCMEI-21-E is a new validated questionnaire that provides clinicians with a short, comprehensive and reliable instrument to quantify health-related quality of life in patients suffering from COM. The ZCMEI-21-E may be of use in clinical routine as well as in outcome research and monitoring. This article is protected by copyright. All rights reserved.

PURPOSE: The purpose of the current study was to evaluate differences in reported use of sun protection, tanning behaviors, skin cancer-related knowledge, and perceived risk between rural and urban high school students in a geographic area with high rates of melanoma. METHODS: A total of 1,570 high school students (56.8% female) from urban (6 schools) and rural (7 schools) geographic areas in Utah completed questionnaires assessing sun protection and tanning behaviors, skin cancer-related knowledge, and perceived risk for skin cancer. Analyses examined potential differences in these outcomes between rural and urban students and by gender. RESULTS: Compared to students in urban areas, those in rural areas had lower odds of wearing sunscreen (OR 0.71; 95% CI 0.53, 0.95; p = 0.022), re-applying sunscreen (OR 0.61; 95% CI 0.74, 1.02; p = 0.002), wearing long-sleeved shirts (OR 0.63 95% CI 0.46, 0.86; p =0.004), and seeking shade (OR 0.67; 95% CI 0.50, 0.88; p = 0.005). CONCLUSIONS: Rural students reported less adequate use of sun protection than urban students. Rural male students reported lower knowledge scores compared to urban males. Future skin cancer prevention efforts targeting rural high schoolers are warranted.

The N-terminally myristoylated matrix domain (MA) of the HIV-1 Gag polyprotein promotes virus assembly by targeting Gag to the inner leaflet of the plasma membrane (PM). Recent studies indicate that, prior to membrane binding, MA associates with cytoplasmic tRNAs (including tRNA(Lys3)), and in vitro studies of tRNA-dependent MA interactions with model membranes have led to proposals that competitive tRNA interactions contribute to membrane discrimination. We have characterized interactions between native, mutant, and unmyristylated (myr-) MA proteins and recombinant tRNA(Lys3) by NMR spectroscopy and isothermal titration calorimetry (ITC). NMR experiments confirm that tRNA(Lys3) interacts with a patch of basic residues that are also important for binding to the plasma membrane marker, phosphatidylinositol-4,5-bisphosphate, [PI(4,5)P(2)]. Unexpectedly, the affinity of MA for tRNA(Lys3) (K(d) = 0.63 ± 0.03 μM) is approximately one order of magnitude greater than its affinity for PI(4,5)P(2) enriched liposomes (K(d(apparent)) = 10.2 ± 2.1 μM), and NMR studies indicate that tRNA(Lys3) binding blocks MA association with liposomes, including those enriched with PI(4,5)P(2), phosphatidylserine (PS), and cholesterol. However, the affinity of MA for tRNA(Lys3) is diminished by mutations or sample conditions that promote myristate exposure. Since Gag-Gag interactions are known to promote myristate exposure, our findings support virus assembly models in which membrane targeting and genome binding are mechanistically coupled.

Data regarding the sensitivity of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for staging of lung cancer in patients with radiographic N0 disease is scant and inconsistent. With increasing use of nonoperative ablative therapies, studies focusing on the performance characteristics of EBUS-TBNA in this population are important.To evaluate the sensitivity and negative predictive value (NPV) of EBUS-TBNA in patients with non-small cell lung cancer and radiographic N0 disease both by computed tomography (CT) and positron emission tomography (PET)-CT.This was a retrospective review of EBUS-TBNA performed for lung cancer staging at two major academic centers from 2009 to 2014. Patients with radiographic N0 disease (lymph nodes [LN]≤1 cm in the short axis and maximum standardized uptake value≤2.5 by PET-CT) were included. Primary outcome was sensitivity and NPV of EBUS-TBNA.Two hundred twenty patients with radiographic N0 disease underwent EBUS-TBNA, and 734 LN were sampled (median 3, range 1-6). Median LN diameter was 0.72 cm. One hundred patients (45.5%) underwent surgery, and 120 patients (54.5%) had nonsurgical therapy. N status was up-staged in 49 patients (22.3%): 18 by EBUS-TBNA (N1=11, N2=6, N3=1), 27 by surgery (N1 intralobar=16, N1 extralobar=3, N2=8 [5 LN in stations 4 and 7, and 3 LN in stations 5-6), and 4 by imaging follow-up (N1=2, N2=2). Overall false-negative rate of EBUS was 14.1% (sensitivity, 36.7%; specificity, 100%; and NPV, 84.7%). False-negative rate was 27 and 3.3% in surgical and nonsurgical populations, respectively. Excluding patients with occult disease "outside" the reach of EBUS, the overall false-negative rate of EBUS-TBNA was 5.5% (sensitivity, 60%; specificity, 100%; and NPV, 93.4%).This is the largest report of EBUS-TBNA in patients with N0 disease by "integrated" PET-CT. The majority of false-negative EBUS results were in LN stations outside its reach. In our study, both sensitivity and NPV of EBUS-TBNA were lower than early reports despite more extensive LN sampling. Given the high false-negative rate of imaging modalities, EBUS-TBNA may still play an important role in patients with radiographic N0 disease, particularly when nonsurgical ablative therapies are planned. Prospective studies are needed to corroborate our findings in the nonsurgical population.

A reservoir that could be remotely triggered to release a drug would enable the patient or physician to achieve on-demand, reproducible, repeated, and tunable dosing. Such a device would allow precise adjustment of dosage to desired effect, with a consequent minimization of toxicity, and could obviate repeated drug administrations or device implantations, enhancing patient compliance. It should exhibit low off-state leakage to minimize basal effects, and tunable on-state release profiles that could be adjusted from pulsatile to sustained in real time. Despite the clear clinical need for a device that meets these criteria, none has been reported to date to our knowledge. To address this deficiency, we developed an implantable reservoir capped by a nanocomposite membrane whose permeability was modulated by irradiation with a near-infrared laser. Irradiated devices could exhibit sustained on-state drug release for at least 3 h, and could reproducibly deliver short pulses over at least 10 cycles, with an on/off ratio of 30. Devices containing aspart, a fast-acting insulin analog, could achieve glycemic control after s.c. implantation in diabetic rats, with reproducible dosing controlled by the intensity and timing of irradiation over a 2-wk period. These devices can be loaded with a wide range of drug types, and therefore represent a platform technology that might be used to address a wide variety of clinical indications.

Background: Stereotactic body radiation therapy (SBRT) is considered the standard treatment for medically inoperable early stage lung cancer. Bronchoscopy has shown to be effective in obtaining diagnosis of peripheral lung tumors, staging the mediastinum (with endobronchial ultrasound- EBUS-), and placing fiducial markers (FMs). However, the combination of these 3 procedures in a single bronchoscopy has not been studied. The aim of this study is to describe safety and feasibility of performing diagnosis, systematic nodal staging, and placement of FMs in a single bronchoscopic procedure. Methods: Retrospective review of patients who underwent bronchoscopy with diagnosis of peripheral lung cancer, EBUS for nodal staging, and FM placement in a single procedure at Michael E. DeBakey VA Medical Center between January 2011 and July 2015. Results: Twenty-one patients met our criteria, one having 2 synchronous tumors. 95% of patients had an ASA score of at least 3. Twenty-two tumors were diagnosed with a size of 2.72±1.06 cm. Distance from pleura was 1.33±1.42 cm. Median duration of bronchoscopy was 96 minutes (range, 75 to 136 minutes). Guided-bronchoscopy provided diagnosis of lung cancer in all cases. Fluoroscopy and RP-EBUS were utilized in 21 patients, “hybrid” scope in 14, and electromagnetic navigational bronchoscopy in 3. A total of 100 lymph nodes (LN) were sampled with EBUS-TBNA, with 95% of the patients having at least 4 LN sampled. A total of 71 FM were placed for 22 tumors. All markers were retained and allowed for successful SBRT. There were no pneumothoraces and no major complications. Conclusions: Although it results in lengthy procedures, a single bronchoscopy obtaining diagnosis of peripheral lung nodules, systematic nodal staging, and FM placement can be safely performed in high-risk patients. Our “all-in-one” strategy could potentially expedite treatment, decrease complications, and reduce costs. Further prospective studies are needed to corroborate our findings.

p27 is an atypical tumor suppressor that can regulate the activity of cyclin-dependent kinases and G(0)-to-S phase transitions. More recent studies reveal that p27 may also exhibit its tumor-suppressive function through regulating many other essential cellular events. However, the molecular mechanisms underlying these anticancer effects of p27 are largely unknown. In this study, we found that depletion of p27 expression by either gene knock-out or knockdown approaches resulted in up-regulation of both Hsp27 and Hsp70 expression at mRNA- and promoter-derived transcription as well as protein levels upon arsenite exposure, indicating that p27 provides a negative signal for regulating the expression of Hsp27 and Hsp70. Consistently, arsenite-induced activation of JNK2/c-Jun and HSF-1 pathways was also markedly elevated in p27 knock-out (p27(-/-)) and knockdown (p27 shRNA) cells. Moreover, interference with the expression or function of JNK2, c-Jun, and HSF-1, but not JNK1, led to dramatic inhibition of arsenite-induced Hsp27 and Hsp70 expression. Collectively, our results demonstrate that p27 suppresses Hsp27 and Hsp70 expression at the transcriptional level specifically through JNK2/c-Jun- and HSF-1-dependent pathways upon arsenite exposure, which provides additional important molecular mechanisms for the tumor-suppressive function of p27.

Taste alterations (dysgeusia) are well described in head and neck cancer patients who undergo radiotherapy (RT). Anecdotal observations and pilot studies have suggested zinc may mitigate these symptoms. This multi-institutional, double-blind, placebo-controlled trial was conducted to provide definitive evidence of this mineral's palliative efficacy.A total of 169 evaluable patients were randomly assigned to zinc sulfate 45 mg orally three times daily vs. placebo. Treatment was to be given throughout RT and for 1 month after. All patients were scheduled to receiveor =2,000 cGy of external beam RT toor =30% of the oral cavity, were able to take oral medication, and had no oral thrush at study entry. Changes in taste were assessed using the previously validated Wickham questionnaire.At baseline, the groups were comparable in age, gender, and planned radiation dose (6,000 vs.or =6,000 cGy). Overall, 61 zinc-treated (73%) and 71 placebo-exposed (84%) patients described taste alterations during the first 2 months (p = 0.16). The median interval to taste alterations was 2.3 vs. 1.6 weeks in the zinc-treated and placebo-exposed patients, respectively (p = 0.09). The reported taste alterations included the absence of any taste (16%), bitter taste (8%), salty taste (5%), sour taste (4%), sweet taste (5%), and the presence of a metallic taste (10%), as well as other descriptions provided by a write in response (81%). Zinc sulfate did not favorably affect the interval to taste recovery.Zinc sulfate, as prescribed in this trial, did not prevent taste alterations in cancer patients who were undergoing RT to the oral pharynx.

Purpose We describe an inexpensive, simple, and effective endothelium-Descemet membrane (EDM) graft injector assembled from regular operating room supplies in Descemet membrane endothelial keratoplasty (DMEK). Methods To assemble the injector, standard intravenous tubing was cut approximately 2 inches from the Luer lock end, leaving a steep bevel. The cut end of the tubing was firmly wedged bevel up and advanced into the back of an Alcon IOL B cartridge. The Luer lock end of the tubing was then attached to a 5- or 10-mL syringe filled with BSS Plus. The EDM graft was then placed into a Petri dish filled with BSS. After the graft was sucked into an injector with bevel-side up under the surgical microscope, the graft was then inserted into the anterior chamber with the injector through the main incision in the superotemporal quadrant. Results In seven eyes of seven patients with Fuchs endothelial corneal dystrophy treated with DMEK using our injector, clear attached grafts and improved visual acuity were achieved. Conclusions This simple, inexpensive, and effective injector is a safe and viable device to facilitate this part of DMEK surgery.

7536 Background: National Comprehensive Cancer Network (NCCN) guidelines recommend adjuvant radiotherapy (XRT) for NSCLC patients with N2 disease after lobectomy. The purpose of this study is to id...

A new type of compliant interconnect derived from a thin metal film fabricated with a controlled stress profile is being developed for flip- flop interconnects and probing devices. Interconnections have been demonstrated on lateral pitches as tight as 6 microns. The interconnect is highly elastic and can provide up to hundreds of microns of vertical compliance.

Purpose To assess if intensity-modulated radiotherapy (IMRT) can possibly lead to improved local control and lower incidence of vision impairment/blindness in comparison to non-IMRT techniques when treating sinonasal malignancies; what is the most optimal dose constraints for the optic pathway; and the impact of different IMRT strategies on optic pathway sparing in this setting. Methods and materials A literature search in the PubMed databases was conducted in July, 2012. Results Clinical studies on IMRT and 2D/3D (2 dimensional/3 dimensional) RT for sinonasal malignancies suggest improved local control and lower incidence of severe vision impairment with IMRT in comparison to non-IMRT techniques. As observed in the non-IMRT studies, blindness due to disease progression may occur despite a lack of severe toxicity possibly due to the difficulty of controlling locally very advanced disease with a dose ≤ 70 Gy. Concurrent chemotherapy’s influence on the the risk of severe optic toxicity after radiotherapy is unclear. A maximum dose of ≤ 54 Gy with conventional fractionation to the optic pathway may decrease the risk of blindness. Increased magnitude of intensity modulation through increasing the number of segments, beams, and using a combination of coplanar and non-coplanar arrangements may help increase dose conformality and optic pathway sparing when IMRT is used. Conclusion IMRT optimized with appropriate strategies may be the treatment of choice for the most optimal local control and optic pathway sparing when treating sinonasal malignancy.