Structural insights into the role and targeting of EGFRvIII.

The epidermal growth factor receptor (EGFR) is a well-known oncogenic driver in lung and other cancers. In glioblastoma multiforme (GBM), the EGFR deletion variant III (EGFRvIII) is frequently found alongside EGFR amplification. Agents targeting the EGFR axis have shown limited clinical benefits in GBM and the role of EGFRvIII in GBM is poorly understood. To shed light on the role of EGFRvIII and its potential as a therapeutic target, we determined X-ray crystal structures of a monomeric EGFRvIII extracellular region (ECR). The EGFRvIII ECR resembles the unliganded conformation of EGFR, including the orientation of the C-terminal region of domain II. Domain II is mostly disordered, but the ECR structure is compact. We selected a nanobody with preferential binding to EGFRvIII relative to EGFR and structurally defined an epitope on domain IV that is occluded in the unliganded intact EGFR. These findings suggest new avenues for EGFRvIII targeting in GBM.

Individual differences link sensory processing and motor control.

Research on saccadic and pursuit eye movements led to great advances in our understanding of sensorimotor processing and human behavior. However, studies often have focused on isolated saccadic and pursuit eye movements measured with respect to different sensory information (static vs. dynamic targets). Here, we leveraged interindividual differences across a carefully balanced combination of different tasks to demonstrate that critical links in the control of oculomotor behavior were previously missed. We observed correlations in eye movement behavior across tasks, but only when compared with the same sensory information (e.g., pursuit gain and accuracy of saccades to moving targets). Within the same task, the coordination of saccadic and pursuit eye movements was tailored to the strengths of the individual: observers with more accurate saccades to moving targets rely on them more to catch up with moving targets. Our results have profound implications for the theoretical understanding of sensorimotor processing for oculomotor control. They necessitate a reevaluation of previous data used to map brain circuits for saccadic and pursuit eye movements measured with different types of relevant sensory information. Additionally, they underscore the importance of moving beyond average observations to embrace individual differences as a rich source of information. These individual differences not only reveal the strengths and weaknesses of observers. When combined across different tasks, they allow insights about why observers behave differently in a given task. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The most remarkable migrants-systematic analysis of the Western European insect flyway at a Pyrenean mountain pass.

In autumn 1950 David and Elizabeth Lack chanced upon a huge migration of insects and birds flying through the Pyrenean Pass of Bujaruelo, from France into Spain, later describing the spectacle as combining both grandeur and novelty. The intervening years have seen many changes to land use and climate, posing the question as to the current status of this migratory phenomenon. In addition, a lack of quantitative data has prevented insights into the ecological impact of this mass insect migration and the factors that may influence it. To address this, we revisited the site in autumn over a 4 year period and systematically monitored abundance and species composition of diurnal insect migrants. We estimate an annual mean of 17.1 million day-flying insect migrants from five orders (Diptera, Hymenoptera, Hemiptera, Lepidoptera and Odonata) moving south, with observations of southward 'mass migration' events associated with warmer temperatures, the presence of a headwind, sunlight, low windspeed and low rainfall. Diptera dominated the migratory assemblage, and annual numbers varied by more than fourfold. Numbers at this single site hint at the likely billions of insects crossing the entire Pyrenean mountain range each year, and we highlight the importance of this route for seasonal insect migrants.

Molecular Pathways and Animal Models of Atrial Septal Defect.

The relative simplicity of the clinical presentation and management of an atrial septal defect belies the complexity of the developmental pathogenesis. Here, we describe the anatomic development of the atrial septum and the venous return to the atrial chambers. Experimental models suggest how mutations and naturally occurring genetic variation could affect developmental steps to cause a defect within the oval fossa, the so-called secundum defect, or other interatrial communications, such as the sinus venosus defect or ostium primum defect.

The execution of saccadic eye movements suppresses visual processing of both color and luminance in the early visual cortex of humans.

Our eyes execute rapid, directional movements known as saccades, occurring several times per second, to focus on objects of interest in our environment. During these movements, visual sensitivity is temporarily reduced. Despite numerous studies on this topic, the underlying mechanism remains elusive, including a lingering debate on whether saccadic suppression affects the parvocellular visual pathway. To address this issue, we conducted a study employing steady-state visual evoked potentials (SSVEPs) elicited by chromatic and luminance stimuli while observers performed saccadic eye movements. We also employed an innovative analysis pipeline to enhance the signal-to-noise ratio, yielding superior results compared to the previous method. Our findings revealed a clear suppression effect on SSVEP signals during saccades compared to fixation periods. Notably, this suppression effect was comparable for both chromatic and luminance stimuli. We went further to measure the suppression effect across various contrast levels, which enabled us to model SSVEP responses with contrast response functions. The results suggest that saccades primarily reduce response gain without significantly affecting contrast gain and that this reduction applies uniformly to both chromatic and luminance pathways. In summary, our study provides robust evidence that saccades similarly suppress visual processing in both the parvocellular and magnocellular pathways within the human early visual cortex, as indicated by SSVEP responses. The observation that saccadic eye movements impact response gain rather than contrast gain implies that they influence visual processing through a multiplicative mechanism.NEW & NOTEWORTHY The present study demonstrates that saccadic eye movements reduce the processing of both luminance and chromatic stimuli in the early visual cortex of humans. By modeling the contrast response function, the study further shows that saccades affect visual processing by reducing the response gain rather than altering the contrast gain, suggesting that a multiplicative mechanism of visual attenuation affects both parvocellular and magnocellular pathways.

Management and Pharmacological Treatment of Peripheral Arterial Disease.

Background: Peripheral arterial disease (PAD) is a complex, heterogeneous condition that has become a leading health concern globally. Peripheral arterial disease often co-exists with other vascular disease states, including cerebrovascular and cardiovascular disease. Optimal therapy for managing symptoms and progression of disease employs non-pharmacological, pharmacological, and contemporary revascularisation techniques to improve clinical outcomes and quality of life. However, large well-designed randomised control trials (RCT) and corresponding evidence-based guidelines for management of PAD are lacking, with current practice standards often extrapolated from evidence in coronary artery disease.Purpose: This review article aims to discuss currently accepted best pharmacological practice for PAD.Method: Relevant articles were searched between May 2023 and January 2024 through PubMed, Cochrane Library, Google Scholar and international guidelines, focusing on pharmacological management for PAD.Results: This narrative review discusses holistic pharmacological treatments for PAD.

Repeat Radiosurgery for Sporadic Vestibular Schwannoma After Primary Radiosurgical Failure: An International Multi-institutional Investigation.

OBJECTIVE: To describe outcomes of patients with sporadic vestibular schwannoma (VS) who underwent repeat stereotactic radiosurgery (SRS) after primary SRS failure. STUDY DESIGN: Multi-institutional historical cohort study. SETTING: Five tertiary care referral centers. PATIENTS: Adults ≥18 years old with sporadic VS. INTERVENTION: Primary and repeat treatment with SRS. MAIN OUTCOME MEASURE: Microsurgery-free survival after repeat SRS. RESULTS: Across institutions, 32 patients underwent repeat SRS after primary SRS. Most patients (74%) had tumors with cerebellopontine angle extension at primary SRS (median size, 13.5 mm [interquartile range, 7.5-18.8] mm). After primary SRS, patients underwent repeat SRS at a median of 4.8 years (interquartile range, 3.2-5.7 yr). For treatment modality, 30 (94%) patients received gamma knife for primary treatment and 31 (97%) patients received gamma knife as their repeat treatment. Median tumor volume increased from 0.970 cm3 at primary SRS to 2.200 cm3 at repeat SRS. Facial nerve function worsened in two patients after primary SRS and in two patients after repeat SRS. There were no instances of intracranial complications after repeat SRS. Microsurgery-free survival rates (95% confidence interval; number still at risk) at 1, 3, and 5 years after repeat SRS were 97% (90-100%, 24), 84% (71-100%, 13), and 68% (48-96%, 6), respectively. There was one occurrence of malignancy diagnosed after repeat radiosurgery. CONCLUSION: Overall, repeat SRS for sporadic VS has comparable risk profile, but lower rates of tumor control, compared with primary SRS.

Color constancy mechanisms in virtual reality environments.

Prior research has demonstrated high levels of color constancy in real-world scenarios featuring single light sources, extensive fields of view, and prolonged adaptation periods. However, exploring the specific cues humans rely on becomes challenging, if not unfeasible, with actual objects and lighting conditions. To circumvent these obstacles, we employed virtual reality technology to craft immersive, realistic settings that can be manipulated in real time. We designed forest and office scenes illuminated by five colors. Participants selected a test object most resembling a previously shown achromatic reference. To study color constancy mechanisms, we modified scenes to neutralize three contributors: local surround (placing a uniform-colored leaf under test objects), maximum flux (keeping the brightest object constant), and spatial mean (maintaining a neutral average light reflectance), employing two methods for the latter: changing object reflectances or introducing new elements. We found that color constancy was high in conditions with all cues present, aligning with past research. However, removing individual cues led to varied impacts on constancy. Local surrounds significantly reduced performance, especially under green illumination, showing strong interaction between greenish light and rose-colored contexts. In contrast, the maximum flux mechanism barely affected performance, challenging assumptions used in white balancing algorithms. The spatial mean experiment showed disparate effects: Adding objects slightly impacted performance, while changing reflectances nearly eliminated constancy, suggesting human color constancy relies more on scene interpretation than pixel-based calculations.

Stapedotomy Versus Cochlear Implantation for Far Advanced Otosclerosis: Insights From a Patient With Matched Preoperative and Postoperative Function.

OBJECTIVE: To examine patient preference after stapedotomy versus cochlear implantation in a unique case of a patient with symmetrical profound mixed hearing loss and similar postoperative speech perception improvement. PATIENTS: An adult patient with bilateral symmetrical far advanced otosclerosis, with profound mixed hearing loss. INTERVENTION: Stapedotomy in the left ear, cochlear implantation in the right ear. MAIN OUTCOME MEASURE: Performance on behavioral audiometry, and subjective report of hearing and intervention preference. RESULTS: A patient successfully underwent left stapedotomy and subsequent cochlear implantation on the right side, per patient preference. Preoperative audiometric characteristics were similar between ears (pure-tone average [PTA] [R: 114; L: 113 dB]; word recognition score [WRS]: 22%). Postprocedural audiometry demonstrated significant improvement after stapedotomy (PTA: 59 dB, WRS: 75%) and from cochlear implant (PTA: 20 dB, WRS: 60%). The patient subjectively reported a preference for the cochlear implant ear despite having substantial gains from stapedotomy. A nuanced discussion highlighting potentially overlooked benefits of cochlear implants in far advanced otosclerosis is conducted. CONCLUSION: In comparison with stapedotomy and hearing aids, cochlear implantation generally permits greater access to sound among patients with far advanced otosclerosis. Though the cochlear implant literature mainly focuses on speech perception outcomes, an underappreciated benefit of cochlear implantation is the high likelihood of achieving "normal" sound levels across the audiogram.

Oculomotor routines for perceptual judgments.

In everyday life we frequently make simple visual judgments about object properties, for example, how big or wide is a certain object? Our goal is to test whether there are also task-specific oculomotor routines that support perceptual judgments, similar to the well-established exploratory routines for haptic perception. In a first study, observers saw different scenes with two objects presented in a photorealistic virtual reality environment. Observers were asked to judge which of two objects was taller or wider while gaze was tracked. All tasks were performed with the same set of virtual objects in the same scenes, so that we can compare spatial characteristics of exploratory gaze behavior to quantify oculomotor routines for each task. Width judgments showed fixations around the center of the objects with larger horizontal spread. In contrast, for height judgments, gaze was shifted toward the top of the objects with larger vertical spread. These results suggest specific strategies in gaze behavior that presumably are used for perceptual judgments. To test the causal link between oculomotor behavior and perception, in a second study, observers could freely gaze at the object or we introduced a gaze-contingent setup forcing observers to fixate specific positions on the object. Discrimination performance was similar between free-gaze and the gaze-contingent conditions for width and height judgments. These results suggest that although gaze is adapted for different tasks, performance seems to be based on a perceptual strategy, independent of potential cues that can be provided by the oculomotor system.

Evolution of tissue-specific expression of ancestral genes across vertebrates and insects.

Regulation of gene expression is arguably the main mechanism underlying the phenotypic diversity of tissues within and between species. Here we assembled an extensive transcriptomic dataset covering 8 tissues across 20 bilaterian species and performed analyses using a symmetric phylogeny that allowed the combined and parallel investigation of gene expression evolution between vertebrates and insects. We specifically focused on widely conserved ancestral genes, identifying strong cores of pan-bilaterian tissue-specific genes and even larger groups that diverged to define vertebrate and insect tissues. Systematic inferences of tissue-specificity gains and losses show that nearly half of all ancestral genes have been recruited into tissue-specific transcriptomes. This occurred during both ancient and, especially, recent bilaterian evolution, with several gains being associated with the emergence of unique phenotypes (for example, novel cell types). Such pervasive evolution of tissue specificity was linked to gene duplication coupled with expression specialization of one of the copies, revealing an unappreciated prolonged effect of whole-genome duplications on recent vertebrate evolution.

Tensor Tympani and Stapedial Tendon Reconstruction for Postoperative Hyperacusis after Tendon Lysis for Middle Ear Myoclonus.

OBJECTIVE: To present a method for repair of the stapedial and tensor tympani tendons in a patient with hyperacusis after a tendon lysis procedure. PATIENTS: A 71-year-old professional musician who presented to clinic with debilitating hyperacusis following a tensor tympani and stapedial tendon lysis procedure to treat middle ear myoclonus. INTERVENTIONS: A novel procedure for reapproximation of the tensor tympani and stapedial tendons into their native insertion points using periosteal grafts and nitinol wire. MAIN OUTCOMES MEASURES: Stapedial reflex measurements, uncomfortable loudness level, and subjective patient experience. RESULTS: Postoperatively, the patient had objective improvement in hyperacusis with return of acoustic reflexes in the affected ear and durable improvements in their frequency-specific uncomfortable loudness levels. CONCLUSIONS: This case describes the debilitating complication of hyperacusis following tendon lysis and highlights the importance of maximizing behavioral and medical measures prior to undergoing surgical intervention for middle ear myoclonus.

Color constancy in real-world settings.

Color constancy denotes the ability to assign a particular and stable color percept to an object, irrespective of its surroundings and illumination. The light reaching the eye confounds illumination and spectral reflectance of the object, making the recovery of constant object color an ill-posed problem. How good the visual system is at accomplishing this task is still a matter of heated debate, despite more than a 100 years of research. Depending on the laboratory task and the specific cues available to observers, color constancy was found to be at levels ranging between 15% and 80%, which seems incompatible with the relatively stable color appearance of objects around us and the consistent usage of color names in real life. Here, we show close-to-perfect color constancy using real objects in a natural task and natural environmental conditions, chosen to mimic the role of color constancy in everyday life. Participants had to identify the color of a (non-present) item familiar to them in an office room under five different experimental illuminations. They mostly selected the same colored Munsell chip as their match to the absent object, even though the light reaching the eye in each case differed substantially. Our results demonstrate that color constancy under ideal conditions in the real world can indeed be exceptionally good. We found it to be as good as visual memory permits and not generally compromised by sensory uncertainty.

The prevalence of bilateral hearing loss in the United States in 2019: a small area estimation modelling approach for obtaining national, state, and county level estimates by demographic subgroup.

Background: The goal of this study was to re-estimate rates of bilateral hearing loss Nationally, and create new estimates of hearing loss prevalence at the U.S. State and County levels. Methods: We developed small area estimation models of mild, and moderate or worse bilateral hearing loss in the U.S. using data from the National Health and Nutrition Examination Survey (2001-2012, 2015-2018), the American Community Survey (2019), Census County Business Patterns (2019); Social Security Administration Data (2019); Medicare Fee-for-Service and Advantage claims data (2019); the Area Health Resources File (2019), and other sources. We defined hearing loss as mild (>25 dB through 40 dB), moderate or worse (>40 dB), or any (>25 dB) in the better hearing ear based on a 4-frequency pure-tone-average threshold, and created estimates by age group (0-4, 5-17, 18-34, 35-64, 65-74, 75+), gender, race and ethnicity, state, and county. Findings: We estimated that 37.9 million (95% Uncertainty Interval [U.I.] 36.6-39.1) Americans experienced any bilateral hearing loss; 24.9 million (95% U.I. 23.6-26.0) with mild and 13.0 million (95% U.I. 12.1-13.9) with moderate or worse. The prevalence rate of any hearing loss was 11.6% (95% U.I. 11.2%-12.0%). Hearing loss increased with age. Men were more likely to have hearing loss than women after age 35, and non-Hispanic Whites had higher rates of hearing loss than other races and ethnicities. Higher hearing loss prevalence was associated with smaller population size. West Virginia, Alaska, Wyoming, Oklahoma, and Arkansas had the highest standardised rate of bilateral hearing loss, and Washington D.C., New Jersey, New York, Maryland, and Connecticut had the lowest. Interpretation: Bilateral Hearing loss varies by State and County, with variation associated with population age, race and ethnicity, and population size. Geographic estimates can be used to raise local awareness of hearing loss as a problem, to prioritize areas for hearing loss prevention, identification, and treatment, and to guide future research on the hearing loss risk factors that contribute to these differences. Funding: CDC's National Center for Chronic Disease Prevention and Health Promotion, Division of Population Health.

Assessment of clinical pregnancies in up to eight ovarian stimulation with intrauterine insemination treatment cycles in those unable to proceed with in vitro fertilization.

OBJECTIVE: To study the primary objective of clinical pregnancy (CP) rate per ovarian stimulation with intrauterine insemination (OS-IUI) treatment cycle in patients with repetitive cycles up to a maximum of 8 cycles. DESIGN: Retrospective cohort. SETTING: Large fertility clinic. PATIENTS: A total of 37,565 consecutive OS-IUI cycles from 18,509 patients were included in this study. INTERVENTIONS: Those with anovulatory diagnoses, tubal factor infertility, male factor infertility, using donor sperm, canceled cycles, and those with missing data for either baseline characteristics or outcome were excluded. The CP rate was analyzed using generalized estimating equations and controlled for age, stimulation protocol, and body mass index. MAIN OUTCOMES MEASURES: Clinical pregnancy was defined as intrauterine gestation with fetal heartbeat visible on ultrasound. RESULTS: A total of 37,565 consecutive OS-IUI cycles from 2002 through 2019 at a private practice facility were evaluated. All cycles met inclusion criteria and were used in generalized estimating equation modeling. Patients aged <35 years comprised 47.6% of the cohort. After adjustment for confounders, the mean predicted probability of CP for cycles one to 8 was 15.7% per cycle. The mean predicted probability of CP in aggregated data from cycles 2 to 4 was only 1.7% lower compared with cycle 1 as the referent (16.7% vs. 15.0%, 95% confidence interval [CI] 2nd: 0.88 {0.82, 0.95}, 3rd: 0.86 {0.79, 0.93}, 4th: 0.88 {0.79, 0.98}). However, the 15.0% mean predicted probability of CP for the second through the fourth cycle was concordant with the mean for all included cycles (15.7%). The mean predicted probability of CP of cycles 5 to 8 was not significantly different compared with the referent (16.7% vs. 16.1%, 95% CI 5th: 0.97 [0.85, 1.11], 6th: 0.93 [0.79, 1.10], 7th: 1.01 [0.81, 1.26], 8th: 1.01 [0.76, 1.34]). The modeling of consecutive cycles suggested that the adjusted cumulative predicted probability of CP from OS-IUI continues to increase with each of the 8 successive cycles. CONCLUSION: Clinical pregnancy rates are satisfactory in up to 8 consecutive OS-IUI treatment cycles. These data are useful for counseling, especially in those patients for whom in vitro fertilization is not financially or ethically feasible.

Toxin-based screening of C-terminal tags in Escherichia coli reveals the exceptional potency of ssrA-like degrons.

All bacteria possess ATP-dependent proteases that destroy cytosolic proteins. These enzymes help cells mitigate proteotoxic stress, adapt to changing nutrient availability, regulate virulence phenotypes, and transition to pathogenic lifestyles. Moreover, ATP-dependent proteases have emerged as promising antibacterial and antivirulence targets in a variety of pathogens. The physiological roles of these proteases are largely defined by the complement of proteins that they degrade. Substrates are typically recognized in a highly selective manner, often via short unstructured sequences termed degrons. While a few degrons have been identified and rigorously characterized, we lack a systematic understanding of how proteases select valid degrons from the vast complexity of protein sequence space. Here, we describe a novel high-throughput screening approach in Escherichia coli that couples proteolysis of a protein toxin to cell survival. We used this method to screen a combinatorial library of C-terminal pentapeptide sequences for functionality as proteolytic degrons in wild type E. coli, and in strains lacking components of the ClpXP and ClpAP proteases. By examining the competitive enrichment of sequences over time, we found that about one percent of pentapeptide tags lead to toxin proteolysis. Interestingly, the most enriched degrons were ClpXP-dependent and highly similar to the ssrA tag, one of the most extensively characterized degrons in bacteria. Among ssrA-like sequences, we observed that specific upstream residues correlate with successful recognition. The lack of diversity among strongly enriched sequences suggests that ssrA-like tags comprise a uniquely potent class of short C-terminal degron in E. coli. Efficient proteolysis of substrates lacking such degrons likely requires adaptors or multivalent interactions. These findings broaden our understanding of the constraints that shape the bacterial proteolytic landscape. Our screening approach may be broadly applicable to probing aspects of proteolytic substrate selection in other bacterial systems.

Salvage Microsurgery Following Failed Primary Radiosurgery in Sporadic Vestibular Schwannoma.

Importance: Management of sporadic vestibular schwannoma with radiosurgery is becoming increasingly common globally; however, limited data currently characterize patient outcomes in the setting of microsurgical salvage for radiosurgical failure. Objective: To describe the clinical outcomes of salvage microsurgery following failed primary stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) among patients with sporadic vestibular schwannoma. Design, Setting, and Participants: This was a cohort study of adults (≥18 years old) with sporadic vestibular schwannoma who underwent salvage microsurgery following failed primary SRS/FSRT in 7 vestibular schwannoma treatment centers across the US and Norway. Data collection was performed between July 2022 and January 2023, with data analysis performed between January and July 2023. Exposure: Salvage microsurgical tumor resection. Main Outcomes and Measures: Composite outcome of undergoing less than gross total resection (GTR) or experiencing long-term facial paresis. Results: Among 126 patients, the median (IQR) age at time of salvage microsurgery was 62 (53-70) years, 69 (55%) were female, and 113 of 117 (97%) had tumors that extended into the cerebellopontine angle at time of salvage. Of 125 patients, 96 (76%) underwent primary gamma knife SRS, while 24 (19%) underwent linear accelerator-based SRS; the remaining patients underwent FSRT using other modalities. Postoperative cerebrospinal fluid leak was seen in 15 of 126 patients (12%), hydrocephalus in 8 (6%), symptomatic stroke in 7 (6%), and meningitis in 2 (2%). Each 1-mm increase in cerebellopontine angle tumor size was associated with a 13% increased likelihood of foregoing GTR (64 of 102 patients [63%]) or long-term postoperative House-Brackmann grade higher than I (48 of 102 patients [47%]) (odds ratio, 1.13; 95% CI, 1.04-1.23). Following salvage microsurgery, tumor growth-free survival rates at 1, 3, and 5 years were 97% (95% CI, 94%-100%), 93% (95% CI, 87%-99%), and 91% (95% CI, 84%-98%), respectively. Conclusions: In this cohort study, more than half of patients who received salvage microsurgery following primary SRS/FSRT underwent less than GTR or experienced some degree of facial paresis long term. These data suggest that the cumulative risk of developing facial paresis following primary SRS/FSRT by the end of the patient's journey with treatment approximates 2.5% to 7.5% when using published primary SRS/FSRT long-term tumor control rates.

Systematic Review of Auditory Training Outcomes in Adult Cochlear Implant Recipients and Meta-Analysis of Outcomes.

Objective: to review evidence on the efficacy of auditory training in adult cochlear implant recipients. Data Sources: PRISMA guidelines for a systematic review of the literature were followed. PubMed, Scopus, and CINAHL databases were queried on 29 June 2023 for terms involving cochlear implantation and auditory training. Studies were limited to the English language and adult patient populations. Study Selection: Three authors independently reviewed publications for inclusion in the review based on a priori inclusion and exclusion criteria. Inclusion criteria encompassed adult cochlear implant populations, an analysis of clinician- or patient-directed auditory training, and an analysis of one or more measures of speech recognition and/or patient-reported outcome. Exclusion criteria included studies with only pediatric implant populations, music or localization training in isolation, and single-sample case studies. Data Extraction: The data were collected regarding study design, patient population, auditory training modality, auditory training timing, speech outcomes, and data on the durability of outcomes. A quality assessment of the literature was performed using a quality metric adapted from the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group guidelines. Data Synthesis and Meta-Analysis: Data were qualitatively summarized for 23 studies. All but four studies demonstrated significant improvement in at least one measured or patient-reported outcome measure with training. For 11 studies with sufficient data reporting, pre-intervention and post-intervention pooled means of different outcome measures were compared for 132 patients using meta-analysis. Patient-direct training was associated with significant improvement in vowel-phoneme recognition and speech recognition in noise (p < 0.05 and p < 0.001, respectively), and clinician-directed training showed significant improvement in sentence recognition in noise (p < 0.001). Conclusions: The literature on auditory training for adult cochlear implant recipients is limited and heterogeneous, including a small number of studies with limited levels of evidence and external validity. However, the current evidence suggests that auditory training can improve speech recognition in adult cochlear implant recipients.

Comparative Analysis of the Osmoprotective Effects of Daily Disposable Contact Lens Packaging Solutions on Human Corneal Epithelial Cells.

Purpose: Contact lens (CL) wear challenges the balance of the ocular surface environment by increasing water evaporation and tear osmolarity. Maintaining ocular surface homeostasis during CL wear remains a goal of lens manufacturers and an important consideration for eye care professionals. The purpose of this study was to measure the metabolic activity and inflammatory responses of a transformed human corneal epithelial cell (THCEpiC) line under hyperosmotic conditions in the presence of CL packaging solutions. Methods: CL packaging solutions sampled from seven daily disposable silicone hydrogel CL blister packages were prepared at 25% and made hyperosmolar (400 mOsm/kg) with NaCl. THCEpiCs were incubated with each solution for 24 hr, after which cell culture supernatants were collected. THCEpiC metabolic activity was determined by an alamarBlue assay. Concentrations in cell culture supernatants of inflammatory cytokine (interleukin [IL]-6) and chemokine (IL-8), as well as monocyte chemoattractant protein-1 (MCP-1), were quantitated by specific enzyme-linked immunosorbent assays. Results: THCEpiC metabolic activity under hyperosmolar conditions decreased in the presence of somofilcon A and senofilcon A solutions (p=0.04 and 0.004, respectively), but no other solution (all p≥0.09). Concentrations of IL-6 increased in the presence of delefilcon A, somofilcon A, narafilcon A, and senofilcon A solutions (all p≤0.001), but no other solution (all p≥0.08), while those of IL-8 increased in the presence of all solutions (all p≤0.03) but kalifilcon A (p>0.99), and those of MCP-1 increased in the presence of delefilcon A, verofilcon A, somofilcon A, and stenfilcon A solutions (all p<0.0001), but no other solution (all p>0.99). Conclusion: CL packaging solutions differ in their capacity to inhibit epithelial inflammation. THCEpiC inflammatory response was less in the presence of a CL packaging solution containing osmoprotectants than in solutions lacking osmoprotectants under moderately hyperosmolar conditions in vitro. Clinical studies are warranted to further substantiate the benefit of osmoprotectants.

Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma.

A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames (ORFs). To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a stepwise approach using multiple CRISPR-Cas9 screens to elucidate non-canonical ORFs and putative microproteins implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream ORFs (uORFs) exhibited selective functionality independent of main coding sequences. A microprotein encoded by one of these ORFs, ASNSD1-uORF or ASDURF, was upregulated, associated with MYC-family oncogenes, and promoted medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future studies seeking to define new cancer targets.