Self-Assembling Peptides with Insulin-Like Growth Factor Mimicry.

Growth factor (GF) mimicry involves recapitulating the signaling of larger molecules or cells. Although GF mimicry holds considerable promise in tissue engineering and drug design applications, difficulties in targeting the signaling molecule to the site of delivery and dissociation of mimicking peptides from their target receptors continue to limit its clinical application. To address these challenges, we utilized a self-assembling peptide (SAP) platform to generate synthetic insulin-like growth factor (IGF)-signaling, self-assembling GFs. Our peptide hydrogels are biocompatible and bind target IGF receptors in a dose-dependent fashion, activate proangiogenic signaling, and facilitate formation of angiogenic microtubules in vitro. Furthermore, infiltrated hydrogels are stable for weeks to months. We conclude that the enhanced targeting and long-term stability of our SAP/GF mimicry implants may improve the efficacy and safety of future GF mimic therapeutics.

Sex Differences in Age at Onset and Presentation of Trichotillomania and Trichobezoar: A 120-Year Systematic Review of Cases.

Trichotillomania (hair-pulling disorder) has high female preponderance. It has been suggested that onset in early childhood represents a distinct developmental subtype that is characterized by higher prevalence of males compared to later onset cases. However, the empirical literature is scarce. We conducted a systematic review of case reports to examine the distribution of age at onset/presentation in males and females with trichotillomania or trichobezoar (a mass of hair in the gastrointestinal tract resulting from ingesting hair). We identified 1065 individuals with trichotillomania and 1248 with trichobezoar. In both samples, males, compared to females, had earlier age at presentation and greater proportion of cases in early childhood. These sex differences remained after potential confounding variables were accounted for. The results showed similar sex differences for age at onset, which was reported in 734 and 337 of the trichotillomania and trichobezoar cases, respectively. The findings may reflect neurodevelopmental underpinnings in early childhood trichotillomania.

Subacute Polymicrobial Bacterial Pericarditis Mimicking Tuberculous Pericarditis: A Case Report.

BACKGROUND Bacterial pericarditis can present a diagnostic challenge due to the difficulty of obtaining tissue for bacterial identification. This report is of a 34-year-old man who presented with fever and cough. Diagnosis was initially delayed without a tissue sample, but the patient was later found to have polymicrobial bacterial pericarditis. CASE REPORT A 34-year-old man from the Democratic Republic of Congo presented to the emergency room with cough, fever, and night sweats. He was admitted and found to have pericardial thickening and fluid collection with calcifications. A tissue sample was not obtained for diagnosis, and he was discharged on RIPE (rifampin, isoniazid, pyrazinamide, and ethambutol) and steroids for presumed tuberculosis pericarditis. He worsened clinically and was readmitted to the hospital with evolving pericardial effusion with air present, in addition to new pleural effusion and parenchymal consolidation. He subsequently underwent thoracotomy and pericardial biopsy. Tissue cultures and sequence-based bacterial analysis eventually revealed the presence of Prevotella oris and Fusobacterium nucleatum. He improved dramatically with appropriate antibiotic therapy. CONCLUSIONS This report demonstrates the importance of undergoing further diagnostic work-up for bacterial pericarditis, especially in resource-rich settings. Although tuberculosis pericarditis should remain high on the differential, it is imperative not to anchor on that diagnosis. Instead, when feasible and safe, tissue biopsy should be obtained and sent for organism identification. AFB smears and cultures, Xpert MTB/RIF, and sequence-based bacterial analysis have all been used for identification. Delay in diagnosis can lead to progression of disease and unnecessary incorrect therapies.

Anchoring Vignettes as a Method to Address Implicit Gender Bias in Patient Experience Scores.

STUDY OBJECTIVE: Patient experience metrics have become increasingly important in evaluations of health care organizations and physician performance. Although such measures have been touted as a way to make objective comparisons of performance, they are subject to many of the same biases as other survey instruments, including gender bias. METHODS: A total of 320 surveys were conducted between February and October 2020. Surveys included vignettes describing different scenarios, and respondents were asked to rate the vignette physician in each scenario on 1 of 3 themes: listening, time, or courtesy. Three vignettes per theme were used. Half of the surveys used a male physician and half used a female physician. Using tests of difference, we compared the ratings of male and female vignette physicians. We also used a statistical technique known as anchoring vignettes to show how respondents' ratings of vignette physicians related to their ratings of their own physicians. RESULTS: In all 9 vignette scenarios, the male vignette physician was rated more highly than the female vignette physician. These differences were statistically significant in 2 of 9 scenarios. Male vignette physicians were given more top-box ratings than female vignette physicians. Anchoring vignettes showed a statistically nonsignificant association between vignette ratings and ratings of respondents' own physicians. CONCLUSION: Our findings revealed a pattern of higher ratings of male vignette physicians when compared to female vignette physicians, which may translate to ratings of patients' own physicians. These findings suggest that current methods to evaluate patients' experiences with their own physicians may disadvantage female physicians.

Single and Dual Vector Gene Therapy with AAV9-PHP.B Rescues Hearing in Tmc1 Mutant Mice.

AAV-mediated gene therapy is a promising approach for treating genetic hearing loss. Replacement or editing of the Tmc1 gene, encoding hair cell mechanosensory ion channels, is effective for hearing restoration in mice with some limitations. Efficient rescue of outer hair cell function and lack of hearing recovery with later-stage treatment remain issues to be solved. Exogenous genes delivered with the adeno-associated virus (AAV)9-PHP.B capsid via the utricle transduce both inner and outer hair cells of the mouse cochlea with high efficacy. Here, we demonstrate that AAV9-PHP.B gene therapy can promote hair cell survival and successfully rescues hearing in three distinct mouse models of hearing loss. Tmc1 replacement with AAV9-PHP.B in a Tmc1 knockout mouse rescues hearing and promotes hair cell survival with equal efficacy in inner and outer hair cells. The same treatment in a recessive Tmc1 hearing-loss model, Baringo, partially recovers hearing even with later-stage treatment. Finally, dual delivery of Streptococcus pyogenes Cas9 (SpCas9) and guide RNA (gRNA) in separate AAV9-PHP.B vectors selectively disrupts a dominant Tmc1 allele and preserves hearing in Beethoven mice, a model of dominant, progressive hearing loss. Tmc1-targeted gene therapies using single or dual AAV9-PHP.B vectors offer potent and versatile approaches for treating dominant and recessive deafness.

Direct Delivery of Antisense Oligonucleotides to the Middle and Inner Ear Improves Hearing and Balance in Usher Mice.

Usher syndrome is a syndromic form of hereditary hearing impairment that includes sensorineural hearing loss and delayed-onset retinitis pigmentosa (RP). Type 1 Usher syndrome (USH1) is characterized by congenital profound sensorineural hearing impairment and vestibular areflexia, with adolescent-onset RP. Systemic treatment with antisense oligonucleotides (ASOs) targeting the human USH1C c.216G>A splicing mutation in a knockin mouse model of USH1 restores hearing and balance. Herein, we explore the effect of delivering ASOs locally to the ear to treat hearing and vestibular dysfunction associated with Usher syndrome. Three localized delivery strategies were investigated in USH1C mice: inner ear injection, trans-tympanic membrane injection, and topical tympanic membrane application. We demonstrate, for the first time, that ASOs delivered directly to the ear correct Ush1c expression in inner ear tissue, improve cochlear hair cell transduction currents, restore vestibular afferent irregularity, spontaneous firing rate, and sensitivity to head rotation, and successfully recover hearing thresholds and balance behaviors in USH1C mice. We conclude that local delivery of ASOs to the middle and inner ear reach hair cells and can rescue both hearing and balance. These results also demonstrate the therapeutic potential of ASOs to treat hearing and balance deficits associated with Usher syndrome and other ear diseases.

Efficient viral transduction in mouse inner ear hair cells with utricle injection and AAV9-PHP.B.

Viral delivery of exogenous coding sequences into the inner ear has the potential for therapeutic benefit for patients suffering genetic or acquired hearing loss. To devise improved strategies for viral delivery, we investigated two injection techniques, round window membrane injection or a novel utricle injection method, for their ability to safely and efficiently transduce sensory hair cells and neurons of the mouse inner ear. In addition, we evaluated three synthetic AAV vectors (Anc80L65, AAV9-PHP.B, AAV2.7m8) encoding enhanced green fluorescent protein (eGFP) and three promoters (Cmv, Synapsin, Gfap) for their ability to transduce and drive expression in desired cell types. We found the utricle injection method with AAV9-PHP.B and a Cmv promoter was the most efficient combination for driving robust eGFP expression in both inner and outer hair cells. We found eGFP expression levels rose over 3-5 days post-injection, a viral dose of 1.5 × 109 gc yielded half maximal eGFP expression and that the utricle injection method yielded transduced hair cells even when delivered as late as postnatal day 16. Sensory transduction and auditory thresholds were unaltered in injected mice relative to uninjected wild-type controls. Vestibular end organs were also transduced without affecting balance behavior. The Synapsin promoter and the Gfap promoter drove strong eGFP expression in inner ear neurons and supporting cells, respectively. We conclude the AAV9-PHP.B vector and the utricle injection method are well-suited for delivery of exogenous gene constructs into inner ears of mouse models of auditory and vestibular dysfunction.

Sleep Sufficiency in Pediatric and Adolescent Tourette's Disorder: National Survey of Children's Health.

OBJECTIVE: The present study compared sleep sufficiency in youth with current Tourette's disorder (TD), history of TD and matched case controls, and examined predictors of sufficient sleep using a large US population-based survey. METHOD: Participants were 673 caregivers of youth aged 6 to 17 years (298 with current TD, 122 with a history of TD with no endorsement of current diagnosis, and 254 matched case controls) from the 2007 and 2011-2012 versions of the National Survey of Children's Health. History and current TD status, current comorbidity (attention deficit/hyperactivity disorder, anxiety, and depression) and psychiatric medication status were assessed by yes/no items. Current TD severity was dichotomized into mild or moderate/severe symptoms. Sleep was assessed by parent-reported number of sufficient nights their child slept in the past week. RESULTS: Univariate analysis of variance yielded significant group differences in nights of sufficient sleep (F[2,369.70] = 71.53, p < .001), with controls having 1.5 more nights per week relative to both TD groups (p < .001). With respect to predictors of sufficient sleep, the analysis of covariance yielded a significant age × sex × TD severity interaction (F[1,15.84] = 4.28, p = .04) such that older adolescent males with mild TD had significantly fewer nights of sufficient sleep than children (p = .004) and early adolescents (p = .002; F[2,54.93] = 7.45, p = .001). Early adolescent females with moderate/severe TD had fewer nights of sufficient sleep relative to males (p = .008). Comorbidity type and psychiatric medication status did not significantly predict sleep. CONCLUSION: Findings suggest that insufficient sleep in youth with TD persists independently of comorbidity or psychiatric medication status. Findings highlight the importance of clinical sleep monitoring in this population.

Getting Drugs Across Biological Barriers.

The delivery of drugs to a target site frequently involves crossing biological barriers. The degree and nature of the impediment to flux, as well as the potential approaches to overcoming it, depend on the tissue, the drug, and numerous other factors. Here an overview of approaches that have been taken to crossing biological barriers is presented, with special attention to transdermal drug delivery. Technology and knowledge pertaining to addressing these issues in a variety of organs could have a significant clinical impact.

Bi-directional audiovisual influences on temporal modulation discrimination.

Cross-modal interactions of auditory and visual temporal modulation were examined in a game-like experimental framework. Participants observed an audiovisual stimulus (an animated, sound-emitting fish) whose sound intensity and/or visual size oscillated sinusoidally at either 6 or 7 Hz. Participants made speeded judgments about the modulation rate in either the auditory or visual modality while doing their best to ignore information from the other modality. Modulation rate in the task-irrelevant modality matched the modulation rate in the task-relevant modality (congruent conditions), was at the other rate (incongruent conditions), or had no modulation (unmodulated conditions). Both performance accuracy and parameter estimates from drift-diffusion decision modeling indicated that (1) the presence of temporal modulation in both modalities, regardless of whether modulations were matched or mismatched in rate, resulted in audiovisual interactions; (2) congruence in audiovisual temporal modulation resulted in more reliable information processing; and (3) the effects of congruence appeared to be stronger when judging visual modulation rates (i.e., audition influencing vision), than when judging auditory modulation rates (i.e., vision influencing audition). The results demonstrate that audiovisual interactions from temporal modulations are bi-directional in nature, but with potential asymmetries in the size of the effect in each direction.

Sensory coding and cognitive processing of sound in Veterans with blast exposure.

Recent anecdotal reports from VA audiology clinics as well as a few published studies have identified a sub-population of Service Members seeking treatment for problems communicating in everyday, noisy listening environments despite having normal to near-normal hearing thresholds. Because of their increased risk of exposure to dangerous levels of prolonged noise and transient explosive blast events, communication problems in these soldiers could be due to either hearing loss (traditional or "hidden") in the auditory sensory periphery or from blast-induced injury to cortical networks associated with attention. We found that out of the 14 blast-exposed Service Members recruited for this study, 12 had hearing thresholds in the normal to near-normal range. A majority of these participants reported having problems specifically related to failures with selective attention. Envelope following responses (EFRs) measuring neural coding fidelity of the auditory brainstem to suprathreshold sounds were similar between blast-exposed and non-blast controls. Blast-exposed subjects performed substantially worse than non-blast controls in an auditory selective attention task in which listeners classified the melodic contour (rising, falling, or "zig-zagging") of one of three simultaneous, competing tone sequences. Salient pitch and spatial differences made for easy segregation of the three concurrent melodies. Poor performance in the blast-exposed subjects was associated with weaker evoked response potentials (ERPs) in frontal EEG channels, as well as a failure of attention to enhance the neural responses evoked by a sequence when it was the target compared to when it was a distractor. These results suggest that communication problems in these listeners cannot be explained by compromised sensory representations in the auditory periphery, but rather point to lingering blast-induced damage to cortical networks implicated in the control of attention. Because all study participants also suffered from post-traumatic disorder (PTSD), follow-up studies are required to tease apart the contributions of PTSD and blast-induced injury on cognitive performance.

Auditory Brainstem Response Latency in Noise as a Marker of Cochlear Synaptopathy.

Evidence from animal and human studies suggests that moderate acoustic exposure, causing only transient threshold elevation, can nonetheless cause "hidden hearing loss" that interferes with coding of suprathreshold sound. Such noise exposure destroys synaptic connections between cochlear hair cells and auditory nerve fibers; however, there is no clinical test of this synaptopathy in humans. In animals, synaptopathy reduces the amplitude of auditory brainstem response (ABR) wave-I. Unfortunately, ABR wave-I is difficult to measure in humans, limiting its clinical use. Here, using analogous measurements in humans and mice, we show that the effect of masking noise on the latency of the more robust ABR wave-V mirrors changes in ABR wave-I amplitude. Furthermore, in our human cohort, the effect of noise on wave-V latency predicts perceptual temporal sensitivity. Our results suggest that measures of the effects of noise on ABR wave-V latency can be used to diagnose cochlear synaptopathy in humans. SIGNIFICANCE STATEMENT: Although there are suspicions that cochlear synaptopathy affects humans with normal hearing thresholds, no one has yet reported a clinical measure that is a reliable marker of such loss. By combining human and animal data, we demonstrate that the latency of auditory brainstem response wave-V in noise reflects auditory nerve loss. This is the first study of human listeners with normal hearing thresholds that links individual differences observed in behavior and auditory brainstem response timing to cochlear synaptopathy. These results can guide development of a clinical test to reveal this previously unknown form of noise-induced hearing loss in humans.

Emerging roles of ATRX in cancer.

ATRX was identified over 20 years ago as the gene responsible for a rare developmental disorder characterized by α-thalassemia and intellectual disability. Similarities to the sucrose nonfermentable SNF2 type chromatin remodelers initially suggested a role in transcriptional regulation. However, over the last years, our knowledge of the epigenetic activities of ATRX has expanded steadily. Recent exciting discoveries have propelled ATRX into the limelight of chromatin and telomere biology, development and cancer research. This review summarizes recent breakthroughs in understanding ATRX function in heterochromatin structure, genome stability and its frequent dysregulation in a variety of cancers.

Policing Fish at Boston's Museum of Science: Studying Audiovisual Interaction in the Wild.

Boston's Museum of Science supports researchers whose projects advance science and provide educational opportunities to the Museum's visitors. For our project, 60 visitors to the Museum played "Fish Police!!," a video game that examines audiovisual integration, including the ability to ignore irrelevant sensory information. Players, who ranged in age from 6 to 82 years, made speeded responses to computer-generated fish that swam rapidly across a tablet display. Responses were to be based solely on the rate (6 or 8 Hz) at which a fish's size modulated, sinusoidally growing and shrinking. Accompanying each fish was a task-irrelevant broadband sound, amplitude modulated at either 6 or 8 Hz. The rates of visual and auditory modulation were either Congruent (both 6 Hz or 8 Hz) or Incongruent (6 and 8 or 8 and 6 Hz). Despite being instructed to ignore the sound, players of all ages responded more accurately and faster when a fish's auditory and visual signatures were Congruent. In a controlled laboratory setting, a related task produced comparable results, demonstrating the robustness of the audiovisual interaction reported here. Some suggestions are made for conducting research in public settings.