Nacc1 Mutation in Mice Models Rare Neurodevelopmental Disorder with Underlying Synaptic Dysfunction.

A missense mutation in the transcription repressor Nucleus accumbens-associated 1 (NACC1) gene at c.892C>T (p.Arg298Trp) on chromosome 19 causes severe neurodevelopmental delay ( Schoch et al., 2017). To model this disorder, we engineered the first mouse model with the homologous mutation (Nacc1+/R284W ) and examined mice from E17.5 to 8 months. Both genders had delayed weight gain, epileptiform discharges and altered power spectral distribution in cortical electroencephalogram, behavioral seizures, and marked hindlimb clasping; females displayed thigmotaxis in an open field. In the cortex, NACC1 long isoform, which harbors the mutation, increased from 3 to 6 months, whereas the short isoform, which is not present in humans and lacks aaR284 in mice, rose steadily from postnatal day (P) 7. Nuclear NACC1 immunoreactivity increased in cortical pyramidal neurons and parvalbumin containing interneurons but not in nuclei of astrocytes or oligodendroglia. Glial fibrillary acidic protein staining in astrocytic processes was diminished. RNA-seq of P14 mutant mice cortex revealed over 1,000 differentially expressed genes (DEGs). Glial transcripts were downregulated and synaptic genes upregulated. Top gene ontology terms from upregulated DEGs relate to postsynapse and ion channel function, while downregulated DEGs enriched for terms relating to metabolic function, mitochondria, and ribosomes. Levels of synaptic proteins were changed, but number and length of synaptic contacts were unaltered at 3 months. Homozygosity worsened some phenotypes including postnatal survival, weight gain delay, and increase in nuclear NACC1. This mouse model simulates a rare form of autism and will be indispensable for assessing pathophysiology and targets for therapeutic intervention.

A Comparative Study of Large Language Models, Human Experts, and Expert-Edited Large Language Models to Neuro-Ophthalmology Questions.

BACKGROUND: While large language models (LLMs) are increasingly used in medicine, their effectiveness compared with human experts remains unclear. This study evaluates the quality and empathy of Expert + AI, human experts, and LLM responses in neuro-ophthalmology. METHODS: This randomized, masked, multicenter cross-sectional study was conducted from June to July 2023. We randomly assigned 21 neuro-ophthalmology questions to 13 experts. Each expert provided an answer and then edited a ChatGPT-4-generated response, timing both tasks. In addition, 5 LLMs (ChatGPT-3.5, ChatGPT-4, Claude 2, Bing, Bard) generated responses. Anonymized and randomized responses from Expert + AI, human experts, and LLMs were evaluated by the remaining 12 experts. The main outcome was the mean score for quality and empathy, rated on a 1-5 scale. RESULTS: Significant differences existed between response types for both quality and empathy (P < 0.0001, P < 0.0001). For quality, Expert + AI (4.16 ± 0.81) performed the best, followed by GPT-4 (4.04 ± 0.92), GPT-3.5 (3.99 ± 0.87), Claude (3.6 ± 1.09), Expert (3.56 ± 1.01), Bard (3.5 ± 1.15), and Bing (3.04 ± 1.12). For empathy, Expert + AI (3.63 ± 0.87) had the highest score, followed by GPT-4 (3.6 ± 0.88), Bard (3.54 ± 0.89), GPT-3.5 (3.5 ± 0.83), Bing (3.27 ± 1.03), Expert (3.26 ± 1.08), and Claude (3.11 ± 0.78). For quality (P < 0.0001) and empathy (P = 0.002), Expert + AI performed better than Expert. Time taken for expert-created and expert-edited LLM responses was similar (P = 0.75). CONCLUSIONS: Expert-edited LLM responses had the highest expert-determined ratings of quality and empathy warranting further exploration of their potential benefits in clinical settings.

Analysis of homeodomain specificities allows the family-wide prediction of preferred recognition sites.

We describe the comprehensive characterization of homeodomain DNA-binding specificities from a metazoan genome. The analysis of all 84 independent homeodomains from D. melanogaster reveals the breadth of DNA sequences that can be specified by this recognition motif. The majority of these factors can be organized into 11 different specificity groups, where the preferred recognition sequence between these groups can differ at up to four of the six core recognition positions. Analysis of the recognition motifs within these groups led to a catalog of common specificity determinants that may cooperate or compete to define the binding site preference. With these recognition principles, a homeodomain can be reengineered to create factors where its specificity is altered at the majority of recognition positions. This resource also allows prediction of homeodomain specificities from other organisms, which is demonstrated by the prediction and analysis of human homeodomain specificities.

Temporal Slant Recession of the Inferior Rectus Muscle: A Simple Surgical Treatment for Diplopia Caused by Small Vertical Deviations.

BACKGROUND: To evaluate the therapeutic effect of temporal slant recession of the inferior rectus muscle (TSRIRM) for the treatment of small vertical deviations in patients with vertical diplopia, with consideration of the theoretical additive effects of this procedure on ocular torsion and horizontal incomitance. METHODS: Retrospective review of 11 patients who were treated with TSRIRM. Eight patients with vertical diplopia and small hyperdeviations (up to 6 prism diopters (PDs)) were treated with isolated TSRIRMs. Three patients with vertical diplopia from unilateral superior oblique palsies with large hyperdeviations (>15 PDs) were treated with TSRIRMs in conjunction with contralateral inferior oblique recessions. RESULTS: Six of the 8 patients with small vertical deviations had successful vertical realignment with elimination of symptomatic diplopia after an isolated TSRIRM. Two of the eight patients had residual hypertropia with symptomatic diplopia. Three additional patients with unilateral superior oblique palsy had successful vertical realignment with elimination of symptomatic diplopia after ipsilateral inferior oblique recession and contralateral TSRIRM. In total, 9 of 11 patients had successful surgical results after TSRIRM. CONCLUSIONS: TSRIRM provides an effective and reliable treatment for small angle vertical strabismus. Its ease of surgical access renders it useful for implementation in an outpatient neuro-ophthalmology setting.

Ocular Torsional Instability-A Neurodiagnostic Sign of Prenuclear Disease.

BACKGROUND: Accurate diagnosis of efferent visual system disease in neuro-ophthalmology involves the classification of clinical signs as prenuclear, nuclear, or infranuclear in origin. Over many years, I have come to recognize ocular torsional instability as a clinical sign of prenuclear disease. METHODS: Retrospective chart review of patients in whom ocular torsional instability was diagnosed using indirect ophthalmoscopy. RESULTS: Twenty patients were diagnosed as having ocular torsional instability (OTI). Eight had neuro-ophthalmologic disease caused by structural injury to prenuclear ocular motor areas. Six of these had structural lesions primarily involving the cerebellum, one had a midbrain glioma, and one had traumatic encephalomalacia. Eight additional patients had infantile strabismus (esotropia in 7, exotropia in 1) associated with various combinations of monocular nasotemporal optokinetic asymmetry, latent nystagmus, and dissociated vertical divergence (DVD), indicating prenuclear involvement of subcortical visuovestibular pathways within the brain. Three additional patients presented with intermittent exotropia with DVD signifying early onset, while 2 had acquired esotropia that was noninfantile in origin. One had partially accommodative esotropia with bilateral inferior oblique overaction, and one presented with acquired esotropia followed by spontaneous secondary exotropia. CONCLUSIONS: OTI provides a useful clinical sign of prenuclear ocular motor dysfunction. When detected in patients without any signs of infantile or early-onset strabismus, OTI signifies the need for neuroimaging to rule out neurovestibular or cerebellar causes of prenuclear disease.

Interprofessional Electronic Consultations for the Diagnosis and Management of Neuro-Ophthalmic Conditions.

BACKGROUND: Interprofessional electronic consultation (eConsult) is a telemedicine modality in which consulting providers review outside records and provide recommendations without in-person consultation. The purpose of this study was to describe the utilization of eConsults in the management of neuro-ophthalmic conditions. METHODS: Retrospective cohort study of all patients who received an eConsult for a neuro-ophthalmic condition at a single quaternary referral center from 2018 to 2020. Main outcome measures included proportion of eConsults in which sufficient data were provided to the neuro-ophthalmologist to generate a definitive management decision, proportion of patients for whom an in-person neuro-ophthalmology evaluation was recommended, and the eConsult's impact on patient care. RESULTS: Eighty eConsults were conducted on 78 patients during the 3-year study period. Forty-eight (60.0%) subjects were female, mean age was 54 years, and 65 (81.3%) were White. The median time from eConsult request to completion was 4 days (range: 0-34 days). The most frequent eConsult questions were vision/visual field disturbances in 28 (35.0%) cases, optic neuropathies in 22 (27.5%), and optic disc edema in 17 (21.3%). At the time of eConsult, sufficient prior information was provided in 35 (43.8%) cases for the neuro-ophthalmologist to provide a definitive management decision. In 45 (56.3%) eConsults, further diagnostic testing was recommended. In-person neuro-ophthalmology consultation was recommended in 24 (30.0%) cases. Sixty-one (76.3%) eConsults provided diagnostic and/or treatment direction, and 12 (15.0%) provided reassurance. CONCLUSION: eConsults increase access to timely neuro-ophthalmic care and provide diagnostic and treatment direction to non-neuro-ophthalmology providers when sufficient information is provided at the time of eConsult.

The Association of Digital Health Application Use With Heart Failure Care and Outcomes: Insights From CONNECT-HF.

BACKGROUND: It is unknown whether digital applications can improve guideline-directed medical therapy (GDMT) and outcomes in heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Care Optimization Through Patient and Hospital Engagement Clinical Trial for Heart Failure trial (CONNECT-HF) included an optional, prospective ancillary study of a mobile health application among patients hospitalized due to HFrEF. Digital users were matched to nonusers from the usual-care group. Coprimary outcomes included change in opportunity-based composite HF quality scores and HF rehospitalization or all-cause mortality. Among 2431 patients offered digital applications across the United States, 1526 (63%) had limited digital access or insufficient data, 425 (17%) were digital users, and 480 (20%) declined use. Digital users were similar in age to those who declined use (mean 58 vs 60 years; P = 0.031). Digital users (n = 368) vs matched nonusers (n = 368) had improved composite HF quality scores (48.0% vs 43.6%; + 4.76% [3.27-6.24]; P = 0.001) and composite clinical outcomes (33.0% vs 39.6%; HR 0.76 [0.59-0.97]; P = 0.027). CONCLUSIONS: Among participants in the CONNECT-HF trial, use of digital applications was modest but was associated with higher HF quality-of-care scores, including use of GDMT and better clinical outcomes. Although cause and effect cannot be determined from this study, the application of technology to guide GDMT use and dosing among patients with HFrEF warrants further investigation.

Abnormal Vestibular-Ocular Reflexes in Children With Cortical Visual Impairment.

BACKGROUND: To determine whether the vestibular-ocular reflexes (VORs) can be affected by central nervous system injury in children with cortical visual impairment (CVI). METHODS: Retrospective case series. Twenty consecutive children with CVI who presented to a pediatric ophthalmology practice over an 18-month period were included in the study. Horizontal and vertical VORs were assessed by a pediatric neuro-ophthalmologist using the standard doll's head maneuver. MRI studies were independently reviewed by a pediatric neuroradiologist in a masked fashion. The main outcome measures were the integrity of the VORs and the presence of brainstem abnormalities on MRI. RESULTS: VORs were found to be absent or severely impaired in 13/20 (65%) children with CVI. More surprisingly, the doll's head maneuver failed to substantially overcome the deviated eye position in 8/13 (62%) children with conjugate gaze deviations. Reduced brainstem size and signal abnormalities were found in 4/7 children with normal VORs and in 9/13 children with abnormal VORs (P = 0.6), showing noncorrelation with the integrity of the VOR. CONCLUSION: VORs are commonly impaired in children with CVI. This ocular motor deficit reflects the diffuse cortical and subcortical injury that often accompanies perinatal injury to the developing brain. Consequently, these children may lack important visual compensatory mechanisms to stabilize gaze during head movements. This knowledge can help in planning visual rehabilitation.

Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema.

Chronic obstructive pulmonary disease affects 10% of the worldwide population, and the leading genetic cause is α-1 antitrypsin (AAT) deficiency. Due to the complexity of the murine locus, which includes up to six Serpina1 paralogs, no genetic animal model of the disease has been successfully generated until now. Here we create a quintuple Serpina1a-e knockout using CRISPR/Cas9-mediated genome editing. The phenotype recapitulates the human disease phenotype, i.e., absence of hepatic and circulating AAT translates functionally to a reduced capacity to inhibit neutrophil elastase. With age, Serpina1 null mice develop emphysema spontaneously, which can be induced in younger mice by a lipopolysaccharide challenge. This mouse models not only AAT deficiency but also emphysema and is a relevant genetic model and not one based on developmental impairment of alveolarization or elastase administration. We anticipate that this unique model will be highly relevant not only to the preclinical development of therapeutics for AAT deficiency, but also to emphysema and smoking research.

Coupling between waveguides and microresonators: the local approach.

Coupling between optical microresonators and waveguides is a critical characteristic of resonant photonic devices that has complex behavior that is not well understood. When the characteristic variation length of the microresonator modes is much larger than the waveguide width, local coupling parameters emerge that are independent of the resonator mode distributions and offer a simplified description of coupling behavior. We develop a robust numerical-fitting-based methodology for experimental determination of the local coupling parameters in all coupling regimes and demonstrate their characterization along a microfiber waveguide coupled to an elongated bottle microresonator.

Optic Nerve Hypoplasia: "Neural Guidance" and the Role of Mentorship.

Over the past 50 years, our understanding of optic nerve hypoplasia has advanced in a series of waves, with each wave producing a paradigm shift in clinical diagnosis and management. First was the recognition that optic nerve hypoplasia is a condition distinct from optic atrophy and is a frequent cause of blindness in children. Second was the identification of associated brain malformations. Third was the realization that many children with optic nerve hypoplasia have hypopituitarism. Fourth was the identification of segmental forms of optic nerve hypoplasia. Fifth was the recognition that some children are at risk for sudden death, which can often be prevented with preemptive measures. Last was the identification of additional systemic accompaniments. Genetic studies have been largely unfruitful and, for most cases, the cause remains unknown.

Congenital Prepapillary Arterial Convolutions: A Requiem for William F. Hoyt.

This vignette describes a diagnostic telephone consultation with Bill Hoyt regarding a 65-year-old man who was found to have an unusual vascular pattern overlying the left optic disc. Bill recognized and characterized this condition as prepapillary arterial convolutions, a congenital vascular anomaly that has never entered the scientific literature. Close inspection disclosed evidence of mild vascular derangement in the contralateral eye as well. The cause of this condition remains unknown.

Polarization diversity phase modulator for measuring frequency-bin entanglement of a biphoton frequency comb in a depolarized channel.

Phase modulation has emerged as a technique to create and manipulate high-dimensional frequency-bin entanglement. A necessary step to extending this technique to depolarized channels, such as those in a quantum networking environment, is the ability to perform phase modulation independent of photon polarization. This is also necessary to harness hyperentanglement in the polarization and frequency degrees of freedom for operations such as Bell state discrimination. However, practical phase modulators are generally sensitive to the polarization of light, and this makes them unsuited to such applications. We overcome this limitation by implementing a polarization diversity scheme to measure frequency-bin entanglement for arbitrary orientations of co- and cross-polarized time-energy entangled photon pairs.

Congenital Oculonasal Synkinesis.

A 4-year-old girl with maxillary hypoplasia, intermittent exotropia, and high myopia displayed congenital oculonasal synkinesis. We examine the implications for pathogenesis of these disparate craniofacial findings.

DNA-binding-domain fusions enhance the targeting range and precision of Cas9.

The CRISPR-Cas9 system is commonly used in biomedical research; however, the precision of Cas9 is suboptimal for applications that involve editing a large population of cells (for example, gene therapy). Variations on the standard Cas9 system have yielded improvements in the precision of targeted DNA cleavage, but they often restrict the range of targetable sequences. It remains unclear whether these variants can limit lesions to a single site in the human genome over a large cohort of treated cells. Here we show that by fusing a programmable DNA-binding domain (pDBD) to Cas9 and attenuating Cas9's inherent DNA-binding affinity, we were able to produce a Cas9-pDBD chimera with dramatically improved precision and an increased targeting range. Because the specificity and affinity of this framework can be easily tuned, Cas9-pDBDs provide a flexible system that can be tailored to achieve extremely precise genome editing at nearly any genomic locus.

Discovery of parabolic microresonators produced via fiber tapering.

We demonstrate a new method for the creation of surface nanoscale axial photonics (SNAP) microresonators with harmonic profiles via fiber tapering in a laser-heated microfurnace. This simple procedure makes microresonators that support hundreds of axial modes with good spacing uniformity, yielding a promising prospective method for fabricating miniature frequency comb generators and dispersionless delay lines.