Immunotherapy time of infusion impacts survival in head and neck cancer: A propensity score matched analysis.

The adaptive immune response is physiologically regulated by the circadian rhythm. Data in lung and melanoma malignancies suggests immunotherapy infusions earlier in the day may be associated with improved response; however, the optimal time of administration for patients with head and neck squamous cell carcinoma (HNSCC) is not known. We aimed to evaluate the association of immunotherapy infusion time with overall survival (OS) and progression free survival (PFS) in patients with HNSCC in an Institutional Review Board-approved, retrospective cohort study. 113 patients met study inclusion criteria and 98 patients were included in a propensity score-matched cohort. In the full unmatched cohort (N = 113), each additional 20 % of infusions received after 1500 h conferred an OS hazard ratio (HR) of 1.35 (95 % C.I.1.2-1.6; p-value = 0.0003) and a PFS HR of 1.34 (95 % C.I.1.2-1.6; p-value < 0.0001). A propensity score-matched analysis of patients who did or did not receive ≥20 % of infusions after 1500 h showed that those who were administered ≥20 % of infusions after 1500 h trended towards a shorter OS (HR = 1.35; p-value = 0.26) and a shorter PFS (HR = 1.57, 95 % C.I. 1.02-2.42, p-value = 0.04). Each additional 20 % of infusions received after 1500 h remained robust in the matched cohort multivariable analysis and was associated with shorter OS (adjusted HR = 1.4 (95 % C.I.1.2-1.8), p-value < 0.001). Patients with advanced HNSCC who received more of their infusions in the afternoon were associated with shorter OS and PFS and scheduling immunotherapy infusions earlier in the day may be warranted.

Hearing and sociality: the implications of hearing loss on social life.

Hearing is essential to the formation of social relationships and is the principal afferent of social life. Yet hearing loss, which is one of the most prevalent forms of sensory disability worldwide and is critical for social development, has received little attention from the social interventionalist perspective. The purpose of this mini-review is to describe the basic neurobiological principles of hearing and to explore the reciprocal relationships between social support, hearing loss, and its psychosocial comorbidities. We also discuss the role of social enrichment in sensorineural recovery and identify open questions within the fields of hearing physiology and social networks.

Microscopic and transcriptomic changes in porcine synovium one year following disruption of the anterior cruciate ligament.

OBJECTIVE: There is no disease-modifying treatment for posttraumatic osteoarthritis (PTOA). This may be partly due to an incomplete understanding of synovitis, which has been causally linked to PTOA progression. The microscopic and transcriptomic changes in synovium seen in early- to mid-stage PTOA were evaluated to better characterize this knowledge gap. METHODS: Seventy-two Yucatan minipigs underwent transection of the anterior cruciate ligament (ACL). Subjects were randomized to no further intervention, ligament reconstruction, or ligament repair, followed by microscopic synovium evaluation and RNA-sequencing at 1, 4, and 52 weeks. Six additional subjects received no ligament transection and served as 1- and 4-week controls and 12 contralateral knees served as 52-week controls. RESULTS: Synovial lining thickness, stromal cellularity, and overall microscopic synovitis reached their highest levels in the first few weeks following injury. Inflammatory infiltration continued to increase over the course of a year. Leaving the ACL transected, reconstructing the ligament, or repairing the ligament did not modulate synovitis development at 1, 4, or 52 weeks. Differential gene expression analysis of PTOA-affected synovium compared to control synovium revealed increased cell proliferation, angiogenesis, collagen breakdown, and diminished lipid metabolism at 1 and 4 weeks, and increased axonogenesis and focal adhesion with reduced immune activation at 52 weeks. CONCLUSIONS: Synovitis was present one year after ACL injury and was not alleviated by surgical intervention. Gene expression in early synovitis was characterized by cell proliferation, angiogenesis, proteolysis, and reduced lipolysis, which was followed by nerve growth and cellular adhesion with less immune activation at 52 weeks.

Incomplete Partition Type II Cochlear Malformations: Delineating the Three-Dimensional Structure from Digitized Human Histopathological Specimens.

HYPOTHESIS: There are clinically relevant differences in scalae anatomy and spiral ganglion neuron (SGN) quantity between incomplete partition type II (IP-II) and normal cochleae. BACKGROUND: IP-II is a commonly implanted cochlear malformation. Detailed knowledge of intracochlear three-dimensional (3D) morphology may assist with cochlear implant (CI) electrode selection/design and enable optimization of audiologic programming based on SGN maps. METHODS: IP-II (n = 11) human temporal bone histological specimens were identified from the National Institute on Deafness and Other Communication Disorders National Temporal Bone Registry and digitized. The cochlear duct, scalae, and surgically relevant anatomy were reconstructed in 3D. A machine learning algorithm was applied to map the location and number of SGNs. RESULTS: 3D scalae morphology of the basal turn was normal. Scala tympani (ST) remained isolated for 540 degrees before fusing with scala vestibuli. Mean ST volume reduced below 1 mm 2 after the first 340 degrees. Scala media was a distinct endolymphatic compartment throughout; mean ± standard deviation cochlear duct length was 28 ± 3 mm. SGNs were reduced compared with age-matched norms (mean, 48%; range, 5-90%). In some cases, SGNs failed to ascend Rosenthal's canal, remaining in an abnormal basalward modiolar location. Two forms of IP-II were seen: type A and type B. A majority (98-100%) of SGNs were located in the basal modiolus in type B IP-II, compared with 76 to 85% in type A. CONCLUSION: Hallmark features of IP-II cochleae include the following: 1) fusion of the ST and scala vestibuli at a mean of 540 degrees, 2) highly variable and overall reduced SGN quantity compared with normative controls, and 3) abnormal SGN distribution with cell bodies failing to ascend Rosenthal's canal.

Utility of Exome Sequencing for Diagnosis in Unexplained Pediatric-Onset Epilepsy.

Importance: Genomic advances inform our understanding of epilepsy and can be translated to patients as precision diagnoses that influence clinical treatment, prognosis, and counseling. Objective: To delineate the genetic landscape of pediatric epilepsy and clinical utility of genetic diagnoses for patients with epilepsy. Design, Setting, and Participants: This cohort study used phenotypic data from medical records and treating clinicians at a pediatric hospital to identify patients with unexplained pediatric-onset epilepsy. Exome sequencing was performed for 522 patients and available biological parents, and sequencing data were analyzed for single nucleotide variants (SNVs) and copy number variants (CNVs). Variant pathogenicity was assessed, patients were provided with their diagnostic results, and clinical utility was evaluated. Patients were enrolled from August 2018 to October 2021, and data were analyzed through December 2022. Exposures: Phenotypic features associated with diagnostic genetic results. Main Outcomes and Measures: Main outcomes included diagnostic yield and clinical utility. Diagnostic findings included variants curated as pathogenic, likely pathogenic (PLP), or diagnostic variants of uncertain significance (VUS) with clinical features consistent with the involved gene's associated phenotype. The proportion of the cohort with diagnostic findings, the genes involved, and their clinical utility, defined as impact on clinical treatment, prognosis, or surveillance, are reported. Results: A total of 522 children (269 [51.5%] male; mean [SD] age at seizure onset, 1.2 [1.4] years) were enrolled, including 142 children (27%) with developmental epileptic encephalopathy and 263 children (50.4%) with intellectual disability. Of these, 100 participants (19.2%) had identifiable genetic explanations for their seizures: 89 participants had SNVs (87 germline, 2 somatic mosaic) involving 69 genes, and 11 participants had CNVs. The likelihood of identifying a genetic diagnosis was highest in patients with intellectual disability (adjusted odds ratio [aOR], 2.44; 95% CI, 1.40-4.26), early onset seizures (aOR, 0.93; 95% CI, 0.88-0.98), and motor impairment (aOR, 2.19; 95% CI 1.34-3.58). Among 43 patients with apparently de novo variants, 2 were subsequently determined to have asymptomatic parents harboring mosaic variants. Of 71 patients who received diagnostic results and were followed clinically, 29 (41%) had documented clinical utility resulting from their genetic diagnoses. Conclusions and Relevance: These findings suggest that pediatric-onset epilepsy is genetically heterogeneous and that some patients with previously unexplained pediatric-onset epilepsy had genetic diagnoses with direct clinical implications.

Cochlear Ossification After Vestibular Schwannoma Surgery: A Temporal Bone Study.

OBJECTIVE: This study aims to investigate patterns of cochlear ossification (CO) in cadaveric temporal bones of patients who underwent vestibular schwannoma (VS) surgery via the translabyrinthine (TL), middle cranial fossa (MF), or retrosigmoid (RS) approaches. STUDY DESIGN: Histopathologic analysis of cadaveric temporal bones. SETTING: Multi-institutional national temporal bone repository. METHODS: The National Institute of Deafness and Communication Disorders and House Temporal Bone Laboratory at the University of California, Los Angeles and the Massachusetts Eye and Ear Otopathology Laboratory were searched for cadaveric temporal bones with a history of VS for which microsurgery was performed. Exclusion criteria included non-VS and perioperative death within 30 days of surgery. Temporal bones were analyzed histologically for CO of the basal, middle, and apical turns. RESULTS: Of 92 temporal bones with a history of schwannoma from both databases, 12 of these cases met the inclusion criteria. The approaches for tumor excision included 2 MF, 4 RS, and 6 TL approaches. CO was observed in all temporal bones that had undergone TL surgery. Among temporal bones that had undergone MF or RS surgeries, 5/6 had no CO, and 1/6 had partial ossification. This single case was noted to have intraoperative vestibular violation after RS surgery upon histopathologic and chart review. CONCLUSION: In this temporal bone series, all temporal bones that had undergone TL demonstrated varying degrees of CO on histological analysis. MF and RS cases did not exhibit CO except in the case of vestibular violation. When cochlear implantation is planned or possible after VS surgery, surgeons may consider using a surgical approach that does not violate the labyrinth.

Leveraging Social Networks for the Assessment and Management of Neurological Patients.

Social networks are the persons surrounding a patient who provide support, circulate information, and influence health behaviors. For patients seen by neurologists, social networks are one of the most proximate social determinants of health that are actually accessible to clinicians, compared with wider social forces such as structural inequalities. We can measure social networks and related phenomena of social connection using a growing set of scalable and quantitative tools increasing familiarity with social network effects and mechanisms. This scientific approach is built on decades of neurobiological and psychological research highlighting the impact of the social environment on physical and mental well-being, nervous system structure, and neuro-recovery. Here, we review the biology and psychology of social networks, assessment methods including novel social sensors, and the design of network interventions and social therapeutics.

Autism genes converge on asynchronous development of shared neuron classes.

Genetic risk for autism spectrum disorder (ASD) is associated with hundreds of genes spanning a wide range of biological functions1-6. The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals7,8. Here we used organoid models of the human cerebral cortex to identify cell-type-specific developmental abnormalities that result from haploinsufficiency in three ASD risk genes-SUV420H1 (also known as KMT5B), ARID1B and CHD8-in multiple cell lines from different donors, using single-cell RNA-sequencing (scRNA-seq) analysis of more than 745,000 cells and proteomic analysis of individual organoids, to identify phenotypic convergence. Each of the three mutations confers asynchronous development of two main cortical neuronal lineages-γ-aminobutyric-acid-releasing (GABAergic) neurons and deep-layer excitatory projection neurons-but acts through largely distinct molecular pathways. Although these phenotypes are consistent across cell lines, their expressivity is influenced by the individual genomic context, in a manner that is dependent on both the risk gene and the developmental defect. Calcium imaging in intact organoids shows that these early-stage developmental changes are followed by abnormal circuit activity. This research uncovers cell-type-specific neurodevelopmental abnormalities that are shared across ASD risk genes and are finely modulated by human genomic context, finding convergence in the neurobiological basis of how different risk genes contribute to ASD pathology.

Social Network Structure Is Related to Functional Improvement From Home-Based Telerehabilitation After Stroke.

Objective: Telerehabilitation (TR) is now, in the context of COVID-19, more clinically relevant than ever as a major source of outpatient care. The social network of a patient is a critical yet understudied factor in the success of TR that may influence both engagement in therapy programs and post-stroke outcomes. We designed a 12-week home-based TR program for stroke patients and evaluated which social factors might be related to motor gains and reduced depressive symptoms. Methods: Stroke patients (n = 13) with arm motor deficits underwent supervised home-based TR for 12 weeks with routine assessments of motor function and mood. At the 6-week midpoint, we mapped each patient's personal social network and evaluated relationships between social network metrics and functional improvements from TR. Finally, we compared social networks of TR patients with a historical cohort of 176 stroke patients who did not receive any TR to identify social network differences. Results: Both network size and network density were related to walk time improvement (p = 0.025; p = 0.003). Social network density was related to arm motor gains (p = 0.003). Social network size was related to reduced depressive symptoms (p = 0.015). TR patient networks were larger (p = 0.012) and less dense (p = 0.046) than historical stroke control networks. Conclusions: Social network structure is positively related to improvement in motor status and mood from TR. TR patients had larger and more open social networks than stroke patients who did not receive TR. Understanding how social networks intersect with TR outcomes is crucial to maximize effects of virtual rehabilitation.

Songbird Ventral Pallidum Sends Diverse Performance Error Signals to Dopaminergic Midbrain.

Motor skills improve with practice, requiring outcomes to be evaluated against ever-changing performance benchmarks, yet it remains unclear how performance error signals are computed. Here, we show that the songbird ventral pallidum (VP) is required for song learning and sends diverse song timing and performance error signals to the ventral tegmental area (VTA). Viral tracing revealed inputs to VP from auditory and vocal motor thalamus, auditory and vocal motor cortex, and VTA. Our findings show that VP circuits, commonly associated with hedonic functions, signal performance error during motor sequence learning.