Developmental spontaneous activity promotes formation of sensory domains, frequency tuning and proper gain in central auditory circuits.

Neurons that process sensory information exhibit bursts of electrical activity during development, providing early training to circuits that will later encode similar features of the external world. In the mammalian auditory system, this intrinsically generated activity emerges from the cochlea prior to hearing onset, but its role in maturation of auditory circuitry remains poorly understood. We show that selective suppression of cochlear supporting cell spontaneous activity disrupts patterned burst firing of central auditory neurons without affecting cell survival or acoustic thresholds.

Transcriptional and Immune Landscape of Cardiac Sarcoidosis.

Background: Cardiac involvement is an important determinant of mortality among sarcoidosis patients. Although granulomatous inflammation is a hallmark finding in cardiac sarcoidosis, the precise immune cell populations that comprise the granuloma remain unresolved. Furthermore, it is unclear how the cellular and transcriptomic landscape of cardiac sarcoidosis differs from other inflammatory heart diseases.

Health-Related Quality of Life in Adults With Classical Infratentorial Superficial Siderosis: A Cross-sectional Study.

Background And Objectives: Infratentorial superficial siderosis (iSS) is a rare but disabling neurologic condition characterized by progressive hearing loss and balance and mobility problems. The functional decline in these neurologic domains with iSS progression is likely to adversely affect health-related quality of life (HRQoL). We studied the HRQoL of adults with iSS using 2 common generic HRQoL measures (Health Utilities Index Mark III [HUI3] and EuroQoL EQ5D [5 Level]) to determine the most affected domains and evaluate the association between HRQoL scores and disease duration.

Optimization of Nuclear Localization Signal Composition Improves CRISPR-Cas12a Editing Rates in Human Primary Cells.

Type V CRISPR-Cas12a systems are an attractive Cas9-alternative nuclease platform for specific genome editing applications. However, previous studies demonstrate that there is a gap in overall activity between Cas12a and Cas9 in primary cells. Here we describe optimization to the NLS composition and architecture of Cas12a to facilitate highly efficient targeted mutagenesis in human transformed cell lines (HEK293T, Jurkat, and K562 cells) and primary cells (NK cells and CD34+ HSPCs), regardless of Cas12a ortholog.

Tibial tubercle osteotomy for patellofemoral malalignment and chondral disease provided good outcomes: A systematic review.

Importance: Tibial tubercle osteotomy (TTO) is indicated to treat patellofemoral (PF) malalignment and chondral disease refractory to conservative treatment. However, there are no systematic reviews describing TTO outcomes in chondral damages without instability.

Aim: The aims of this study were to (1) assess the quality of the published studies, (2) identify indication for TTO to treat PFP with chondral disease without instability, (3) evaluate the most common TTO techniques, (4) evaluate the clinical outcomes, and (5) evaluate TTO's complication and failure rates.

DSC Perfusion MRI-Derived Fractional Tumor Burden and Relative CBV Differentiate Tumor Progression and Radiation Necrosis in Brain Metastases Treated with Stereotactic Radiosurgery.

Background And Purpose: Differentiation between tumor and radiation necrosis in patients with brain metastases treated with stereotactic radiosurgery is challenging. We hypothesized that MR perfusion and metabolic metrics can differentiate radiation necrosis from progressive tumor in this setting.

Materials And Methods: We retrospectively evaluated MRIs comprising DSC, dynamic contrast-enhanced, and arterial spin-labeling perfusion imaging in subjects with brain metastases previously treated with stereotactic radiosurgery.

Editing outside the body: Ex vivo gene-modification for β-hemoglobinopathy cellular therapy.

Genome editing produces genetic modifications in somatic cells, offering novel curative possibilities for sickle cell disease and β-thalassemia. These opportunities leverage clinical knowledge of hematopoietic stem cell transplant and gene transfer. Advantages to this mode of ex vivo therapy include locus-specific alteration of patient hematopoietic stem cell genomes, lack of allogeneic immune response, and avoidance of insertional mutagenesis.

Dual metabotropic glutamate receptor signaling enables coordination of astrocyte and neuron activity in developing sensory domains.

Astrocytes play an essential role in the development of neural circuits by positioning transporters and receptors near synapses and secreting factors that promote synaptic maturation. However, the mechanisms that coordinate astrocyte and neural maturation remain poorly understood. Using in vivo imaging in unanesthetized neonatal mice, we show that bursts of neuronal activity passing through nascent sound processing networks reliably induce calcium transients in astrocytes.

Preclinical study of a novel therapeutic vaccine for recurrent respiratory papillomatosis.

Activation of antigen-specific T-lymphocyte responses may be needed to cure disorders caused by chronic infection with low-risk human papillomavirus (lrHPV). Safe and effective adjuvant therapies for such disorders are needed. The safety and efficacy of a novel gorilla adenovirus vaccine expressing a protein designed to elicit immune responses directed against HPV6 and HPV11, PRGN-2012, was studied using in vitro stimulation of T lymphocytes from patients with recurrent respiratory papillomatosis, in vivo vaccination studies, and therapeutic studies in mice bearing tumors expressing lrHPV antigen.

Streptococcus pneumoniae binds to host GAPDH on dying lung epithelial cells worsening secondary infection following influenza.

Streptococcus pneumoniae (Spn) alone and during co-infection with influenza A virus (IAV) can result in severe pneumonia with mortality. Pneumococcal surface protein A (PspA) is an established virulence factor required for Spn evasion of lactoferricin and C-reactive protein-activated complement-mediated killing. Herein, we show that PspA functions as an adhesin to dying host cells.

ZNF410 represses fetal globin by singular control of CHD4.

Known fetal hemoglobin (HbF) silencers have potential on-target liabilities for rational β-hemoglobinopathy therapeutic inhibition. Here, through transcription factor (TF) CRISPR screening, we identify zinc-finger protein (ZNF) 410 as an HbF repressor. ZNF410 does not bind directly to the genes encoding γ-globins, but rather its chromatin occupancy is concentrated solely at CHD4, encoding the NuRD nucleosome remodeler, which is itself required for HbF repression.

Traumatic Brain Injury and Incidence Risk of Sleep Disorders in Nearly 200,000 US Veterans.

Objective: To test the hypothesis that veterans with traumatic brain injury (TBI) have an increased subsequent risk of sleep disorders, we studied the longitudinal association between TBI and incident sleep disorders in nearly 200,000 veterans.

Methods: We performed a cohort study of all patients diagnosed with a TBI in the Veterans Health Administration system from October 1, 2001, to September 30, 2015, who were age-matched 1:1 to veterans without TBI. Veterans with prevalent sleep disorders at baseline were excluded.

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension.

Objective: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension.

Methods: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study.

Transforming vaccine development.

The urgency to develop vaccines against Covid-19 is putting pressure on the long and expensive development timelines that are normally required for development of lifesaving vaccines. There is a unique opportunity to take advantage of new technologies, the smart and flexible design of clinical trials, and evolving regulatory science to speed up vaccine development against Covid-19 and transform vaccine development altogether.

Real-world experience with direct brain-responsive neurostimulation for focal onset seizures.

Objective: The RNS System is a direct brain-responsive neurostimulation system that is US Food and Drug Administration-approved for adults with medically intractable focal onset seizures based on safety and effectiveness data from controlled clinical trials. The purpose of this study was to retrospectively evaluate the real-world safety and effectiveness of the RNS System.

Methods: Eight comprehensive epilepsy centers conducted a chart review of patients treated with the RNS System for at least 1 year, in accordance with the indication for use.

Therapeutic base editing of human hematopoietic stem cells.

Base editing by nucleotide deaminases linked to programmable DNA-binding proteins represents a promising approach to permanently remedy blood disorders, although its application in engrafting hematopoietic stem cells (HSCs) remains unexplored. In this study, we purified A3A (N57Q)-BE3 base editor for ribonucleoprotein (RNP) electroporation of human-peripheral-blood-mobilized CD34 hematopoietic stem and progenitor cells (HSPCs). We observed frequent on-target cytosine base edits at the BCL11A erythroid enhancer at +58 with few indels.

Long-Term Outcomes of Pectoralis Major Transfer for the Treatment of Irreparable Subscapularis Tears: Results After a Mean Follow-up of 20 Years.

Background: One recognized salvage option in the treatment of an irreparable subscapularis tear is the pectoralis major tendon transfer (PMT). We aimed to analyze the long-term clinical and imaging outcome of PMT for irreparable subscapularis deficiency.

Methods: Twenty-eight consecutive patients representing 30 shoulders underwent PMT at a mean age of 53.

Perfusion MRI-Based Fractional Tumor Burden Differentiates between Tumor and Treatment Effect in Recurrent Glioblastomas and Informs Clinical Decision-Making.

Background And Purpose: Fractional tumor burden better correlates with histologic tumor volume fraction in treated glioblastoma than other perfusion metrics such as relative CBV. We defined fractional tumor burden classes with low and high blood volume to distinguish tumor from treatment effect and to determine whether fractional tumor burden can inform treatment-related decision-making.

Materials And Methods: Forty-seven patients with high-grade gliomas (primarily glioblastoma) with recurrent contrast-enhancing lesions on DSC-MR imaging were retrospectively evaluated after surgical sampling.

Progressive supranuclear palsy is not associated with neurogenic orthostatic hypotension.

Objective: To evaluate the pattern and severity of autonomic dysfunction in autopsy-confirmed progressive supranuclear palsy (PSP) compared to α-synuclein pathology.

Methods: Autopsy-confirmed cases of 14 patients with PSP, 18 with multiple system atrophy (MSA), and 24 with Lewy body disease (LBD) with antemortem autonomic testing were reviewed retrospectively. All patients underwent comprehensive clinical evaluations by a movement disorder specialist, formal autonomic testing, and postmortem examinations at Mayo Clinic.

Optimizing organic electrosynthesis through controlled voltage dosing and artificial intelligence.

Organic electrosynthesis can transform the chemical industry by introducing electricity-driven processes that are more energy efficient and that can be easily integrated with renewable energy sources. However, their deployment is severely hindered by the difficulties of controlling selectivity and achieving a large energy conversion efficiency at high current density due to the low solubility of organic reactants in practical electrolytes. This control can be improved by carefully balancing the mass transport processes and electrocatalytic reaction rates at the electrode diffusion layer through pulsed electrochemical methods.

A normothermic ex vivo organ perfusion delivery method for cardiac transplantation gene therapy.

Clinically, both percutaneous and surgical approaches to deliver viral vectors to the heart either have resulted in therapeutically inadequate levels of transgene expression or have raised safety concerns associated with extra-cardiac delivery. Recent developments in the field of normothermic ex vivo cardiac perfusion storage have now created opportunities to overcome these limitations and safety concerns of cardiac gene therapy. This study examined the feasibility of ex vivo perfusion as an approach to deliver a viral vector to a donor heart during storage and the resulting bio distribution and expression levels of the transgene in the recipient post-transplant.

Copper-containing glass ceramic with high antimicrobial efficacy.

Hospital acquired infections (HAIs) and the emergence of antibiotic resistant strains are major threats to human health. Copper is well known for its high antimicrobial efficacy, including the ability to kill superbugs and the notorious ESKAPE group of pathogens. We sought a material that maintains the antimicrobial efficacy of copper while minimizing the downsides - cost, appearance and metallic properties - that limit application.

Highly efficient therapeutic gene editing of human hematopoietic stem cells.

Re-expression of the paralogous γ-globin genes (HBG1/2) could be a universal strategy to ameliorate the severe β-globin disorders sickle cell disease (SCD) and β-thalassemia by induction of fetal hemoglobin (HbF, αγ). Previously, we and others have shown that core sequences at the BCL11A erythroid enhancer are required for repression of HbF in adult-stage erythroid cells but are dispensable in non-erythroid cells. CRISPR-Cas9-mediated gene modification has demonstrated variable efficiency, specificity, and persistence in hematopoietic stem cells (HSCs).