GOLGA8 increases bulk antisense oligonucleotide uptake and activity in mammalian cells.

Antisense oligonucleotides (ASOs) are short synthetic nucleic acids that recognize and bind to complementary RNA to modulate gene expression. It is well established that single-stranded, phosphorothioate-modified ASOs enter cells independent of carrier molecules, primarily via endocytic pathways, but that only a small portion of internalized ASO is released into the cytosol and/or nucleus, rendering the majority of ASO inaccessible to the targeted RNA. Identifying pathways that can increase the available ASO pool is valuable as a research tool and therapeutically.

Ingestion of Illicit Substances by Young Children Before and During the COVID-19 Pandemic.

Importance: Information about the trend in illicit substance ingestions among young children during the pandemic is limited.

Objectives: To assess immediate and sustained changes in overall illicit substance ingestion rates among children younger than 6 years before and during the COVID-19 pandemic and to examine changes by substance type (amphetamines, benzodiazepines, cannabis, cocaine, ethanol, and opioids) while controlling for differing statewide medicinal and recreational cannabis legalization policies.

Design, Setting, And Participants: Retrospective cross-sectional study using an interrupted time series at 46 tertiary care children's hospitals within the Pediatric Health Information System (PHIS).

Art Unfolds Words: Expressing Hope Through Creative Art Among Adolescents and Young Adults Who Have Advanced Cancer.

Hope's role in the care of adolescents and young adults (AYAs) who have advanced cancer (AC) is not well understood. This study aimed to conceptualize the essence of hope among AYAs who have AC based on their lived experiences and illustrate hope through verbal and artistic depictions of the AYA's lived experiences. Fifteen AYAs, aged 12 to 21 years, diagnosed with AC completed two semistructured interviews to share their lived experiences of hope perspectives in the form of a descriptive narrative and a creative-art outcome.

Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling.

While skin is a site of active immune surveillance, primary melanomas often escape detection. Here, we have developed an in silico model to determine the local cross-talk between melanomas and Langerhans cells (LCs), the primary antigen-presenting cells at the site of melanoma development. The model predicts that melanomas fail to activate LC migration to lymph nodes until tumors reach a critical size, which is determined by a positive TNF-α feedback loop within melanomas, in line with our observations of murine tumors.

Increasing FDA-accelerated approval of single-arm trials in oncology (1992 to 2020).

Objectives: We aimed to map the characteristics of single-arm trials (SAT), report the Food and Drug Administration (FDA) transparency in presenting historical control, and to assess the confirmatory randomized controlled trials (RCTs).

Study Design And Setting: This metaresearch included a review of all oncology indication approved using SAT by FDA-AA (FDA-Accelerated Approval) from 1992 to 2020. Two independent reviewers identified SAT, extracted data from FDA full medical reviews for historical controls reported and MEDLINE for searching for confirmatory RCT published.

Cardiogenic Shock Classification and Associated Mortality Risk.

The Society for Cardiovascular Angiography and Interventions (SCAI) Shock Classification was developed to create standardized language describing the severity of cardiogenic shock (CS). The purposes of this review were to evaluate short-term and long-term mortality rates at each SCAI shock stage for patients with or at risk for CS, which has not been studied previously, and to propose using the SCAI Shock Classification to develop algorithms for clinical status monitoring. A detailed literature search was conducted for articles published from 2019 through 2022 in which the SCAI shock stages were used to assess the mortality risk.

Activation of inflammasomes and their effects on neuroinflammation at the microelectrode-tissue interface in intracortical implants.

Invasive neuroprosthetics rely on microelectrodes (MEs) to record or stimulate the activity of large neuron assemblies. However, MEs are subjected to tissue reactivity in the central nervous system (CNS) due to the foreign body response (FBR) that contribute to chronic neuroinflammation and ultimately result in ME failure. An endogenous, acute set of mechanisms responsible for the recognition and targeting of foreign objects, called the innate immune response, immediately follows the ME implant-induced trauma.

A survey of neurophysiological differentiation across mouse visual brain areas and timescales.

Neurophysiological differentiation (ND), a measure of the number of distinct activity states that a neural population visits over a time interval, has been used as a correlate of meaningfulness or subjective perception of visual stimuli. ND has largely been studied in non-invasive human whole-brain recordings where spatial resolution is limited. However, it is likely that perception is supported by discrete neuronal populations rather than the whole brain.

COVID-19 (Omicron strain) hospital admissions from a virtual ward - who required further care?

Background: The COVID-19 virtual ward was created to provide care for people at home with COVID-19. Given this was a new model of care, little was known about the clinical characteristics and outcomes of patients requiring admission to hospital from the virtual ward platform. The aims were to characterise hospital admission volume, patient epidemiology, clinical characteristics, and outcome from a virtual ward in the setting of an Omicron (BA.

Adeno-Associated Virus 2 and Human Adenovirus F41 in Wastewater during Outbreak of Severe Acute Hepatitis in Children, Ireland.

During April-July 2022, outbreaks of severe acute hepatitis of unknown etiology (SAHUE) were reported in 35 countries. Five percent of cases required liver transplantation, and 22 patients died. Viral metagenomic studies of clinical samples from SAHUE cases showed a correlation with human adenovirus F type 41 (HAdV-F41) and adeno-associated virus type 2 (AAV2).

Tetracycline-dependent inhibition of mitoribosome protein elongation in mitochondrial disease mutant cells suppresses IRE1α to promote cell survival.

Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations are redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. Depending on the type of mitochondrial mutation, certain mechanisms can efficiently rescue cell death vulnerability.

Chronic BMAA exposure combined with TDP-43 mutation elicits motor neuron dysfunction phenotypes in mice.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an average age-of-onset of ∼60 years and is usually fatal within 2-5 years of diagnosis. Mouse models based upon single gene mutations do not recapitulate all ALS pathological features. Environmental insults may also contribute to ALS, and β-N-methylamino-L-alanine (BMAA) is an environmental toxin linked with an increased risk of developing ALS.

Mechanism of cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies.

Loss of nuclear TDP-43 is a hallmark of neurodegeneration in TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 mislocalization results in cryptic splicing and polyadenylation of pre-messenger RNAs (pre-mRNAs) encoding stathmin-2 (also known as SCG10), a protein that is required for axonal regeneration. We found that TDP-43 binding to a GU-rich region sterically blocked recognition of the cryptic 3' splice site in pre-mRNA.

Accelerated approval drug labels often lack information for clinical decision-making.

Study Objective: We evaluated US Food and Drug Administration labels for drugs approved under the accelerated approval pathway and whether these labels contained in sufficient information regarding their accelerated approval.

Design: Retrospective, observational, cohort study.

Data Source: Label information for drugs with an accelerated approved indication were ascertained from two online platforms: Drugs@FDA and FDA Drug Label Repository.

Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance.

Mineral elements and their relation to anthocyanin content in pigmented rice plants using definitive screening design and self-organizing maps.

Background: Mineral elements are nutrients required by an organism to perform functions necessary for survival. Stress-induced metabolism following nutritional stress has been reported to increase levels of anthocyanin. However, the role of mineral elements commonly found in soil and their contribution to the accumulation of anthocyanin content in rice plants is uncertain.

Long-Term - and -ASO Combinatorial Therapy in SMA Mice and -ASO Treatment in hiPSC-Derived Motor Neurons Show Protective Effects.

For SMA patients with only two copies, available therapies might be insufficient to counteract lifelong motor neuron (MN) dysfunction. Therefore, additional SMN-independent compounds, supporting SMN-dependent therapies, might be beneficial. Neurocalcin delta (NCALD) reduction, an SMA protective genetic modifier, ameliorates SMA across species.

Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial.

Background: Myotonic dystrophy type 1 results from an RNA gain-of-function mutation, in which DM1 protein kinase (DMPK) transcripts carrying expanded trinucleotide repeats exert deleterious effects. Antisense oligonucleotides (ASOs) provide a promising approach to treatment of myotonic dystrophy type 1 because they reduce toxic RNA levels. We aimed to investigate the safety of baliforsen (ISIS 598769), an ASO targeting DMPK mRNA.

A Novel Approach to Clustering Accelerometer Data for Application in Passive Predictions of Changes in Depression Severity.

The treatment of mood disorders, which can become a lifelong process, varies widely in efficacy between individuals. Most options to monitor mood rely on subjective self-reports and clinical visits, which can be burdensome and may not portray an accurate representation of what the individual is experiencing. A passive method to monitor mood could be a useful tool for those with these disorders.