Efficacy of dual intracerebroventricular and intravitreal gene therapy in sheep prompts the first clinical trial to treat CLN5 Batten disease.

Mutations in the gene cause the fatal, pediatric, neurodegenerative disease CLN5 neuronal ceroid lipofuscinosis. Affected children suffer progressive neuronal loss, visual failure and premature death. Presently there is no treatment.

Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease.

CLN5 neuronal ceroid lipofuscinosis (NCL, Batten disease) is a rare, inherited fatal neurodegenerative disorder caused by mutations in the gene. The disease is characterised by progressive neuronal loss, blindness, and premature death. There is no cure.

Intraparenchymal convection enhanced delivery of AAV in sheep to treat Mucopolysaccharidosis IIIC.

Background: Mucopolysaccharidosis IIIC (MPSIIIC) is one of four Sanfilippo diseases sharing clinical symptoms of severe cognitive decline and shortened lifespan. The missing enzyme, heparan sulfate acetyl-CoA: α-glucosaminide-N-acetyltransferase (HGSNAT), is bound to the lysosomal membrane, therefore cannot cross the blood-brain barrier or diffuse between cells. We previously demonstrated disease correction in MPSIIIC mice using an Adeno-Associated Vector (AAV) delivering HGSNAT via intraparenchymal brain injections using an AAV2 derived AAV-truetype (AAV-TT) serotype with improved distribution over AAV9.

The shiny new object: Deconstructing the patient-oriented paradigm in health sciences.

Rationale: A 'patient-oriented' research paradigm, also known as patient and public engagement, has infiltrated the field of health sciences and continues to spread. At first blush, it is difficult to reprove anything labelled 'patient-oriented'; however, the patient-oriented paradigm may easily become an ideological 'good', leading to unintended consequences that may well prove more detrimental than beneficial. While patient-oriented research has its roots in more radical forms of patient and public engagement, its recent instantiation betrays its roots and forecloses on more radical forms of engagement, such as critical participatory research.

Progressive MRI brain volume changes in ovine models of CLN5 and CLN6 neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinoses (Batten disease) are a group of inherited lysosomal storage disorders characterized by progressive neurodegeneration leading to motor and cognitive dysfunction, seizure activity and blindness. The disease can be caused by mutations in 1 of 13 ceroid lipofuscinosis neuronal (CLN) genes. Naturally occurring sheep models of the CLN5 and CLN6 neuronal ceroid lipofuscinoses recapitulate the clinical disease progression and post-mortem pathology of the human disease.

Intravitreal Injections in the Ovine Eye.

There are several methods for the delivery of therapeutic agents to the retina, including intravitreal (IVT), subretinal, suprachoroidal, periocular, or topical administration. IVT drug delivery involves an injection into the vitreous humor of the eye, a gelatinous substance that fills the posterior chamber of the eye and maintains the shape of the eye globe. Although the IVT route is less specifically targeted than subretinal delivery, it is much less invasive and is widely used in clinical settings for a range of ocular diseases.

Aggregation chimeras provide evidence of in vivo intercellular correction in ovine CLN6 neuronal ceroid lipofuscinosis (Batten disease).

The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are fatal, mainly childhood, inherited neurodegenerative lysosomal storage diseases. Sheep affected with a CLN6 form display progressive regionally defined glial activation and subsequent neurodegeneration, indicating that neuroinflammation may be causative of pathogenesis. In this study, aggregation chimeras were generated from homozygous unaffected normal and CLN6 affected sheep embryos, resulting in seven chimeric animals with varied proportions of normal to affected cells.

Natural history of retinal degeneration in ovine models of CLN5 and CLN6 neuronal ceroid lipofuscinoses.

Neuronal ceroid lipofuscinoses (NCL; Batten disease) are a group of inherited neurodegenerative diseases with a common set of symptoms including cognitive and motor decline and vision loss. Naturally occurring sheep models of CLN5 and CLN6 disease display the key clinical features of NCL, including a progressive loss of vision. We assessed retinal histology, astrogliosis, and lysosomal storage accumulation in CLN5 affected (CLN5) and CLN6 affected (CLN6) sheep eyes and age-matched controls at 3, 6, 12, and 18 months of age to determine the onset and progression of retinal pathology in NCL sheep.

The Translational Benefits of Sheep as Large Animal Models of Human Neurological Disorders.

The past two decades have seen a considerable rise in the use of sheep to model human neurological disorders. While each animal model has its merits, sheep have many advantages over small animal models when it comes to studies on the brain. In particular, sheep have brains more comparable in size and structure to the human brain.

Phase II Study of Neoadjuvant Nivolumab in Patients with Locally Advanced Clear Cell Renal Cell Carcinoma Undergoing Nephrectomy.

Immune checkpoint inhibitor therapy improves survival in patients with metastatic renal cell carcinoma (RCC) but has not been studied well preoperatively in patients with localized disease undergoing nephrectomy. We conducted a single-center study to evaluate the safety and feasibility of neoadjuvant nivolumab in patients undergoing nephrectomy for localized RCC. Eligible patients had a >20% risk of recurrence, as estimated by a preoperative nomogram.

Nursing Leadership During COVID-19: Leading an Inpatient Response at a Regional Military Medical Center.

The coronavirus disease 2019 pandemic stressed healthcare systems worldwide and exposed major flaws in military and civilian healthcare systems. Landstuhl Regional Medical Center (LRMC) serves as the only military medical center for over 205,000 U.S.

Remodeling of the maternal gut microbiome during pregnancy is shaped by parity.

Background: The maternal microbiome has emerged as an important factor in gestational health and outcome and is associated with risk of preterm birth and offspring morbidity. Epidemiological evidence also points to successive pregnancies-referred to as maternal parity-as a risk factor for preterm birth, infant mortality, and impaired neonatal growth. Despite the fact that both the maternal microbiome and parity are linked to maternal-infant health, the impact of parity on the microbiome remains largely unexplored, in part due to the challenges of studying parity in humans.

Intravitreal gene therapy protects against retinal dysfunction and degeneration in sheep with CLN5 Batten disease.

Neuronal ceroid lipofuscinoses (NCL; Batten disease) are a group of inherited neurodegenerative diseases primarily affecting children. A common feature across most NCLs is the progressive loss of vision. We performed intravitreal injections of self-complementary AAV9 vectors packaged with either ovine CLN5 or CLN6 into one eye of 3-month-old CLN5 or CLN6 animals, respectively.

"It gets people through the door": a qualitative case study of the use of incentives in the care of people at risk or living with HIV in British Columbia, Canada.

Background: There has been growing interest in the use of incentives to increase the uptake of health-related behaviours and achieve desired health outcomes at the individual and population level. However, the use of incentives remains controversial for ethical reasons. An area in which incentives have been not only proposed but used is HIV prevention, testing, treatment and care-each one representing an interconnecting step in the "HIV Cascade.

'This Is Not a Patient, This Is Property of the State': Nursing, ethics, and the immigrant detention apparatus.

This paper opens with first-hand accounts of critical care medical interventions in which detainees, in the custody of U.S. Immigration and Customs Enforcement (ICE), are brought to the emergency department for treatment.

The Phenomenon of Community Reintegration for Veterans with Burn Injury: Supportive Communities and Future-Oriented Thinking.

Combat missions in the Middle East have resulted in approximately 52,000 U.S. veterans who have been wounded in action, with 10% of whom suffered burn injuries.

A Low-Power, Single-Chip Electronic Skin Interface for Prosthetic Applications.

A low-power, single-chip electronic skin interface is presented. The system on chip (SoC) implementation significantly reduces the physical footprint and power requirements compared to commercial interfaces, which enables the creation nimble prosthetic limbs. Its small size and reduced battery requirements are ideal for advanced prosthetics that utilize electronic skin to provide their user tactile feedback.

The Role of Binocularity in Anisometropic Amblyopia.

Anisometropic amblyopia is unilateral by definition and current treatment recommendations reflect that characteristic. However, recent research suggests a binocular component that deserves consideration. The aim of this review is to consider the levels of anisometropia deemed amblyogenic, and the cortical changes that occur in the presence of anisometropic amblyopia.

Improving Clinician Decisions and Communication in Critical Care Using Novel Information Technology.

Introduction: The electronic medical record (EMR) is presumed to support clinician decisions by documenting and retrieving patient information. Research shows that the EMR variably affects patient care and clinical decision making. The way information is presented likely has a significant impact on this variability.

Chemical neuroanatomy of the substantia nigra in the ovine brain.

The substantia nigra is an integral component of the basal ganglia circuitry for limbic and motor functions. Dysfunction and degeneration of the basal ganglia are fundamental aspects of neurodegenerative diseases such as Parkinson's disease and Huntington's disease. With the increasing use of sheep to model neurological diseases, it is crucial to understand the anatomy and neurochemistry of these key basal ganglia nuclei in the normal sheep brain and how they compare to the human brain.

Understanding human enhancement technologies through critical phenomenology.

Human enhancement technologies raise serious ethical questions about health practices no longer content simply to treat disease, but which now also propose to "optimize" human beings' physical, cognitive and psychological abilities. These technologies call for a reassessment of our relationship to health, the human body and the body's organic, identity and social functions. In nursing, such considerations are in their infancy.

Governing in Community-Based Research: Lessons from Canada's HIV Research Sector on Ethics, Publics and the Care of the Self.

In this paper, we extend Michel Foucault's final works on the 'care of the self' to an empirical examination of research practice in community-based research (CBR). We use Foucault's 'morality of behaviors' to analyze interview data from a national sample of Canadian CBR practitioners working with communities affected by HIV. Despite claims in the literature that ethics review is overly burdensome for non-traditional forms of research, our findings suggest that many researchers using CBR have an ambivalent but ultimately productive relationship with institutional research ethics review requirements.

The role of IL-6 in neurodevelopment after prenatal stress.

Prenatal stress exposure is associated with adverse psychiatric outcomes, including autism and ADHD, as well as locomotor and social inhibition and anxiety-like behaviors in animal offspring. Similarly, maternal immune activation also contributes to psychiatric risk and aberrant offspring behavior. The mechanisms underlying these outcomes are not clear.