Reductions in remnant cholesterol and VLDL cholesterol through inhibition of ANGPTL3 protein synthesis: an analysis from the TRANSLATE-TIMI 70 trial.

Aims: Remnant cholesterol and very low-density lipoprotein cholesterol (VLDL-C) are increasingly recognized risk factors for atherosclerotic disease with few therapeutic options. Angiopoietin-like 3 (ANGPTL3), a key protein in the metabolism of triglyceride-rich lipoproteins, is a promising target.

Methods And Results: TRANSLATE-TIMI 70 was a double-blind, placebo-controlled randomized trial testing seven dose regimens of vupanorsen, an antisense oligonucleotide against ANGPTL3, in adults with non-HDL-C ≥ 100 mg/dL and triglycerides 150-500 mg/dL.

Hepatic fat changes with antisense oligonucleotide therapy targeting ANGPTL3.

Background: Angiopoietin-like protein 3 (ANGPTL3) is a novel therapeutic target for hyperlipidemia. Vupanorsen, an antisense oligonucleotide targeting ANGPTL3, reduced triglycerides up to 57% in a phase 2b trial, but caused dose-dependent increases in hepatic fat fraction (HFF).

Objective: To determine the degree of HFF progression with escalating doses of vupanorsen, differential HFF increases in key patient subgroups, and the correlation between changes in HFF and liver enzymes.

A multi-purpose Japanese phase I study in the global development of vupanorsen: Randomized, placebo-controlled, single-ascending dose study in adults.

Vupanorsen (PF-07285557) is a second-generation tri-N-acetyl galactosamine (GalNAc )-antisense oligonucleotide targeted to angiopoietin-like 3 (ANGPTL3) mRNA, shown to reduce lipids and apolipoproteins in subjects with dyslipidemia. To aid bringing innovative drugs to global patients efficiently, a multi-purpose Japanese phase I study was conducted, with integrated development approaches agreed by the Pharmaceuticals and Medical Devices Agency (PMDA). This randomized, double-blind, placebo-controlled, single-ascending dose (SAD) study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of vupanorsen administered subcutaneously to Japanese adults (20-65 years) with elevated triglycerides (TG).

Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70.

Background: Genetic loss-of-function variants in are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis.

Methods: Adults with non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks).

The Impact of Reducing the Number of Wearable Devices on Measuring Gait in Parkinson Disease: Noninterventional Exploratory Study.

Background: Measuring free-living gait using wearable devices may offer higher granularity and temporal resolution than the current clinical assessments for patients with Parkinson disease (PD). However, increasing the number of devices worn on the body adds to the patient burden and impacts the compliance.

Objective: This study aimed to investigate the impact of reducing the number of wearable devices on the ability to assess gait impairments in patients with PD.

Age and environment-related differences in gait in healthy adults using wearables.

Technological advances in multimodal wearable and connected devices have enabled the measurement of human movement and physiology in naturalistic settings. The ability to collect continuous activity monitoring data with digital devices in real-world environments has opened unprecedented opportunity to establish clinical digital phenotypes across diseases. Many traditional assessments of physical function utilized in clinical trials are limited because they are episodic, therefore, cannot capture the day-to-day temporal fluctuations and longitudinal changes in activity that individuals experience.

Using an unbiased symbolic movement representation to characterize Parkinson's disease states.

Unconstrained human movement can be broken down into a series of stereotyped motifs or 'syllables' in an unsupervised fashion. Sequences of these syllables can be represented by symbols and characterized by a statistical grammar which varies with external situational context and internal neurological state. By first constructing a Markov chain from the transitions between these syllables then calculating the stationary distribution of this chain, we estimate the overall severity of Parkinson's symptoms by capturing the increasingly disorganized transitions between syllables as motor impairment increases.

Hyperbaric oxygen for late sequelae of carbon monoxide poisoning enhances neurological recovery: case report.

Neuropsychiatric sequelae have been reported in 15%-45% of survivors of carbon monoxide (CO) poisoning. Hyperbaric oxygen (HBO₂) therapy reduces the incidence of cognitive and neurological a dysfunction. The efficacy of providing HBO₂ beyond the first one to two days after initial insult is unknown.

FDA Regulation of Neurological and Physical Medicine Devices: Access to Safe and Effective Neurotechnologies for All Americans.

The United States Food and Drug Administration (FDA) ensures that patients in the U.S. have access to safe and effective medical devices.

Temporal discrimination threshold with healthy aging.

The temporal discrimination threshold (TDT) is the shortest interstimulus interval at which a subject can perceive successive stimuli as separate. To investigate the effects of aging on TDT, we studied tactile TDT using the method of limits with 120% of sensory threshold in each hand for each of 100 healthy volunteers, equally divided among men and women, across 10 age groups, from 18 to 79 years. Linear regression analysis showed that age was significantly related to left-hand mean, right-hand mean, and mean of 2 hands with R-square equal to 0.

Inducing LTD-Like Effect in the Human Motor Cortex with Low Frequency and Very Short Duration Paired Associative Stimulation: An Exploratory Study.

Introduction. Paired associative stimulation (PAS) is an established technique to investigate synaptic plasticity in the human motor cortex (M1). Classically, to induce long-term depression- (LTD-) or long-term potentiation-like effects in the human M1, studies have used low frequency and long duration trains of PAS.

Intraoperative neurophysiology in deep brain surgery for psychogenic dystonia.

Psychogenic dystonia is a challenging entity to diagnose and treat because little is known about its pathophysiology. We describe two cases of psychogenic dystonia who underwent deep brain stimulation when thought to have organic dystonia. The intraoperative microelectrode recordings in globus pallidus internus were retrospectively compared with those of five patients with known DYT1 dystonia using spontaneous discharge parameters of rate and bursting, as well as movement-related discharges.

Clinical Response to IncobotulinumtoxinA, after Demonstrated Loss of Clinical Response to OnabotulinumtoxinA and RimabotulininumtoxinB in a Patient with Musician's Dystonia.

Botulinum toxin is a mainstay therapy for dystonia. Formulations available are three types of botulinumtoxinA and one type of botulinumtoxinB. Antibodies can develop against the toxin, leading to treatment failure.

Tricks in dystonia: ordering the complexity.

Sensory tricks are various manoeuvres that can ameliorate dystonia. Common characteristics are well known, but their variety is wide, sensory stimulation is not necessarily the critical feature, and their physiology is unknown. To enumerate the various forms of sensory tricks and describe their nature, research findings and theories that may elucidate their neurophysiologic mechanism, we reviewed the literature pertaining to sensory tricks, including variants like motor tricks, imaginary tricks, forcible tricks and reverse sensory tricks.

Progressive personality and language changes in a 62-year-old woman.

A 62-year-old woman with no known psychiatric illness had a 1.5-year history of progressive personality and language changes, leading to a loss of functional independence. Laboratory results revealed elevated autoimmune antibodies.

A case of fascioscapulohumeral muscular dystrophy misdiagnosed as Becker's muscular dystrophy for 20 years.

A 60-year-old man diagnosed clinically with Becker's muscular dystrophy 20 years ago by another physician presented with gradually progressive proximal muscle weakness since teenage years. Family history revealed a strong paternal familial inheritance pattern of similar distribution of weakness-face, forearm flexion, knee extension and foot dorsiflexion. Work-ups revealed B12 deficiency and allele 1 deletion in fascioscapulohumeral muscular dystrophy (FSHD) DNA testing.