Quantifying years of life lost in Australia: a multiple cause of death analysis.

Background: Deaths in Australia and other high-income countries increasingly involve multiple conditions. However, key burden of disease measures typically only use the underlying cause of death (UC). We quantified sex and cause-specific years of life lost (YLL) based on UC compared with a method integrating multiple causes of death.

Assessing Experiences With Trofinetide for Rett Syndrome: Interviews With Caregivers of Participants in Clinical Trials.

Purpose: Rett syndrome (RTT) is a rare neurodevelopmental disorder that mainly affects girls and women. Trofinetide is approved for the treatment of RTT in adults and children aged ≥2 years. To gain insight into experiences with RTT and effects of trofinetide treatment at different stages of RTT, interviews with caregivers of individuals with RTT were conducted upon their exit from the open-label trofinetide trials.

Population Pharmacokinetics of Trofinetide in a Pediatric Population Aged 2-4 Years with Rett Syndrome.

Introduction: Weight-banded trofinetide dosing improved physician- and caregiver-rated efficacy measures and had acceptable tolerability in patients aged 2‒4 years (DAFFODIL study) and 5‒20 years (LAVENDER study) with Rett syndrome (RTT). Selection of weight-banded dosing regimens for these studies was based on population pharmacokinetic (popPK) modeling and exposure simulations. This study applied an updated popPK model to confirm steady-state trofinetide exposures achieved in DAFFODIL patients were within target range.

Population Pharmacokinetic Modeling to Support Trofinetide Dosing for the Treatment of Rett Syndrome.

Introduction: Oral trofinetide administered using a body weight-banded dosing regimen was approved in the US for the treatment of Rett syndrome (RTT) in patients aged ≥ 2 years. This approval was principally based on efficacy and safety findings of the phase 3 LAVENDER study in girls and women aged 5-20 years with RTT and extended to younger children aged 2-4 years with supporting data from the DAFFODIL study. Weight-banded dosing regimens were selected based on early clinical population pharmacokinetic (popPK) modeling and different scenario simulations.

Perspectives on using peat records to reconstruct past atmospheric Hg levels.

Anthropogenic mercury (Hg) emissions to the atmosphere have increased the concentration of this potent neurotoxin in terrestrial and aquatic ecosystems. The magnitude of regional variation in atmospheric Hg pollution levels raises questions about the interactions between natural processes and human activities at local and regional scales that are shaping global atmospheric Hg cycling. Peatlands are potentially valuable and widespread records of past atmospheric Hg levels that could help address these questions.

Charting new territory: the early lessons in integrating social determinant of health (SDOH) measures into practice.

Quality measures for social determinants of health (SDOH) have been introduced or proposed in more than 20 federal programs, initiatives, or guidance documents to capture performance, but understanding the scope of work needed to effectively collect and align with these new measurement requirements is still in its early stages. The National Committee for Quality Assurance (NCQA) recently developed the Social Need Screening and Intervention (SNS-E) measure and is currently building 2 new domains of interest: utility insecurity and social connection. Before these domains can be leveraged to drive population health, the feasibility of collecting and reporting on them must be assessed.

Physiologically-Based Pharmacokinetic Modeling of Trofinetide in Moderate Renal Impairment for Phase 1 Clinical Study Dose Selection with Model Validation.

Background And Objectives: Trofinetide, the first approved treatment for Rett syndrome (RTT), is primarily excreted unchanged in the urine; therefore, it is important to assess the extent to which the exposure is affected in patients with renal impairment. Pharmacokinetic modeling overcomes the challenge of dose finding in phase 1 studies that include special populations where there is the potential for increased exposure to study drug. The objectives of this phase 1 study were to evaluate trofinetide pharmacokinetics, safety, and tolerability in a population with moderate renal impairment and normal renal function.

Exploration of the barriers and facilitators influencing use of telehealth for orthotic/prosthetic services in the United States of America: An orthotist/prosthetists perspective.

Innovative models of healthcare, such as telehealth, are required to meet the growing demand for orthotic/prosthetic (O&P) services. While O&P users report being very satisfied with telehealth, many clinical facilities have reverted to in-person modes of care as COVID-19 restrictions have eased. As such, there is a disconnect between benefits of telehealth to O&P users, and the clinical services being delivered in-person.

Tree Rings Mercury Controlled by Atmospheric Gaseous Elemental Mercury and Tree Physiology.

Tree rings are an emerging atmospheric mercury (Hg) archive. Questions have arisen, though, regarding their mechanistic controls and reliability. Here, we report contrasting tree-ring Hg records in three collocated conifer species: Norway spruce (), Scots pine (), and European larch (), which are from a remote boreal forest.

Real-time performance improvement optimizes damage control resuscitation best practice adherence: Results of a pilot prospective observational study.

Background: Maintaining balanced blood product ratios during damage control resuscitation (DCR) is independently associated with improved survival. We hypothesized that real-time performance improvement (RT-PI) would increase adherence to DCR best practice.

Study Design And Methods: From December 2020-August 2021, we prospectively used a bedside RT-PI tool to guide DCR in severely injured patients surviving at least 30 min.

Analyzing Sequential Betting with a Kelly-Inspired Convective-Diffusion Equation.

The purpose of this article is to analyze a sequence of independent bets by modeling it with a convective-diffusion equation (CDE). The approach follows the derivation of the Kelly Criterion (i.e.

Axially swept open-top light-sheet microscopy for densely labeled clinical specimens.

Open-top light-sheet (OTLS) microscopy offers rapid 3D imaging of large optically cleared specimens. This enables nondestructive 3D pathology, which provides key advantages over conventional slide-based histology including comprehensive sampling without tissue sectioning/destruction and visualization of diagnostically important 3D structures. With 3D pathology, clinical specimens are often labeled with small-molecule stains that broadly target nucleic acids and proteins, mimicking conventional hematoxylin and eosin (H&E) dyes.

HIV-1 Capsid Rapidly Induces Long-Lived CPSF6 Puncta in Non-Dividing Cells, but Similar Puncta Already Exist in Uninfected T-Cells.

The HIV-1 capsid (CA) protein forms the outer shell of the viral core that is released into the cytoplasm upon infection. CA binds various cellular proteins, including CPSF6, that direct HIV-1 integration into speckle-associated domains in host chromatin. Upon HIV-1 infection, CPSF6 forms puncta in the nucleus.

Classical BSE dismissed as the cause of CWD in Norwegian red deer despite strain similarities between both prion agents.

The first case of CWD in a Norwegian red deer was detected by a routine ELISA test and confirmed by western blotting and immunohistochemistry in the brain stem of the animal. Two different western blotting tests were conducted independently in two different laboratories, showing that the red deer glycoprofile was different from the Norwegian CWD reindeer and CWD moose and from North American CWD. The isolate showed nevertheless features similar to the classical BSE (BSE-C) strain.

Global mercury concentrations in biota: their use as a basis for a global biomonitoring framework.

An important provision of the Minamata Convention on Mercury is to monitor and evaluate the effectiveness of the adopted measures and its implementation. Here, we describe for the first time currently available biotic mercury (Hg) data on a global scale to improve the understanding of global efforts to reduce the impact of Hg pollution on people and the environment. Data from the peer-reviewed literature were compiled in the Global Biotic Mercury Synthesis (GBMS) database (>550,000 data points).

A preoperative use of manual therapy in a patient with idiopathic pulmonary fibrosis awaiting lung transplant: a case report.

Introduction: This case report describes the outcomes of a patient with idiopathic pulmonary fibrosis (IPF) treated with manual therapy (MT) in an outpatient physical therapy setting. IPF is a life-threatening interstitial lung disease, often requiring lung transplant for prolonged health related quality of life and survival. There is little literature to support use of MT for IPF.

Direct three-dimensional segmentation of prostate glands with nnU-Net.

Significance: In recent years, we and others have developed non-destructive methods to obtain three-dimensional (3D) pathology datasets of clinical biopsies and surgical specimens. For prostate cancer risk stratification (prognostication), standard-of-care Gleason grading is based on examining the morphology of prostate glands in thin 2D sections. This motivates us to perform 3D segmentation of prostate glands in our 3D pathology datasets for the purposes of computational analysis of 3D glandular features that could offer improved prognostic performance.