A retrospective review of sildenafil in the Australia and New Zealand Fontan registry: indications and treatment responses.

Introduction: Rates of morbidity and mortality are high in the setting of Fontan physiology and effective medical therapies are not well-established. Clinical trials assessing phosophodiesterase-5-inhibitors, such as sildenafil, have not demonstrated major benefit in patients with a Fontan-type circulation but have only included stable, well-functioning people.

Methods: We sought to retrospectively characterize the people followed by the ANZ Fontan Registry prescribed sildenafil >30 days post Fontan-surgery.

Association that Neuroimaging and Clinical Measures Have with Change in Arm Impairment in a Phase 3 Stroke Recovery Trial.

Objective: Vagus nerve stimulation (VNS) paired with rehabilitation therapy improved motor status compared to rehabilitation alone in the phase III VNS-REHAB stroke trial, but treatment response was variable and not associated with any clinical measures acquired at baseline, such as age or side of paresis. We hypothesized that neuroimaging measures would be associated with treatment-related gains, examining performance of regional injury measures versus global brain health measures in parallel with clinical measures.

Methods: Baseline magnetic resonance imaging (MRI) scans in the VNS-REHAB trial were used to derive regional injury measures (extent of injury to corticospinal tract, the primary regional measure; plus extent of injury to precentral gyrus and postcentral gyrus; lesion volume; and lesion topography) and global brain health measures (degree of white matter hyperintensities, the primary global brain measure; plus volumes of cerebrospinal fluid, cortical gray matter, white matter, each thalamus, and total brain).

Multidisciplinary Delphi Panel on Rehabilitation Approaches and Unmet Needs for Chronic Stroke Walking Impairment and the Role of Rhythmic Auditory Stimulation.

Introduction: Walking or gait impairment is a common consequence of stroke that persists into the chronic phase of recovery for many stroke survivors. The goals of this work were to obtain consensus from a multidisciplinary panel on current practice patterns and treatment options for walking impairment after stroke, to better understand the unmet needs for rehabilitation in the chronic phase of recovery and to explore opportunities to address them, and to discuss the potential role of rhythmic auditory stimulation (RAS) in gait rehabilitation.

Methods: A panel of eight experts specializing in neurology, physical therapy, and physiatry participated in this three-part, modified Delphi study.

Multimodal therapy and use of adjunctive therapies to BoNT-A in spasticity management: defining terminology to help enhance spasticity treatment.

Spasticity management should be provided within the context of a comprehensive person-centered rehabilitation program. Furthermore, active goal setting for specific spasticity interventions is also important, with a well-established "more is better" approach. It is critical to consider adjunctive therapy and multimodal approaches if patients are not attaining their treatment goals.

16 GCC Closed Forum: ICH M10 implementation; NGS, qPCR/dPCR, flow cytometry validation; tissue biomarkers; IS response; immunogenicity harmonization; bioanalytical industry status.

The 16th GCC Closed Forum was held in Orlando, FL, USA, on 23 June 2023. Representatives from international bioanalytical Contract Research Organizations were in attendance in order to discuss scientific and regulatory issues specific to bioanalysis. The issues discussed at the meeting included: IS response, flow cytometry, changes to the bioanalytical industry, NGS assays, biomarker assay for tissues, dPCR validation, immunogenicity harmonization and ICH M10 implementation.

Smad4 restricts injury-provoked biliary proliferation and carcinogenesis.

Cholangiocarcinoma (CCA) is a deadly and heterogeneous type of cancer characterized by a spectrum of epidemiologic associations as well as genetic and epigenetic alterations. We seek to understand how these features inter-relate in the earliest phase of cancer development and through the course of disease progression. For this, we studied murine models of liver injury integrating the most commonly occurring gene mutations of CCA - including Kras, Tp53, Arid1a and Smad4 - as well as murine hepatobiliary cancer models and derived primary cell lines based on these mutations.

Feasibility and Acceptability of a Remotely Delivered Executive Function Intervention That Combines Computerized Cognitive Training and Metacognitive Strategy Training in Chronic Stroke.

Executive dysfunction after stroke is associated with limitations in daily activities and disability. Existing interventions for executive dysfunction show inconsistent transfer to everyday activities and require frequent clinic visits that can be difficult for patients with chronic mobility challenges to access. To address this barrier, we developed a telehealth-based executive function intervention that combines computerized cognitive training and metacognitive strategy.

Stroke Rehabilitation and Motor Recovery.

Objective: Up to 50% of the nearly 800,000 patients who experience a new or recurrent stroke each year in the United States fail to achieve full independence afterward. More effective approaches to enhance motor recovery following stroke are needed. This article reviews the rehabilitative principles and strategies that can be used to maximize post-stroke recovery.

Cognitive impairment predicts engagement in inpatient stroke rehabilitation.

Patient engagement during inpatient rehabilitation is an important component of rehabilitation therapy, as lower levels of engagement are associated with poorer outcomes. Cognitive deficits may impact patient engagement during inpatient stroke rehabilitation. Here, we assess whether patient performance on the cognitive tasks of the 30-min National Institute of Neurologic Disorders and Stroke - Canadian Stroke Network (NINDS-CSN) screening battery predicts engagement in inpatient stroke rehabilitation.

Vagus Nerve Stimulation Paired With Rehabilitation for Upper Limb Motor Impairment and Function After Chronic Ischemic Stroke: Subgroup Analysis of the Randomized, Blinded, Pivotal, VNS-REHAB Device Trial.

Background: Vagus Nerve Stimulation (VNS) paired with rehabilitation improved upper extremity impairment and function in a recent pivotal, randomized, triple-blind, sham-controlled trial in people with chronic arm weakness after stroke.

Objective: We aimed to determine whether treatment effects varied across candidate subgroups, such as younger age or less injury.

Methods: Participants were randomized to receive rehabilitation paired with active VNS or rehabilitation paired with sham stimulation (Control).

Arid1a mutation suppresses TGF-β signaling and induces cholangiocarcinoma.

Activating KRAS mutations and functional loss of members of the SWI/SNF complex, including ARID1A, are found together in the primary liver tumor cholangiocarcinoma (CC). How these mutations cooperate to promote CC has not been established. Using murine models of hepatocyte and biliary-specific lineage tracing, we show that Kras and Arid1a mutations drive the formation of CC and tumor precursors from the biliary compartment, which are accelerated by liver inflammation.

Recommendations on qPCR/ddPCR assay validation by GCC.

Gene therapy, cell therapy and vaccine research have led to an increased use of qPCR/ddPCR in bioanalytical laboratories. CROs are progressively undertaking the development and validation of qPCR and ddPCR assays. Currently, however, there is limited regulatory guidance for the use of qPCR and a complete lack of any regulatory guidelines for the use of the newer ddPCR to support regulated bioanalysis.

Home Aerobic Training for Cerebellar Degenerative Diseases: a Randomized Controlled Trial.

Balance training has shown some benefits in cerebellar ataxia whereas the effects of aerobic training are relatively unknown. To determine whether a phase III trial comparing home aerobic to balance training in ambulatory patients with cerebellar ataxia is warranted, we conducted a single-center, assessor-blinded, randomized controlled trial. Nineteen subjects were randomized to aerobic training and 17 subjects to balance training.

Biological Matrix Supply Chain Shortages: More Matrices Are Now Rare-the Case for Surrogate Matrices.

The COVID-19 pandemic has strained the biological matrix supply chain. An upsurge in demand driven by numerous COVID-19 therapeutic and vaccine development programs to combat the pandemic, along with logistical challenges sourcing and transporting matrix, has led to increased lead times for multiple matrices. Biological matrix shortages can potentially cause significant delays in drug development programs across the pharmaceutical and biotechnology industry.

Alpha-Crystallin Association with the Model of Human and Animal Eye Lens-Lipid Membranes is Modulated by Surface Hydrophobicity of Membranes.

Purpose: This research aims to probe the interaction of α-crystallin with a model of human, porcine, and mouse lens-lipid membranes.

Methods: Cholesterol/model of human lens-lipid (Chol/MHLL), cholesterol/model of porcine lens-lipid (Chol/MPLL), and cholesterol/model of mouse lens-lipid (Chol/MMLL) membranes with 0-60 mol% Chol were prepared using the rapid solvent exchange method and probe-tip sonication. The hydrophobicity near the surface of model lens-lipid membranes and α-crystallin association with these membranes were investigated using the electron paramagnetic resonance spin-labeling approach.

Recommendations on ELISpot assay validation by the GCC.

Gene therapy, cell therapy and vaccine research have led to an increased need to perform cellular immunity testing in a regulated environment to ensure the safety and efficacy of these treatments. The most common method for the measurement of cellular immunity has been Enzyme-Linked Immunospot assays. However, there is a lack of regulatory guidance available discussing the recommendations for developing and validating these types of assays.

Differential Impact of the COVID-19 Pandemic on Health Care Utilization Disruption for Community-Dwelling Individuals With and Without Acquired Brain Injury.

Objective: To delineate health care disruption for individuals with acquired brain injury (ABI) during the peak of the pandemic and to understand the impact of health care disruption on health-related quality of life (HRQoL).

Design: Cross-sectional survey.

Setting: General community.

Detecting change in community participation with the Enfranchisement scale of the community participation indicators.

Objective: This study determined the sensitivity to change of the Enfranchisement scale of the Community Participation Indicators in people with stroke.

Data Sources: We analyzed data from two studies of participants with stroke: an intervention study and an observational study.

Main Measures: The Enfranchisement Scale contains two subscales: the Importance subscale (feeling valued by and contributing to the community; range: 14-70) and the Control subscale (choice and control: range: 13-64).

Discharge Rehabilitation Measures Predict Activity Limitations in Patients With Stroke 6 Months After Inpatient Rehabilitation.

Objective: The aim of this study was to identify rehabilitation measures at discharge from acute inpatient stroke rehabilitation that predict activity limitations at 6 mos postdischarge.

Design: This is a retrospective analysis of a prospective, longitudinal, observational cohort study. It was conducted in an acute inpatient rehabilitation unit at an urban, academic medical center.

Survey of dermatophytes in stray dogs and cats with and without skin lesions in Puerto Rico and confirmed with MALDI-TOF MS.

Dermatophytosis is a common and highly contagious zoonotic skin disease in companion animals. This disease is a major concern in geographical areas that contain large numbers of stray animal populations. Numerous surveys on dermatophytosis among stray animal populations worldwide range between 27% to 50%.

Evaluation of the Humoral Response to Adeno-Associated Virus-Based Gene Therapy Modalities Using Total Antibody Assays.

The number of viral vector-based gene therapies (GTx) continues to grow with two products (Zolgensma® and Luxturna®) approved in the USA as of March 2021. To date, the most commonly used vectors are adeno-associated virus-based (AAV). The pre-existing humoral immunity against AAV (anti-AAV antibodies) has been well described and is expected as a consequence of prior AAV exposure.

Young individuals with stroke in rehabilitation: a cohort study.

Stroke in younger populations is a public health crisis and the prevalence is rising. Little is known about the progress of younger individuals with stroke in rehabilitation. Characterization of the course and speed of recovery is needed so that rehabilitation professionals can set goals and make decisions.

GM-CSF drives myelopoiesis, recruitment and polarisation of tumour-associated macrophages in cholangiocarcinoma and systemic blockade facilitates antitumour immunity.

Objective: Intrahepatic cholangiocarcinoma (iCCA) is rising in incidence, and at present, there are limited effective systemic therapies. iCCA tumours are infiltrated by stromal cells, with high prevalence of suppressive myeloid populations including tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Here, we show that tumour-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) and the host bone marrow is central for monopoiesis and potentiation of TAMs, and abrogation of this signalling axis facilitates antitumour immunity in a novel model of iCCA.