Pulmonary Hypertension: Intensification and Personalization of Combination Rx (PHoenix): A phase IV randomized trial for the evaluation of dose-response and clinical efficacy of riociguat and selexipag using implanted technologies.

Approved therapies for the treatment of patients with pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. International guidelines recommend that patients with an inadequate response to dual therapy with a phosphodiesterase type-5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate-cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides the opportunity for evaluation of individualized therapeutic effects.

Systematic pulmonary embolism follow-up increases diagnostic rates of chronic thromboembolic pulmonary hypertension and identifies less severe disease: results from the ASPIRE Registry.

Background: Diagnostic rates and risk factors for the subsequent development of chronic thromboembolic pulmonary hypertension (CTEPH) following pulmonary embolism (PE) are not well defined.

Methods: Over a 10-year period (2010-2020), consecutive patients attending a PE follow-up clinic in Sheffield, UK (population 554 600) and all patients diagnosed with CTEPH at a pulmonary hypertension (PH) referral centre in Sheffield (referral population estimated 15-20 million) were included.

Results: Of 1956 patients attending the Sheffield PE clinic 3 months following a diagnosis of acute PE, 41 were diagnosed with CTEPH with a cumulative incidence of 2.

Framing Effects of Cognitive Behavioural Therapy for Depression on Perceptions of Believability, Acceptability, and Credibility.

While CBT is an effective treatment for depression, uptake can be low. This is largely due to attitudinal barriers. Accordingly, the goals of the current investigation were to (a) tailor and develop persuasive psychoeducational materials to match dominant cultural beliefs about the causes of depression and (b) examine the effectiveness of tailored CBT descriptions in improving CBT perceptions.

Establishing minimally important differences for cardiac MRI end-points in pulmonary arterial hypertension.

Background: Cardiac magnetic resonance (CMR) is the gold standard technique to assess biventricular volumes and function, and is increasingly being considered as an end-point in clinical studies. Currently, with the exception of right ventricular (RV) stroke volume and RV end-diastolic volume, there is only limited data on minimally important differences (MIDs) reported for CMR metrics. Our study aimed to identify MIDs for CMR metrics based on US Food and Drug Administration recommendations for a clinical outcome measure that should reflect how a patient "feels, functions or survives".

Longitudinal Lung Function Assessment of Patients Hospitalized With COVID-19 Using H and Xe Lung MRI.

Background: Microvascular abnormalities and impaired gas transfer have been observed in patients with COVID-19. The progression of pulmonary changes in these patients remains unclear.

Research Question: Do patients hospitalized with COVID-19 without evidence of architectural distortion on structural imaging exhibit longitudinal improvements in lung function measured by using H and Xe MRI between 6 and 52 weeks following hospitalization?

Study Design And Methods: Patients who were hospitalized with COVID-19 pneumonia underwent a pulmonary H and Xe MRI protocol at 6, 12, 25, and 51 weeks following hospital admission in a prospective cohort study between November 2020 and February 2022.

Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency.

Heterozygous variants in GBA1, encoding glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease (PD). Moreover, sporadic PD patients also have a substantial reduction of GCase activity. Genetic variants of SMPD1 are also overrepresented in PD cohorts, whereas a reduction of its encoded enzyme (acid sphingomyelinase or ASM) activity is linked to an earlier age of PD onset.

Imaging and Risk Stratification in Pulmonary Arterial Hypertension: Time to Include Right Ventricular Assessment.

Background: Current European Society of Cardiology and European Respiratory Society guidelines recommend regular risk stratification with an aim of treating patients with pulmonary arterial hypertension (PAH) to improve or maintain low-risk status (<5% 1-year mortality).

Methods: Consecutive patients with PAH who underwent cardiac magnetic resonance imaging (cMRI) were identified from the Assessing the Spectrum of Pulmonary hypertension Identified at a Referral centre (ASPIRE) registry. Kaplan-Meier survival curves, locally weighted scatterplot smoothing regression and multi-variable logistic regression analysis were performed.

GCH1 Deficiency Activates Brain Innate Immune Response and Impairs Tyrosine Hydroxylase Homeostasis.

The Parkinson's disease (PD) risk gene GTP cyclohydrolase 1 (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin (BH4) synthesis, an essential cofactor in the synthesis of monoaminergic neurotransmitters. To investigate the mechanisms by which GCH1 deficiency may contribute to PD, we generated a loss of function zebrafish mutant (), using CRISPR/Cas technology. zebrafish develop marked monoaminergic neurotransmitter deficiencies by 5 d postfertilization (dpf), movement deficits by 8 dpf and lethality by 12 dpf.

Co-ordinated control of the Aurora B abscission checkpoint by PKCε complex assembly, midbody recruitment and retention.

A requirement for PKCε in exiting from the Aurora B dependent abscission checkpoint is associated with events at the midbody, however, the recruitment, retention and action of PKCε in this compartment are poorly understood. Here, the prerequisite for 14-3-3 complex assembly in this pathway is directly linked to the phosphorylation of Aurora B S227 at the midbody. However, while essential for PKCε control of Aurora B, 14-3-3 association is shown to be unnecessary for the activity-dependent enrichment of PKCε at the midbody.

Cross-Comparison of Human iPSC Motor Neuron Models of Familial and Sporadic ALS Reveals Early and Convergent Transcriptomic Disease Signatures.

Induced pluripotent stem cell (iPSC)-derived neural cultures from amyotrophic lateral sclerosis (ALS) patients can model disease phenotypes. However, heterogeneity arising from genetic and experimental variability limits their utility, impacting reproducibility and the ability to track cellular origins of pathogenesis. Here, we present methodologies using single-cell RNA sequencing (scRNA-seq) analysis to address these limitations.

Equivocal, explicit and emergent actions of PKC isoforms in cancer.

The maturing mutational landscape of cancer genomes, the development and application of clinical interventions and evolving insights into tumour-associated functions reveal unexpected features of the protein kinase C (PKC) family of serine/threonine protein kinases. These advances include recent work showing gain or loss-of-function mutations relating to driver or bystander roles, how conformational constraints and plasticity impact this class of proteins and how emergent cancer-associated properties may offer opportunities for intervention. The profound impact of the tumour microenvironment, reflected in the efficacy of immune checkpoint interventions, further prompts to incorporate PKC family actions and interventions in this ecosystem, informed by insights into the control of stromal and immune cell functions.

Causal explanations of depression on perceptions of and likelihood to choose cognitive behavioural therapy and antidepressant medications as depression treatments.

Objectives: This research examined whether people's causal explanations of depression were associated with acceptability and efficacy-related treatment perceptions and likelihood to choose cognitive behavioural therapy (CBT) and antidepressant medication (ADM) as depression treatments.

Design: A cross-sectional internet-based design was used.

Methods: A general population sample was used over a clinical sample to study those who had not yet chosen to enter treatment.

Perceptions of Cognitive-Behavioral Therapy and Antidepressant Medication for Depression After Brief Psychoeducation: Examining Shifts in Attitudes.

The majority of people with depression in the United States either never seek treatment or gravitate exclusively to antidepressant medication (ADM), despite the existence of other effective treatments, such as cognitive-behavioral therapy (CBT). Reluctance to use psychotherapy is partly due to lack of appropriate mental health literacy and perceptions of low treatment acceptability (appropriateness for a given problem) and credibility (treatment logicalness, and whether the patient expects improvement). In the current investigation, we examined whether providing psychoeducation about CBT for depression would change participant perceptions of the treatment's acceptability and credibility.

Ablation of the pro-inflammatory master regulator miR-155 does not mitigate neuroinflammation or neurodegeneration in a vertebrate model of Gaucher's disease.

Bi-allelic mutations in the glucocerebrosidase gene (GBA1) cause Gaucher's disease, the most common human lysosomal storage disease. We previously reported a marked increase in miR-155 transcript levels and early microglial activation in a zebrafish model of Gaucher's disease (gba1). miR-155 is a master regulator of inflammation and has been implicated in a wide range of different neurodegenerative disorders.

TIGAR inclusion pathology is specific for Lewy body diseases.

Background: We previously reported up-regulation of tigarb (the zebrafish orthologue of human TIGAR, TP53 - Induced Glycolysis and Apoptosis Regulator) in a zebrafish pink1 model of Parkinson's disease (PD). Genetic inactivation of tigarb led to the rescue of dopaminergic neurons and mitochondrial function in pink zebrafish. The aim of this study was to determine the relevance of TIGAR for human PD, investigate its disease specificity and identify relevant upstream and downstream mechanisms.

Clinicians' perceptions of rationales for rehabilitative exercise in a critical care setting: A cross-sectional study.

Background: Rehabilitative exercise for critically ill patients may have many benefits; however, it is unknown what intensive care unit (ICU) clinicians perceive to be important rationale for the implementation of rehabilitative exercise in critical care settings.

Objective: To identify which rationales for rehabilitative exercise interventions were perceived by ICU clinicians to be important and determine whether perceptions were consistent across nursing, medical and physiotherapy clinicians.

Methods: A cross-sectional study was undertaken among clinicians (nursing, medical, physiotherapy) working in a mixed medical surgical ICU in an Australian metropolitan tertiary hospital.

Cultural beliefs and understandings of cervical cancer among Mexican immigrant women in Southeast Georgia.

Rural Mexican immigrant women in the U.S. are infrequently screened and experience health disparities from cervical cancer.

Assessing the learning needs of oncology nurses.

The Nurse Oncology Education Program (NOEP) is a nonprofit organization of the Texas Nurses Foundation that develops and provides education for nurses in all fields of practice on cancer prevention, detection, treatment, and survivorship. To meet the most current educational needs of nurses, NOEP conducts a biannual needs assessment survey to better understand its audience and inform its course development. The 2013 NOEP needs assessment survey used a convenience sample of licensed nurses throughout the United States.

Glucocorticoid receptor binds half sites as a monomer and regulates specific target genes.

Background: Glucocorticoid receptor (GR) is a hormone-activated, DNA-binding transcriptional regulatory factor that controls inflammation, metabolism, stress responses, and other physiological processes. In vitro, GR binds as an inverted dimer to a motif consisting of two imperfectly palindromic 6 bp half sites separated by 3 bp spacers. In vivo, GR employs different patterns of functional surfaces of GR to regulate different target genes.

A naturally occurring insertion of a single amino acid rewires transcriptional regulation by glucocorticoid receptor isoforms.

In addition to guiding proteins to defined genomic loci, DNA can act as an allosteric ligand that influences protein structure and activity. Here we compared genome-wide binding, transcriptional regulation, and, using NMR, the conformation of two glucocorticoid receptor (GR) isoforms that differ by a single amino acid insertion in the lever arm, a domain that adopts DNA sequence-specific conformations. We show that these isoforms differentially regulate gene expression levels through two mechanisms: differential DNA binding and altered communication between GR domains.

The glucocorticoid receptor dimer interface allosterically transmits sequence-specific DNA signals.

Glucocorticoid receptor (GR) binds to genomic response elements and regulates gene transcription with cell and gene specificity. Within a response element, the precise sequence to which the receptor binds has been implicated in directing its structure and activity. Here, we use NMR chemical-shift difference mapping to show that nonspecific interactions with bases at particular positions in the binding sequence, such as those of the 'spacer', affect the conformation of distinct regions of the rat GR DNA-binding domain.

Geographic disparities in late-stage cancer diagnosis: multilevel factors and spatial interactions.

In 2009 in the United States, breast cancer was the most common cancer in women, and colorectal cancer was the third most common cancer in both men and women. Currently, over 40% of these cancers are diagnosed at an advanced stage, which results in higher morbidity and mortality than would obtain with optimal cancer screening utilization. To provide information that might improve these cancer outcomes we use spatial analysis to answer questions related to both Why and Where disparities in late-stage cancer diagnoses are observed.