Background: An increasing number of patients with pulmonary arterial hypertension (PAH) have cardiovascular comorbidities. However, the effects of comorbidities on responses to PAH treatment are not well understood.
Research Question: Do cardiovascular comorbidities in patients with PAH influence the efficacy and tolerability of inhaled or oral treprostinil?
Study Design And Methods: All patients from phase 3 studies TRIUMPH (N = 235) and FREEDOM-EV (N = 690) were included in this post hoc analysis and were classified as having 0, ≥1, or ≥2 cardiovascular comorbidities of interest based on patients' medical histories.
Marginal structural models (MSMs) are often used to estimate causal effects of treatments on survival time outcomes from observational data when time-dependent confounding may be present. They can be fitted using, for example, inverse probability of treatment weighting (IPTW). It is important to evaluate the performance of statistical methods in different scenarios, and simulation studies are a key tool for such evaluations.
View Article and Find Full Text PDFOper Neurosurg (Hagerstown)
August 2024
Background And Objectives: The impact of prior local therapies, including radiation and surgery, on reconstruction outcomes after endonasal surgery is currently not well known. Reconstruction nuances in the preoperative setting merit further evaluation to avoid potential postoperative complications that can hinder overall tumor management and negatively impact patient outcome. We sought to determine whether prior treatments increase risk of reconstruction-related postoperative morbidity and to evaluate the effectiveness of our current treatment paradigm for skull base reconstruction.
View Article and Find Full Text PDFBackground: Risk prediction models are routinely used to assist in clinical decision making. A small sample size for model development can compromise model performance when the model is applied to new patients. For binary outcomes, the calibration slope (CS) and the mean absolute prediction error (MAPE) are two key measures on which sample size calculations for the development of risk models have been based.
View Article and Find Full Text PDFIntegrin αβ+ T cells perpetuate tissue injury in chronic inflammatory diseases, yet their role in hepatic fibrosis progression remains poorly understood. Here, we report increased accumulation of αβ+ T cells in the liver of people with cirrhosis relative to disease controls. Similarly, hepatic fibrosis in the established mouse model of CCl-induced liver fibrosis was associated with enrichment of intrahepatic αβ+ CD4 and CD8 T cells.
View Article and Find Full Text PDFThe role of systemic therapy in primary or advanced and metastatic chordoma has been traditionally limited because of the inherent resistance to cytotoxic therapies and lack of specific or effective therapeutic targets. Despite resection and adjuvant radiation therapy, local recurrence rates in clival chordoma remain high and the risk of systemic metastases is not trivial, leading to significant morbidity and mortality. Recently, molecular targeted therapies (MTTs) and immune checkpoint inhibitors (ICIs) have emerged as promising therapeutic avenues in chordoma.
View Article and Find Full Text PDFIntroduction: Opioid agonist treatment (OAT) tapering involves a gradual reduction in daily medication dose to ultimately reach a state of opioid abstinence. Due to the high risk of relapse and overdose after tapering, this practice is not recommended by clinical guidelines, however, clients may still request to taper off medication. The ideal time to initiate an OAT taper is not known.
View Article and Find Full Text PDFObjective: The aging global population presents an increasing challenge for spine surgeons. Advancements in spine surgery, including minimally invasive techniques, have broadened treatment options, potentially benefiting older patients. This study aims to explore the clinical outcomes of spine surgery in septuagenarians and octogenarians.
View Article and Find Full Text PDFThe majority of clinically approved drugs target proteins that are secreted or cell surface bound. However, further advances in this area have been hindered by the challenging nature of receptor deorphanization, as there are still many secreted and cell-bound proteins with unknown binding partners. Here, we developed an advanced screening platform that combines CRISPR-CAS9 guide-mediated gene activation (CRISPRa) and high-avidity bead-based selection.
View Article and Find Full Text PDFAssessing the impact of an intervention by using time-series observational data on multiple units and outcomes is a frequent problem in many fields of scientific research. Here, we propose a novel Bayesian multivariate factor analysis model for estimating intervention effects in such settings and develop an efficient Markov chain Monte Carlo algorithm to sample from the high-dimensional and nontractable posterior of interest. The proposed method is one of the few that can simultaneously deal with outcomes of mixed type (continuous, binomial, count), increase efficiency in the estimates of the causal effects by jointly modeling multiple outcomes affected by the intervention, and easily provide uncertainty quantification for all causal estimands of interest.
View Article and Find Full Text PDFIntroduction: In the event-driven FREEDOM-EV trial, oral treprostinil delayed clinical worsening in patients with pulmonary arterial hypertension (PAH). Open-label extension studies offer additional data about tolerability, efficacy, and survival, especially for those initially assigned placebo. The aim of the current study was to determine if oral treprostinil changed survival when considering the parent and extension study, if treprostinil provides functional benefits for participants initially assigned to placebo, and if the benefits observed for those treated with treprostinil were durable.
View Article and Find Full Text PDFCD276/B7-H3 represents a promising target for cancer therapy based on widespread overexpression in both cancer cells and tumor-associated stroma. In previous preclinical studies, CD276 antibody-drug conjugates (ADCs) exploiting a talirine-type pyrrolobenzodiazepine (PBD) payload showed potent activity against various solid tumors but with a narrow therapeutic index and dosing regimen higher than that tolerated in clinical trials using other antibody-talirine conjugates. Here, we describe the development of a modified talirine PBD-based fully human CD276 ADC, called m276-SL-PBD, that is cross-species (human/mouse) reactive and can eradicate large 500-1,000-mm triple-negative breast cancer xenografts at doses 10- to 40-fold lower than the maximum tolerated dose.
View Article and Find Full Text PDFObjective: In September 2020, 15 861 SARS-CoV-2 case records failed to upload from the Second Generation Surveillance System (SGSS) to the Contact Tracing Advisory Service (CTAS) tool, delaying the contact tracing of these cases. This study used CTAS data to determine the impact of this delay on population health outcomes: transmission events, hospitalisations and mortality. Previously, a modelling study suggested a substantial impact.
View Article and Find Full Text PDFUnderstanding patients' wishes regarding organ and tissue donation is an important aspect of advance care planning (ACP). Many patients with life-limiting illnesses are still eligible to be corneal donors. A quality improvement (QI) approach has promoted a positive change in culture at an inpatient hospice, making the discussion of patients' wishes on corneal donation the norm.
View Article and Find Full Text PDFRationale: Oral treprostinil slows disease progression and improves exercise capacity in pulmonary arterial hypertension; however, titration can be prolonged. Published data suggests prostacyclin-naïve patients achieve total daily oral treprostinil doses of about 6 mg by Week 16, while those on prior parenteral treprostinil reach higher doses at the same timepoint.
Objectives: EXPEDITE (NCT03497689), a single-arm, multicenter study, assessed the efficacy of rapid parenteral treprostinil induction to quickly reach higher doses of oral treprostinil for the treatment of pulmonary arterial hypertension.
Treprostinil is a prostacyclin analogue that targets multiple cellular receptors to treat pulmonary arterial hypertension (PAH). In certain scenarios, patients may require aggressive treprostinil titration. Several studies have demonstrated that higher doses of treprostinil lead to greater clinical benefit.
View Article and Find Full Text PDFPurpose: Oral treprostinil and selexipag are drugs targeting the prostacyclin pathway and are approved for treatment of pulmonary arterial hypertension (PAH). In the setting of unsatisfactory clinical response or tolerability issues while on selexipag, there is little data on clinical benefit, safety, or strategies on transitioning to oral treprostinil. Using prospective data from the ADAPT registry, we aimed to evaluate clinical outcomes, safety, and transition strategies in ten patients with PAH transitioning from selexipag to oral treprostinil.
View Article and Find Full Text PDFObjectives: To determine how the intrinsic severity of successively dominant SARS-CoV-2 variants changed over the course of the pandemic.
Methods: A retrospective cohort analysis in the NHS Greater Glasgow and Clyde (NHS GGC) Health Board. All sequenced non-nosocomial adult COVID-19 cases in NHS GGC with relevant SARS-CoV-2 lineages (B.
Longitudinal observational data on patients can be used to investigate causal effects of time-varying treatments on time-to-event outcomes. Several methods have been developed for estimating such effects by controlling for the time-dependent confounding that typically occurs. The most commonly used is marginal structural models (MSM) estimated using inverse probability of treatment weights (IPTW) (MSM-IPTW).
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