Citations

AbstractPulmonary arterial hypertension (PAH) is a rare, life‐limiting disease. PAH registries provide real‐world data that complement clinical trial data and inform treatment decisions. The TRIO comprehensive, integrated patient data repository (TRIO CIPDR), is an innovative US repository capturing data on contemporary patients diagnosed with pulmonary hypertension and receiving US Food and Drug Administration‐approved PAH therapies. This repository uniquely combines clinical data from electronic medical records with the ability to track drug‐prescription and drug‐dispensing characteristics, and includes 946 adult patients with PAH (data collected January 2019 to December 2020) enrolled from nine representative US specialist tertiary care centers. Potentially eligible patients were identified based on dispensing data from specialty pharmacies. Hemodynamic and clinical data, as well as dispensing information on prescribed PAH medications, were provided by tertiary centers. At enrollment, 75% of patients were female, 67% were White, median age at PAH diagnosis was 53 years (median time from diagnosis to enrollment was 5 years), and 37% were obese. Comorbidity profiles were as expected for a PAH population, although the proportion with atrial fibrillation (34%) was higher than expected. Overall, 38% of patients had idiopathic PAH and 30% had connective tissue disease‐related PAH. Among 917 patients receiving PAH‐specific therapy, 40% were on monotherapy, 43% on dual therapy, and 17% on triple therapy. Longitudinal data from this repository will allow tracking of the PAH treatment journey in relation to clinical characteristics and outcomes.

The regulation of bone mineral density (BMD) is highly influenced by genetics and age. Although genome‐wide association studies (GWAS) for BMD have uncovered many genes through their proximity to associated variants (variant nearest‐neighbor [VNN] genes), the cell‐specific mechanisms of each VNN gene remain unclear. This is primarily due to the inability to prioritize these genes by cell type and age‐related expression. Using age‐related transcriptomics, we found that the expression of many VNN genes was upregulated in the bone and marrow from aged mice. Candidate genes from GWAS were investigated using single‐cell RNA‐sequencing (scRNA‐seq) datasets to enrich for cell‐specific expression signatures. VNN candidate genes are highly enriched in osteo‐lineage cells, osteocytes, hypertrophic chondrocytes, and Lepr+ mesenchymal stem cells. These data were used to generate a “blueprint” for Cre‐loxp mouse line selection for functional validation of candidate genes and further investigation of their role in BMD maintenance throughout aging. In VNN‐gene‐enriched cells, Sparc , encoding the extracellular matrix (ECM) protein osteonectin, was robustly expressed. This, along with expression of numerous other ECM genes, indicates that many VNN genes likely have roles in ECM deposition by osteoblasts. Overall, we provide data supporting streamlined translation of GWAS candidate genes to potential novel therapeutic targets for the treatment of osteoporosis. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Abstract Objectives Inflatable penile prosthesis (IPP) placement on active anticoagulation (AC) is controversial. Techniques utilized to decrease complications include use of malleable implant, partial inflation of IPP for hemostasis, and placement of drain; however risk and benefits must be weighed. We sought to assess outcomes of IPP in men on AC in a multi-institutional study. Methods Data from 3 high-volume implant centers was retrospectively analyzed. Demographics, comorbidities, secondary procedures, drain placement/output, and complications were recorded. Aspirin was excluded as it is not routinely held. Center 1 utilizes a penoscrotal approach without drain placement, center 2 a penoscrotal approach with drain placement (removal when output <50 mL/8 hours), and center 3 an infra-pubic approach with drain for 3 days. Results 202 patients were continued on AC throughout surgery: 112 on clopidogrel, 35 warfarin, 38 apixaban, 1 enoxaparin, 15 rivaroxaban, and 1 combination therapy with clopidogrel and enoxaparin. AC was most continued for peripheral vascular disease (55%), cardiac stents (11.6%), CHF (11%), and atrial fibrillation (11%). Nine patients (3.98%) experienced complications. Four significant events (1 retropubic bleed requiring transfusion, 3 IPP infections) and 5 minor events (3 hematomas, 1 wound dehiscence,1 CT-negative stroke) occurred. Average drain output for center 1 was 223 mL with no hematomas or infections noted. Average drain output for center 2 was 121 mL with most drains removed postoperative day 1. Drain output was significantly higher than historical non-AC controls (p=0.001), however complication rates were not significantly different (p>0.05). AC type, revision surgery, scrotoplasty, or reservoir technique did not affect outcomes or drainage. Conclusions In high-volume implant centers, major complication rate of 1.9% occurred in IPP patients on AC. Although IPP is feasible in this patient population, drain for 3 days and submuscular reservoir placement may be indicated. In most, elective IPP surgery should be delayed until it is safe to discontinue anticoagulation. Conflicts of Interest None

We assessed the available evidence regarding adverse effects on surrogate and patient-important health outcomes of third- and fourth-generation combined oral contraceptives among premenopausal women. We performed a systematic review and meta-analysis including randomized controlled trials and observational studies comparing third- and fourth-generation combined oral contraceptives with other generation contraceptives or placebo. Studies that enrolled women aged 15 to 50 years, with at least three cycles of intervention and 6 months of follow-up were included. A total of 33 studies comprising 629,783 women were included. Low-density lipoprotein cholesterol levels were significantly lower in fourth-generation oral contraceptives (mean differences (MD): −0.24 mmol/L; [95% CI −0.39 to −0.08]), while total cholesterol was significantly increased in levonorgestrel users when compared to third-generation oral contraceptives (MD: 0.27 mmol/L; [95% CI 0.04 to 0.50]). A decreased arterial thrombosis incidence was shown in fourth-generation oral contraceptive users, as compared to levonorgestrel (incidence rate ratio (IRR): 0.41; [95% CI 0.19 to 0.86]). No difference was found in the occurrence of deep venous thrombosis between fourth-generation oral contraceptives and levonorgestrel users (IRR: 0.91; [95% CI 0.66 to 1.27]; p = 0.60; I 2 = 0%). Regarding the remaining outcomes, data were heterogeneous and showed no clear difference. In premenopausal women, the use of third- and fourth-generation oral contraceptives is associated with an improved lipid profile and lower risk of arterial thrombosis. Data were inconclusive regarding the rest of outcomes assessed. This review was registered in PROSPERO with CRD42020211133.

Abstract Purpose This work proposes a 2D/3D hybrid inflow MRA technique for fast scanning and high SNR and contrast‐to‐noise (CNR) efficiencies. Methods Localized quadratic (LQ) encoding was combined with a sliding‐slice spiral acquisition. Inflow MRAs around the circle of Willis and the carotid bifurcations were collected on four healthy volunteers. Spiral images were deblurred without or with water–fat separation for sliding‐slice LQ (ssLQ) out‐of‐phase (OP) and Dixon inflow MRAs, respectively. Results were compared to multiple overlapping thin slab acquisitions (MOTSA) and 2D OP inflow MRAs. Noise data were also acquired with RF and gradients turned off to compute maps of SNR and SNR efficiency. Quantitative assessment of relative contrast, CNR, and CNR efficiency for flow were performed in regions of interest. Results The sliding‐slice spiral technique alone reduces scan time by 10% to 40% compared with a standard spiral acquisition scheme. The proposed spiral ssLQ OP achieves 50% higher scan speed than the spiral MOTSA with comparable SNR and CNR efficiencies, which are ∼100% higher than the Cartesian MOTSA for intracranial inflow MRAs. Spiral ssLQ Dixon inflow MRA provides better visibility for vessels around the fat compared to spiral ssLQ OP inflow MRA, with a trade‐off of scan speed. Spiral ssLQ MRA with thinner slice thickness is two to five times faster than the 2D Cartesian inflow neck MRA around the carotid bifurcations, while also achieving higher SNR efficiency. Conclusion The proposed spiral ssLQ is a fast and flexible MRA method with improved SNR and CNR efficiencies over traditional Cartesian inflow MRAs.

Introduction The superficial and deep parasternal intercostal plane (DPIP) blocks are two new blocks for thoracic pain. There are limited cadaveric studies evaluating the dye spread with these blocks. In this study, we examined the dye spread of an ultrasound-guided DPIP block in a human cadaveric model. Methods Five ultrasound-guided DPIP blocks were performed in four unembalmed human cadavers using an in-plane approach with a linear transducer oriented in a transverse plane adjacent to the sternum. Twenty milliliters of 0.1% methylene blue were injected between ribs 3 and 4 into the plane deep to the internal intercostal muscles and superficial to the transversus thoracis muscle layer. The chest muscles were dissected, and the extent of dye spread was documented in both cephalocaudal and mediolateral directions. Results The transversus thoracis muscle slips were stained in all cadavers from 4 to 6 levels. Intercostal nerves were dyed in all specimens. Four levels of intercostal nerves were dyed in each specimen with variability in number of levels stained above and below the level of the injection. Conclusions The DPIP block spreads along the tissue plane above the transversus thoracis muscles to multiple levels to dye the intercostal nerves in this cadaver study. This block may be of clinical value for analgesia in anterior thoracic surgical procedures.

PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is largely considered a nonimmunogenic malignancy; however, approximately 1%, of patients may have tumors with deficient mismatch repair, high microsatellite instability, or high tumor mutational burden (TMB ≥10 mutations/Mb), which may be predictive of response to immune checkpoint inhibitor (ICI) therapy. We sought to analyze outcomes of patients with high-TMB and pathogenic genomic alterations observed in this population. METHODS This study included patients with PDAC who underwent comprehensive genomic profiling (CGP) at Foundation Medicine (Cambridge, MA). Clinical data were obtained from a US-wide real-world clinicogenomic pancreatic database. We report genomic alterations in those with high and low TMB, and compare outcomes on the basis of receipt of single-agent ICI or therapy regimens not containing ICI. RESULTS We evaluated 21,932 patients with PDAC who had tissue CGP data available, including 21,639 (98.7%) with low-TMB and 293 (1.3%) with high-TMB. Among patients with high-TMB, a greater number of alterations were observed in BRCA2, BRAF, PALB2, and genes of the mismatch repair pathway, whereas fewer alterations were observed in KRAS. Among patients who received an ICI (n = 51), those with high-TMB had more favorable median overall survival when compared with the low-TMB subset (25.7 v 5.2 months; hazard ratio, 0.32; 95% CI, 0.11 to 0.91; P = .034). CONCLUSION Longer survival was observed in patients with high-TMB receiving ICI compared with those with low-TMB. This supports the role of high-TMB as a predictive biomarker for efficacy of ICI therapy in PDAC. Additionally, we report higher rates of BRAF and BRCA2 mutations and lower rates of KRAS mutation among patients with PDAC and high-TMB, which to our knowledge, is a novel finding.