Practical management of oral treprostinil in patients with pulmonary arterial hypertension: Lessons from ADAPT, EXPEDITE, and expert consensus.

BACKGROUND: Oral treprostinil is a prostacyclin analogue approved to treat pulmonary arterial hypertension (PAH) by delaying disease progression and improving exercise capacity. Higher doses of oral treprostinil correlate with increased treatment benefit. Titrations may be challenging due to common side effects of prostacyclin-class therapies. STUDY DESIGN AND METHODS: The multicenter, prospective, real-world, observational ADAPT Registry study followed adult patients with PAH for up to 78 weeks after initiating oral treprostinil (NCT03045029). Dosing, titration, and transitions of oral treprostinil were at the discretion of the prescriber. Patient-reported incidence and treatment of common side effects were collected to understand side effect management and tolerability. Insights from literature and expert recommendations were added to provide a consolidated resource for oral treprostinil use. RESULTS: In total, 139 participants in ADAPT completed ≥1 weekly survey; (median age 60.0 years, 76% female). Median treatment duration of oral treprostinil was 13.1 months. During early therapy (Months 1-5), 62% (78/126) of patients reported headache and diarrhea, and 40% (50/126) reported nausea. At Month 6, many patients who reported side effects during early therapy reported an improvement (61% headache, 44% diarrhea, 70% nausea). Common side effect treatments, including acetaminophen, loperamide, and ondansetron were effective. Approximately one-quarter of patients reporting the most common side effects were untreated at Month 6. CONCLUSION: Patient selection for, and initiation and titration of oral treprostinil should be individualized and may include parenteral treprostinil induction-transition for faster titration. Assertive side effect management may help reach higher and more efficacious doses of oral treprostinil.

Automated selection of abdominal MRI series using a DICOM metadata classifier and selective use of a pixel-based classifier.

Accurate, automated MRI series identification is important for many applications, including display ("hanging") protocols, machine learning, and radiomics. The use of the series description or a pixel-based classifier each has limitations. We demonstrate a combined approach utilizing a DICOM metadata-based classifier and selective use of a pixel-based classifier to identify abdominal MRI series. The metadata classifier was assessed alone as Group metadata and combined with selective use of the pixel-based classifier for predictions with less than 70% certainty (Group combined). The overall accuracy (mean and 95% confidence intervals) for Groups metadata and combined on the test dataset were 0.870 CI (0.824,0.912) and 0.930 CI (0.893,0.963), respectively. With this combined metadata and pixel-based approach, we demonstrate accurate classification of 95% or greater for all pre-contrast MRI series and improved performance for some post-contrast series.

White by Another Name? Can Anti-Christian Bias Claims Serve as a Racial Dog Whistle?

Four preregistered experiments (N = 4,307) explored whether anti-Christian bias claims can discreetly signal White allyship among Christian American adults. In Experiments 1 and 2, reading about anti-Christian bias led White, but not Black, Christians to perceive more anti-White bias. Experiments 3 and 4 demonstrate the connection between Christian and White can be leveraged by politicians in the form of a racial dog whistle. In Experiment 3, White Christians perceived a politician concerned about anti-Christian bias as caring more about anti-White bias and more willing to fight for White people (relative to a control). This politician was also perceived as less offensive than a politician concerned about anti-White bias. In Experiment 4, Black Christians perceived a politician concerned about anti-Christian bias as less offensive than one concerned about anti-White bias yet still unlikely to fight for Black people. Results suggest "anti-Christian bias" can provide a relatively palatable way to signal allegiance to White people.

A comprehensive review on ecology, life cycle and use of Tecoma stans (bignoneaceae).

Tecoma stans is a widely distributed tall ornamental shrub in the plains of Indian subcontinent and is considered an invasive species across Argentina, Australia, South Africa, Pacific Islands and tropical regions of Asia. Besides having an ornamental significance, T. stans has been extensively investigated for its pharmaceutical applications as a source of bioactive compounds. In addition, the shrub is cultivated commercially as a potted flowering plant. We believe that T. stans, being a hardy, invasive and aggressively growing species, holds a considerable potential and a promising solution for re-greening waste and degraded lands outside its invasive range, due to its wider adaptability and drought tolerant characteristics. The shrub is an excellent source of pollen and nectar, that attracts diverse insect-pollinators and several species of birds. The prudent plantation of this shrub has the potential to restore the ecology of barren landscapes, that can change its perspective of 'being invasive' to 'being ecologically healthy' across the tropical, semi-arid and subtropical regions worldwide. This paper reviews the current updates on ecology, life cycle including morphology, plant growth characteristics, flowering phenology, reproductive biology, breeding system and fruiting of T. stans. In addition, details on insect-pollinator diversity and natural regeneration potential have also been discussed, besides highlighting its therapeutic and landscape use.

Parenteral treprostinil induction for rapid attainment of therapeutic doses of oral treprostinil.

RATIONALE: 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. METHODS: Parenteral treprostinil was titrated for 2-8 weeks, followed by cross-titration of oral treprostinil. The primary endpoint was percentage of patients reaching ≥12 mg daily of oral treprostinil at Week 16. Secondary endpoints included clinical changes from baseline to Week 16. RESULTS: Twenty-nine prostacyclin-naïve patients were included in efficacy analyses. At Week 16, the mean daily oral treprostinil dose was 16.4 mg; 79% of patients met the primary endpoint. From baseline to Week 16, median REVEAL Lite 2 score improved (decreased) from 6 to 3.5 (p = 0.0006). Statistically significant improvements were also seen in World Health Organization Functional Class, N-terminal-pro brain natriuretic peptide levels, 6-minute walk distance, right atrial area, Borg Dyspnea Score, and emPHasis-10 score. Favorable trends were seen in risk stratification, echocardiography parameters, disease symptoms, and treatment satisfaction. CONCLUSION: Short-course parenteral treprostinil induction resulted in oral treprostinil doses over twice those reported in de novo initiations and may be a useful approach to quickly achieve the therapeutic benefits of oral treprostinil.

Implementing the EXPEDITE parenteral induction protocol: Rapid parenteral treprostinil titration and transition to oral treprostinil.

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. Data supports successful transitions from parenteral to oral treprostinil; however, administration routes, transition duration, and transition setting vary in the real-world. The EXPEDITE clinical trial (NCT03497689) prospectively studied whether rapid parenteral treprostinil induction can be used to achieve high doses of oral treprostinil (total daily dose: ≥12 mg) in prostacyclin naïve PAH patients. Parenteral prostacyclin induction may be more appropriate for patients who need to reach therapeutic dosing more urgently than longer titration durations reported with conventional de novo oral treprostinil initiation. This summary provides strategies utilized in EXPEDITE. Parenteral treprostinil was initiated at 2 ng/kg/min intravenously or subcutaneously; clinicians determined the frequency and dose increment of up-titration. Two distinct transition schedules from parenteral to oral treprostinil were employed: rapid cross-titration in an inpatient setting (median: 2 days) or gradual cross-titration in an outpatient setting (median: 5 days). Patient status was closely monitored after transition; oral treprostinil dose was titrated to clinical effect and tolerability. Factors considered when individualizing dosing strategies included parenteral and oral treprostinil target doses, nursing support, patient education, medication counseling and adverse events management. EXPEDITE demonstrated the time to a therapeutic dose of oral treprostinil is significantly shorter when utilizing a short-term parenteral induction strategy and may be suitable for patients requiring aggressive titration of oral treprostinil.

Deep learning for classification of thyroid nodules on ultrasound: validation on an independent dataset.

OBJECTIVES: The purpose is to apply a previously validated deep learning algorithm to a new thyroid nodule ultrasound image dataset and compare its performances with radiologists. METHODS: Prior study presented an algorithm which is able to detect thyroid nodules and then make malignancy classifications with two ultrasound images. A multi-task deep convolutional neural network was trained from 1278 nodules and originally tested with 99 separate nodules. The results were comparable with that of radiologists. The algorithm was further tested with 378 nodules imaged with ultrasound machines from different manufacturers and product types than the training cases. Four experienced radiologists were requested to evaluate the nodules for comparison with deep learning. RESULTS: The Area Under Curve (AUC) of the deep learning algorithm and four radiologists were calculated with parametric, binormal estimation. For the deep learning algorithm, the AUC was 0.69 (95% CI: 0.64-0.75). The AUC of radiologists were 0.63 (95% CI: 0.59-0.67), 0.66 (95% CI:0.61-0.71), 0.65 (95% CI: 0.60-0.70), and 0.63 (95%CI: 0.58-0.67). CONCLUSION: In the new testing dataset, the deep learning algorithm achieved similar performances with all four radiologists. The relative performance difference between the algorithm and the radiologists is not significantly affected by the difference of ultrasound scanner.

Anti-Black attitudes predict decreased concern about COVID-19 among Whites in the U.S. and Brazil.

RATIONALE: From the earliest days of the COVID-19 pandemic, public health officials and news organizations reported pervasive racial disparities in the infection, morbidity, and mortality of the virus. In both the U.S. and Brazil, Black, Native, and mixed-race individuals were more negatively impacted by COVID-19 than White people. Simultaneously, significant social factions downplayed the threat and insisted on living "normally". We examined how these two factors coexisted. OBJECTIVE: We sought to establish whether Whites' anti-Black attitudes predicted their concern about the pandemic and tendency to behave in ways that exacerbated the pandemic. METHODS: and Results: In five studies, conducted in two countries (total N = 3425), we found that anti-Black attitudes (above and beyond political orientation, White racial identification, and perceptions of racial disparities) were associated with less concern about COVID-19, lower adoption of health and social distancing behaviors, and greater interest in returning to normalcy. DISCUSSION: We discuss how efforts to combat anti-Blackness may improve the health of the general population.

Retroperitoneal dermoid cyst presenting with radiculopathy symptoms: a case report.

Dermoid cysts rarely present in the retroperitoneal space or during adulthood. In this case report, we describe the clinical presentation, operative and post-operative course of a 31-year old with a retroperitoneal dermoid cyst. The patient presented with buttock and leg pain/paresthesia found to have a retroperitoneal mass between the psoas muscle and L5/S1 disk space. We describe the operative approach, including intra-operative images, of the resection by a team of urologists and neurosurgeons. The histology is also presented. Finally, we discuss the benefits of use of intra-operative ultrasound and neuromonitoring.

Safety of macitentan for the treatment of pulmonary hypertension: Real-world experience from the OPsumit® USers Registry (OPUS) and OPsumit® Historical USers cohort (OrPHeUS).

Macitentan is an oral endothelin receptor antagonist for the management of pulmonary arterial hypertension (PAH). The OPsumit® USers Registry (OPUS) and the OPsumit® Historical USers cohort (OrPHeUS) medical chart review provide real-world data for patients newly initiating macitentan. This study aims to describe the characteristics, safety profile, and clinical outcomes of PAH patients newly treated with macitentan in the combined OPUS/OrPHeUS data set. OPUS was a prospective, multicenter, long-term, observational drug registry from April 2014 to June 2020. OrPHeUS was a retrospective, US, multicenter chart review: observation period October 2013 to March 2017. All analyses were descriptive. At registry closure in June 2020, the combined population consisted of 5654 patients, of whom 81.9% were diagnosed with PAH. For these 4626 patients, median duration of macitentan exposure observed was 14.5 (Q1 = 5.2, Q3 = 29.0) months; idiopathic PAH (54.8%) was the most common form of PAH; macitentan was initiated as monotherapy (37.9%), or as part of double (48.0%) or triple therapy (14.1%); discontinuation due to nonhepatic/hepatic adverse events occurred in 17.1%/0.3% of patients; 9.9% of patients experienced ≥1 hepatic adverse events; Kaplan-Meier estimates showed that at 1 year 59.9% (95% confidence interval: 58.3, 61.5) of patients were free from hospitalization and survival was 90.4% (89.3, 91.3). This analysis of real-world data from the combined OPUS and OrPHeUS populations demonstrated that macitentan is well tolerated in a large, diverse population of PAH patients, with overall and hepatic safety profiles consistent with previous macitentan clinical trials.

Molecular dynamics of fibric acids.

1H- and 13C-NMR chemical shifts were measured for four fibric acids (bezafibrate, clofibric acid, fenofibric acid, and gemfibrozil), which are lipid-lowering drugs. Correlation is found with DFT-computed chemical shifts from the conformational analysis. Equilibrium populations of optimized conformers at 298 K are very different when based on computed Gibbs energies rather than on potential energies. This is due to the significant entropic advantages of extended rather than bent conformational shapes. Abundant conformers with intramolecular hydrogen bonding via five-member rings are computed for three fibric acids, but not gemfibrozil, which lacks suitable connectivity of carboxyl and phenoxy groups. Trends in computed atom-positional deviations, molecular volumes, surface areas, and dipole moments among the fibric acids and their constituent conformations indicate that bezafibrate has the greatest hydrophilicity and fenofibric acid has the greatest flexibility. Theoretical and experimental comparison of chemical shifts of standards with sufficient overlap of fragments containing common atoms, groups, and connectivity may provide a reliable minimal set to benchmark and generate leads.

The Impact of Internal Medicine Clerkship Characteristics and NBME Subject Exams on USMLE Step 2 Clinical Knowledge Exam Performance.

BACKGROUND: Residency program directors will likely emphasize the United States Medical Licensing Exam (USMLE) Step 2 clinical knowledge (CK) exam more during residency application given the recent USMLE Step 1 transition to pass/fail scoring. We examined how internal medicine clerkship characteristics and NBME subject exam scores affect USMLE Step 2 CK performance. DESIGN: The authors used univariable and multivariable generalized estimating equations to determine associations between Step 2 CK performance and internal medicine clerkship characteristics and NBME subject exams. The sample had 21,280 examinees' first Step 2 CK scores for analysis. RESULTS: On multivariable analysis, Step 1 performance (standardized ß = 0.45, p < .001) and NBME medicine subject exam performance (standardized ß = 0.40, p < .001) accounted for approximately 60% of the variance in Step 2 CK performance. Students who completed the internal medicine clerkship last in the academic year scored lower on Step 2 CK (Mdiff = -3.17 p < .001). Students who had a criterion score for passing the NBME medicine subject exam scored higher on Step 2 CK (Mdiff = 1.10, p = .03). There was no association between Step 2 CK performance and other internal medicine clerkship characteristics (all p > 0.05) nor with the total NBME subject exams completed (ß=0.05, p = .78). CONCLUSION: Despite similarities between NBME subject exams and Step 2 CK, the authors did not identify improved Step 2 CK performance for students who had more NBME subject exams. The lack of association of Step 2 CK performance with many internal medicine clerkship characteristics and more NBME subject exams has implications for future clerkship structure and summative assessment. The improved Step 2 CK performance in students that completed their internal medicine clerkship earlier warrants further study given the anticipated increase in emphasis on Step 2 CK.

The Validity of MCAT Scores in Predicting Students' Performance and Progress in Medical School: Results From a Multisite Study.

PURPOSE: This is the first multisite investigation of the validity of scores from the current version of the Medical College Admission Test (MCAT) in clerkship and licensure contexts. It examined the predictive validity of MCAT scores and undergraduate grade point averages (UGPAs) for performance in preclerkship and clerkship courses and on the United States Medical Licensing Examination Step 1 and Step 2 Clinical Knowledge examinations. It also studied students' progress in medical school. METHOD: Researchers examined data from 17 U.S. and Canadian MD-granting medical schools for 2016 and 2017 entrants who volunteered for the research and applied with scores from the current MCAT exam. They also examined data for all U.S. medical schools for 2016 and 2017 entrants to regular-MD programs who applied with scores from the current exam. Researchers conducted linear and logistic regression analyses to determine whether MCAT total scores added value beyond UGPAs in predicting medical students' performance and progress. Importantly, they examined the comparability of prediction by sex, race and ethnicity, and socioeconomic status. RESULTS: Researchers reported medium to large correlations between MCAT total scores and medical student outcomes. Correlations between total UGPAs and medical student outcomes were similar but slightly lower. When MCAT scores and UGPAs were used together, they predicted student performance and progress better than either alone. Despite differences in average MCAT scores and UGPAs between students who self-identified as White or Asian and those from underrepresented racial and ethnic groups, predictive validity results were comparable. The same was true for students from different socioeconomic backgrounds, and for males and females. CONCLUSIONS: These data demonstrate that MCAT scores add value to the prediction of medical student performance and progress and that applicants from different backgrounds who enter medical school with similar ranges of MCAT scores and UGPAs perform similarly in the curriculum.

3D Pyramid Pooling Network for Abdominal MRI Series Classification.

Recognizing and organizing different series in an MRI examination is important both for clinical review and research, but it is poorly addressed by the current generation of picture archiving and communication systems (PACSs) and post-processing workstations. In this paper, we study the problem of using deep convolutional neural networks for automatic classification of abdominal MRI series to one of many series types. Our contributions are three-fold. First, we created a large abdominal MRI dataset containing 3717 MRI series including 188,665 individual images, derived from liver examinations. 30 different series types are represented in this dataset. The dataset was annotated by consensus readings from two radiologists. Both the MRIs and the annotations were made publicly available. Second, we proposed a 3D pyramid pooling network, which can elegantly handle abdominal MRI series with varied sizes of each dimension, and achieved state-of-the-art classification performance. Third, we performed the first ever comparison between the algorithm and the radiologists on an additional dataset and had several meaningful findings.

Residency match interview scheduling: quantifying the applicant experience.

BACKGROUND: The process of offering and scheduling residency interviews varies widely among programmes. Applicants report distress and have advocated for reform. However, there is a paucity of quantitative data to characterise applicant concerns. OBJECTIVE: We quantified the interview scheduling experience for US allopathic medical students in the 2020 main residency match. METHODS: An anonymous, 13 question survey was sent to student representatives from each Association of American Medical Colleges member institution. Recipients were asked to forward the survey to their entire fourth-year class. RESULTS: Of 4314 applicants to whom the survey was sent, 786 (18.2%) responded. Overall, 20.4% reported missing the opportunity to interview at a programme because they did not have adequate time to respond to an invitation; applicants into surgical specialties were significantly more likely than their non-surgical peers to report this experience (26.4% vs 18.4%, p<0.05). Most (57.4%) respondents scheduled an interview knowing they would likely cancel it in the future. The most commonly cited reason for this behaviour was concern that applicants would not receive invitations from other programmes (85.6%). A majority (56.4%) of respondents did not believe the match interview process functions based on equity and merit. CONCLUSIONS: About one in five respondents missed the opportunity to interview at a programme because they did not respond to an invitation in time. Most respondents scheduled interviews knowing that they were likely to cancel them in the future. Standardisation of the interview invitation timeline would address these concerns.

Is LGBT progress seen as an attack on Christians?: Examining Christian/sexual orientation zero-sum beliefs.

As social policies have changed to grant more rights to lesbian, gay, bisexual, and transgender (LGBT) individuals, some Christians in the United States have suggested that LGBT rights impede Christians' religious freedom. Across five studies, we examined the causes and consequences of zero-sum beliefs (ZSBs) about Christians and LGBT individuals. We demonstrate that Christians' beliefs about conflict with sexual minorities are shaped by their understandings of Christian values, social change, interpretation of the Bible, and in response to religious institutions. In Study 1, heterosexual cisgender Christians endorsed ZSBs more than other groups. Christians reported perceiving that anti-LGBT bias has decreased over time while anti-Christian bias has correspondingly increased. In Study 2, Christians' zero-sum beliefs increased after they reflected on religious values, suggesting that intergroup conflict is seen as being a function of Christian beliefs. Study 3 confirmed the role of symbolic threat in driving ZSBs; perceived conflict was accentuated when Christians read about a changing cultural climate in which Christians' influence is waning. An intervention using Biblical scripture to encourage acceptance successfully lowered zero-sum beliefs for mainline but not fundamentalist Christians (Study 4). A final field study examined how ZSBs predict sexual prejudice in response to changing group norms. After a special conference in which the United Methodist Church voted to restrict LGBT people from marriage and serving as clergy, zero-sum beliefs became a stronger predictor of sexual prejudice (Study 5). We discuss the implications of Christian/LGBT ZSBs for religious freedom legislation, attitudes toward sexual minorities, and intergroup conflict more generally. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Computational design of a synthetic PD-1 agonist.

Programmed cell death protein-1 (PD-1) expressed on activated T cells inhibits T cell function and proliferation to prevent an excessive immune response, and disease can result if this delicate balance is shifted in either direction. Tumor cells often take advantage of this pathway by overexpressing the PD-1 ligand PD-L1 to evade destruction by the immune system. Alternatively, if there is a decrease in function of the PD-1 pathway, unchecked activation of the immune system and autoimmunity can result. Using a combination of computation and experiment, we designed a hyperstable 40-residue miniprotein, PD-MP1, that specifically binds murine and human PD-1 at the PD-L1 interface with a Kd of ∼100 nM. The apo crystal structure shows that the binder folds as designed with a backbone RMSD of 1.3 Što the design model. Trimerization of PD-MP1 resulted in a PD-1 agonist that strongly inhibits murine T cell activation. This small, hyperstable PD-1 binding protein was computationally designed with an all-beta interface, and the trimeric agonist could contribute to treatments for autoimmune and inflammatory diseases.

Infective endocarditis initially manifesting as pseudogout.

Infective endocarditis is a commonly encountered disease in which diagnosis is often challenging due to the variety of clinical manifestations. Early identification is key due to risk of mortality without treatment. In this case, a 31-year-old man presented with pseudogout of the right ankle and COVID-19 infection. Further workup showed blood cultures growing Staphylococcus aureus, and the diagnosis of infective endocarditis was confirmed by echocardiography. Independently, pseudogout and infective endocarditis result in activation of the innate immune system and can manifest with joint inflammation. Their co-occurrence likely resulted in an augmented inflammatory response due to overlap in their pathophysiologic pathways.

Phosphorylated WNK kinase networks in recoded bacteria recapitulate physiological function.

Advances in genetic code expansion have enabled the production of proteins containing site-specific, authentic post-translational modifications. Here, we use a recoded bacterial strain with an expanded genetic code to encode phosphoserine into a human kinase protein. We directly encode phosphoserine into WNK1 (with-no-lysine [K] 1) or WNK4 kinases at multiple, distinct sites, which produced activated, phosphorylated WNK that phosphorylated and activated SPAK/OSR kinases, thereby synthetically activating this human kinase network in recoded bacteria. We used this approach to identify biochemical properties of WNK kinases, a motif for SPAK substrates, and small-molecule kinase inhibitors for phosphorylated SPAK. We show that the kinase inhibitors modulate SPAK substrates in cells, alter cell volume, and reduce migration of glioblastoma cells. Our work establishes a protein-engineering platform technology that demonstrates that synthetically active WNK kinase networks can accurately model cellular systems and can be used more broadly to target networks of phosphorylated proteins for research and discovery.