Redefining the molecular rejection states in 3230 heart transplant biopsies: Relationships to parenchymal injury and graft survival.

The first-generation Molecular Microscope (MMDx) system for heart transplant endomyocardial biopsies used expression of rejection-associated transcripts (RATs) to diagnose not only T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) but also acute injury. However, the ideal system should detect rejection without being influenced by injury, to permit analysis of the relationship between rejection and parenchymal injury. To achieve this, we developed a new rejection classification in an expanded cohort of 3230 biopsies: 1641 from INTERHEART (ClinicalTrials.gov NCT02670408), plus 1589 service biopsies added to improve the power of the machine learning algorithms. The new system used 6 rejection classifiers instead of RATs and generated 7 rejection archetypes: No rejection, 48%; Minor, 24%; TCMR1, 2.3%; TCMR2, 2.7%; TCMR/mixed, 2.7%; early-stage ABMR, 3.9%; and fully developed ABMR, 16%. Using rejection classifiers eliminated cross-reactions with acute injury, permitting separate assessment of rejection and injury. TCMR was associated with severe-recent injury and late atrophy-fibrosis and rarely had normal parenchyma. ABMR was better tolerated, seldom producing severe injury, but in later biopsies was often associated with atrophy-fibrosis, indicating long-term risk. Graft survival and left ventricular ejection fraction were reduced not only in hearts with TCMR but also in hearts with severe-recent injury and atrophy-fibrosis, even without rejection.

How Are We Teaching Advocacy? A National Survey of Internal Medicine Residency Program Directors.

BACKGROUND: Although internal medicine (IM) physicians accept public advocacy as a professional responsibility, there is little evidence that IM training programs teach advocacy skills. The prevalence and characteristics of public advocacy curricula in US IM residency programs are unknown. OBJECTIVES: To describe the prevalence and characteristics of curricula in US IM residencies addressing public advocacy for communities and populations; to describe barriers to the provision of such curricula. DESIGN: Nationally representative, web-based, cross-sectional survey of IM residency program directors with membership in an academic professional association. PARTICIPANTS: A total of 276 IM residency program directors (61%) responded between August and December 2022. MAIN MEASUREMENTS: Percentage of US IM residency programs that teach advocacy curricula; characteristics of advocacy curricula; perceptions of barriers to teaching advocacy. KEY RESULTS: More than half of respondents reported that their programs offer no advocacy curricula (148/276, 53.6%). Ninety-five programs (95/276, 34.4%) reported required advocacy curricula; 33 programs (33/276, 12%) provided curricula as elective only. The content, structure, and teaching methods of advocacy curricula in IM programs were heterogeneous; experiential learning in required curricula was low (23/95, 24.2%) compared to that in elective curricula (51/65, 78.5%). The most highly reported barriers to implementing or improving upon advocacy curricula (multiple responses allowed) were lack of faculty expertise in advocacy (200/276, 72%), inadequate faculty time (190/276, 69%), and limited curricular flexibility (148/276, 54%). CONCLUSION: Over half of US IM residency programs offer no formal training in public advocacy skills and many reported lack of faculty expertise in public advocacy as a barrier. These findings suggest many IM residents are not taught how to advocate for communities and populations. Further, less than one-quarter of required curricula in public advocacy involves experiential learning.

Assessment of immunosuppression induction with basiliximab compared to antithymocyte-globulin in adult heart transplant patients.

BACKGROUND: Patients undergoing heart transplants are at risk of rejection which can have significant morbidity and mortality. Induction immunosuppression at the time of transplant reduces the early risk and has additional benefits. The induction agent of choice within our program was changed from rabbit antithymocyte-globulin (rATG) to basiliximab, so it was necessary to evaluate whether this had any impact on patient outcomes. OBJECTIVES: Our primary objective was to describe rejection, infection, and other outcomes in adult heart transplant patients at the University of Alberta Hospital in Edmonton, Canada. METHODS: This study was a nonrandomized, retrospective cohort study. RESULTS: Sixty-three patients were included with median ages 50 years versus 54 years. More female patients received rATG (20% vs. 42.4%). The most common indication for transplant in both cohorts was ICM (63.3% vs. 57.6%). Patients who received rATG had significantly higher PRA (0% vs. 43%, p < .001). Acute rejection episodes were similar between basiliximab and rATG at 3 months (16.7% vs. 15.1%; p = 1.0) and 6-months (30.0% vs. 18.1%; p = .376). Infections were not statistically different with basiliximab compared to rATG at 3-months, 43.3% vs. 63.6% and at 6-months 60.0% vs. 66.7%). There were no fatalities in either group. CONCLUSIONS: Our study did not demonstrate differences in rejection with basiliximab compared to rATG. Mortality did not differ, but basiliximab-treated patients had fewer infections and infection-related hospitalizations than those treated with rATG. Larger studies with longer durations are needed to more completely describe the differences in rejection and infectious outcomes.

Lack of Association Between Donor-Derived Cell-Free DNA and Cardiac Allograft Vasculopathy.

Cardiac allograft vasculopathy (CAV) is a leading cause of death after heart transplantation (HT). We evaluated donor-derived cell-free DNA (dd-cfDNA) as a noninvasive biomarker of CAV development after HT. The INSPIRE registry at the Intermountain Medical Center was queried for stored plasma samples from HT patients with and without CAV. At Stanford University, HT patients with CAV (cases) and without CAV (controls) were enrolled prospectively, and blood samples were collected. All the samples were analyzed for dd-cfDNA using the AlloSure assay (CareDx, Inc.). CAV was defined per the ISHLT 2010 standardized classification system. Univariate associations between patient demographics and clinical characteristics and their CAV grade were tested using chi-square and Wilcoxon rank sum tests. Associations between their dd-cfDNA levels and CAV grades were examined using a nonparametric Kruskal-Wallis test. A total of 69 pts were included, and 101 samples were analyzed for dd-cfDNA. The mean age at sample collection was 58.6 ± 13.7 years; 66.7% of the patients were male, and 81% were White. CAV 0, 1, 2, and 3 were present in 37.6%, 22.8%, 22.8%, and 16.8% of included samples, respectively. The median dd-cfDNA level was 0.13% (0.06, 0.33). The median dd-cfDNA level was not significantly different between CAV (-) and CAV (+): 0.09% (0.05%-0.32%) and 0.15% (0.07%-0.33%), respectively, p = 0.25 and with similar results across all CAV grades. In our study, dd-cfDNA levels did not correlate with the presence of CAV and did not differ across CAV grades. As such, dd-cfDNA does not appear to be a reliable noninvasive biomarker for CAV surveillance.

Safety and Effectiveness of Track Cauterization for Lung Cryoablation.

PURPOSE: To evaluate the safety and effectiveness of track cauterization for lung cryoablation through comparison of postprocedural adverse event (AE) rates. MATERIALS AND METHODS: Fifty-nine patients who underwent 164 percutaneous lung cryoablation procedures between 2013 and 2018 were included in this retrospective study. The study cohort was subdivided by whether track cauterization was conducted or not at the end of the procedure. The study cohort was also subdivided by the number of probes (1-2 probes vs 3-4 probes). Postablation AE rates were assessed by immediate and delayed (at 1 month or later) AEs, pneumothorax, hemothorax, pleural effusion, and whether intervention was required. Univariate and multivariate logistic regression analyses were used to compare differences in AE rates. RESULTS: Patients who underwent procedures with track cautery were 2.6 times less likely to exhibit pleural effusion (P = .017). Patients who underwent procedures conducted with a higher number of probes were 3.8 times more likely to receive interventions (P < .001), 1.6 times more likely to experience pneumothorax (P = .037), and 2.1 times more likely to experience pleural effusion (P = .003). History of lung surgery, increased number of probes, size of the probe, and absence of track cautery were noted to be significant predictors of AEs and need for interventions (all P < .05). CONCLUSIONS: Track cauterization in lung cryoablation was proven to reduce pleural effusion, but no difference in pneumothorax or delayed AEs was noted. The use of fewer probes was associated with a lower rate of AEs.

Patient-Specific Prediction of Immediate Phase Lung Microwave Ablation Zone Size.

PURPOSE: To investigate the effect of patient and tumor-specific characteristics on the size of immediate phase lung microwave ablation (MWA) zone and establish a prediction model. METHODS AND MATERIALS: This IRB-approved, HIPAA compliant cohort included 164 lesions from 99 patients who underwent CT-guided lung MWA and the two-dimensional elliptical ground-glass opacity ablation zone was measured. Duration, maximum temperature, tumor depth, presence of emphysema, history of ipsilateral lung ablation, surgery, and radiation were recorded. K-fold cross validation with k=5 and Least Absolute Shrinkage and Selection Operator were used to build prediction models for the major and minor axes, and area of the ablation zone. RESULTS: The median of immediate phase ablation duration was 2 minutes (IQR: 1.5 - 4.25) with 65W of power for all ablations. The mean major, minor axes, and area of ablation zone were 3.1±0.6cm, 2.0±0.5cm, and 5.1±2.1cm2. The major axis, minor axis, and area of immediate phase ablation zone dimensions were significantly associated with duration (p<0.001, p<0.001, p<0.001), maximum temperature (p<0.001, p<0.001, p<0.001), tumor depth (p=0.387, p<0.001, p<0.001), history of ipsilateral lung ablation (p=0.008, p=0.286, p=0.076), and lung radiation (p=0.001, p=0.042, p=0.015). The prediction model showed R2 values for major and minor axes and area of the ablation zone to be 0.50, 0.45, and 0.53, respectively. CONCLUSION: Duration, maximum temperature, tumor depth, history of ipsilateral lung ablation, surgery, and radiation were significantly associated with the ablation zone dimensions and size and can be used to build the prediction model to approximate the immediate phase lung MWA zone.

Technical Feasibility and Safety of Image-Guided Biphasic Monopolar Pulsed Electric Field Ablation of Metastatic and Primary Malignancies.

PURPOSE: To assess the technical feasibility and safety of image-guided percutaneous biphasic monopolar pulsed electric field (PEF) ablation of primary and metastatic tumors. METHODS AND METHODS: With IRB approval and HIPAA compliance, this retrospective, single-institution study cohort of 17 patients (mean age: 53.5 years, range: 20 - 94 years) with overall progressive disease underwent 26 PEF ablation procedures for 30 metastatic (90%) and primary (10%) target lesions in the thorax (n=20), abdomen (n=7), and head and neck (n=3). Concurrent systemic therapy was used in 14/17 patients (82%). Follow-up imaging was scheduled for 1, 3, and 6 months after PEF ablation, and target and off-target lesion sizes were recorded. The overall response was assessed by the RECIST 1.1 criteria with imaging immediately before PEF serving as baseline. Adverse events (AEs) were determined by the Society of Interventional Radiology classification. RESULTS: PEF ablation procedures were well tolerated and technically feasible for all 17 of 17 patients. The mean initial size of the target and off-target tumors were 2.6±1.5 cm (range: 0.4 - 6.9cm) and 2.2±1.1 cm (range: 1.0 - 5.2cm), respectively. Overall, 15/30 (50%) target lesions and 12/24 (50%) off-target lesions were unchanged or decreased in size at the patient's last follow-up. Eight patients had overall stable disease (47%) at the last follow-up. There were nine mild (9/26, 35%) and one moderate (1/26, 4%) AE. CONCLUSION: All PEF procedures were technically feasible with one moderate AE and stable disease for 47% of patients with a median follow-up period of three months.

SCMR expert consensus statement for cardiovascular magnetic resonance of patients with a cardiac implantable electronic device.

Cardiovascular magnetic resonance (CMR) is a proven imaging modality for informing diagnosis and prognosis, guiding therapeutic decisions, and risk stratifying surgical intervention. Patients with a cardiac implantable electronic device (CIED) would be expected to derive particular benefit from CMR given high prevalence of cardiomyopathy and arrhythmia. While several guidelines have been published over the last 16 years, it is important to recognize that both the CIED and CMR technologies, as well as our knowledge in MR safety, have evolved rapidly during that period. Given increasing utilization of CIED over the past decades, there is an unmet need to establish a consensus statement that integrates latest evidence concerning MR safety and CIED and CMR technologies. While experienced centers currently perform CMR in CIED patients, broad availability of CMR in this population is lacking, partially due to limited availability of resources for programming devices and appropriate monitoring, but also related to knowledge gaps regarding the risk-benefit ratio of CMR in this growing population. To address the knowledge gaps, this SCMR Expert Consensus Statement integrates consensus guidelines, primary data, and opinions from experts across disparate fields towards the shared goal of informing evidenced-based decision-making regarding the risk-benefit ratio of CMR for patients with CIEDs.

Defining blood hematology reference values in female pig-tailed macaques (Macaca nemestrina) using the Isolation Forest algorithm.

BACKGROUND: Pig-tailed macaques (PTMs) are commonly used as preclinical models to assess antiretroviral drugs for HIV prevention research. Drug toxicities and disease pathologies are often preceded by changes in blood hematology. To better assess the safety profile of pharmaceuticals, we defined normal ranges of hematological values in PTMs using an Isolation Forest (iForest) algorithm. METHODS: Eighteen female PTMs were evaluated. Blood was collected 1-24 times per animal for a total of 159 samples. Complete blood counts were performed, and iForest was used to analyze the hematology data to detect outliers. RESULTS: Median, IQR, and ranges were calculated for 13 hematology parameters. From all samples, 22 outliers were detected. These outliers were excluded from the reference index. CONCLUSIONS: Using iForest, we defined a normal range for hematology parameters in female PTMs. This reference index can be a valuable tool for future studies evaluating drug toxicities in PTMs.

Biomarkers of Airway Disease, Barrett's and Underdiagnosed Reflux Noninvasively (BAD-BURN) in World Trade Center exposed firefighters: a case-control observational study protocol.

BACKGROUND: Particulate matter exposure (PM) is a cause of aerodigestive disease globally. The destruction of the World Trade Center (WTC) exposed first responders and inhabitants of New York City to WTC-PM and caused obstructive airways disease (OAD), gastroesophageal reflux disease (GERD) and Barrett's Esophagus (BE). GERD not only diminishes health-related quality of life but also gives rise to complications that extend beyond the scope of BE. GERD can incite or exacerbate allergies, sinusitis, bronchitis, and asthma. Disease features of the aerodigestive axis can overlap, often necessitating more invasive diagnostic testing and treatment modalities. This presents a need to develop novel non-invasive biomarkers of GERD, BE, airway hyperreactivity (AHR), treatment efficacy, and severity of symptoms. METHODS: Our observational case-cohort study will leverage the longitudinally phenotyped Fire Department of New York (FDNY)-WTC exposed cohort to identify Biomarkers of Airway Disease, Barrett's and Underdiagnosed Reflux Noninvasively (BAD-BURN). Our study population consists of n = 4,192 individuals from which we have randomly selected a sub-cohort control group (n = 837). We will then recruit subgroups of i. AHR only ii. GERD only iii. BE iv. GERD/BE and AHR overlap or v. No GERD or AHR, from the sub-cohort control group. We will then phenotype and examine non-invasive biomarkers of these subgroups to identify under-diagnosis and/or treatment efficacy. The findings may further contribute to the development of future biologically plausible therapies, ultimately enhance patient care and quality of life. DISCUSSION: Although many studies have suggested interdependence between airway and digestive diseases, the causative factors and specific mechanisms remain unclear. The detection of the disease is further complicated by the invasiveness of conventional GERD diagnosis procedures and the limited availability of disease-specific biomarkers. The management of reflux is important, as it directly increases risk of cancer and negatively impacts quality of life. Therefore, it is vital to develop novel noninvasive disease markers that can effectively phenotype, facilitate early diagnosis of premalignant disease and identify potential therapeutic targets to improve patient care. TRIAL REGISTRATION: Name of Primary Registry: "Biomarkers of Airway Disease, Barrett's and Underdiagnosed Reflux Noninvasively (BADBURN)". Trial Identifying Number: NCT05216133 . Date of Registration: January 31, 2022.

The impact of the titanium cranial hardware in proton single-field uniform dose plans.

BACKGROUND: Neurosurgical cranial titanium mesh and screws are commonly encountered in postoperative radiation therapy. However, only a limited number of reports are available in the context of proton therapy, resulting in a lack of consensus among the proton centers regarding the protocol for handling the hardware. PURPOSE: This study is to examine the impact of the hardware in proton plans. The results serve as evidence for proton centers to generate standard operating procedures to manage the hardware in proton treatment. METHODS: Plans with different gantry angles and material overrides are generated on the CT images of a phantom made of the hardware. The dose distributions of the plans with and without material override, at different depths are compared. Films and ionization chambers are used to measure the plans and the measurements are compared to the treatment planning system (TPS) calculations by gamma analysis. RESULTS: There are some overdose and underdose regions downstream of the hardware. The overdose and underdose values are within a few percent of the prescribed dose when multiple fields with large hinge angles are used. The gamma analysis results show that the measurements agree with the TPS calculations within limits that are clinically relevant. CONCLUSION: The study has demonstrated the influence of the hardware on proton plans. Based on the result of this study, a standard operating procedure of managing the hardware has been implemented in our clinic.

Fetal dose assessment in a pregnant patient with brain tumor: A comparative study of proton PBS and 3DCRT/VMAT radiation therapy techniques.

PURPOSE: The treatment of brain tumors in pregnant patients poses challenges, as the out-of-field dose exposure to the fetus can potentially be harmful. A pregnant patient with prior radiation treatment was presented with a brain tumor at our clinic. This work reports on our pre-treatment study that compared fetal dose exposure between intensity-modulated proton therapy (IMPT) using pencil beam scanning (PBS) and conventional photon 3D conformal radiation therapy (3DCRT) and volumetric-modulated arc therapy (VMAT), and the subsequent pregnant patient's radiation treatment. MATERIALS AND METHODS: Pre-treatment measurements of clinical plans, 3DCRT, VMAT, and IMPT, were conducted on a phantom. Measurements were performed using a device capable of neutron detections, closely following AAPM guidelines, TG158. For photon measurements, fetus shielding was utilized. On patient treatment days, which was determined to be proton treatment, shielding was used only during daily imaging for patient setup. Additionally, an in vivo measurement was conducted on the patient. RESULTS: Measurements showed that IMPT delivered the lowest fetal dose, considering both photon and neutron out-of-field doses to the fetus, even when shielding was implemented for photon measurements. Additionally, the proton plans demonstrated superior treatment for the mother, a reirradiation case. CONCLUSION: The patient was treated with proton therapy, and the baby was subsequently delivered at full term with no complications. This case study supports previous clinical findings and advocates for the expanded use of proton therapy in this patient population.

Use of point-of-care ultrasound in rural British Columbia: Scale, training, and barriers.

OBJECTIVE: To determine the scale and scope of use of point-of-care ultrasound (POCUS) in rural British Columbia (BC). DESIGN: Online survey. SETTING: Rural BC. PARTICIPANTS: Physicians practising in rural BC communities. MAIN OUTCOME MEASURES: Practitioner demographic and practice characteristics, locations and frequency of POCUS use, POCUS education and training, and practitioner attitudes about and barriers to POCUS use. RESULTS: Two hundred twenty-seven surveys were completed in fall 2021, corresponding to a response rate of 11.9% of all rural practitioners in BC. A total of 52.1% of respondents worked in communities with less than 10,000 people, while 24.9% had practices with relatively large proportions of Indigenous patients (more than 20% of the practice population). Respondents reported ease of access to local POCUS devices, with use highest in emergency departments (87.2%) followed by ambulatory care clinic (54.7%) and inpatient (50.3%) settings. Use of POCUS influenced clinical decision making in half the occasions in which it was employed, including a range of diagnostic and procedural applications. Barriers to use included lack of training, limited time to perform POCUS scans, and absence of image review or consultative support. Needed support for POCUS identified by respondents included real-time image acquisition advice and funding for both device acquisition and training. Recommendations for including POCUS training in undergraduate and residency education were strongly supported. CONCLUSION: Use of POCUS in BC is expanding in frequency, scope, and scale in practices serving rural areas and in rural communities with large Indigenous populations, with practitioners reporting important improvements in clinical care as a result. Future research could help improve systemic support for POCUS use, guide needed curriculum changes in medical school and postgraduate training, and be used to inform continuing professional development needs.

Photoinduced Group Transposition via Iridium-Nitrenoid Leading to Amidative Inner-Sphere Aryl Migration.

We herein report a fundamental mechanistic investigation into photochemical metal-nitrenoid generation and inner-sphere transposition reactivity using organometallic photoprecursors. By designing Cp*Ir(hydroxamate)(Ar) complexes, we induced photo-initiated ligand activation, allowing us to explore the amidative σ(Ir-aryl) migration reactivity. A combination of experimental mechanistic studies, femtosecond transient absorption spectroscopy, and density functional theory (DFT) calculations revealed that the metal-to-ligand charge transfer enables the σ(N-O) cleavage, followed by Ir-acylnitrenoid generation. The final inner-sphere σ(Ir-aryl) group migration results in a net amidative group transposition.

The benefits of reflecting on gratitude received at home for leaders at work: Insights from three field experiments.

Expressions of gratitude by leaders tend to yield positive effects in the workplace. Leaders, however, are not solely bestowers of gratitude but also recipients of it. Although leaders are often studied for their influence on others in the workplace, it is crucial to acknowledge that they are also complete individuals with personal lives outside of work that can spill over and affect their feelings and leadership behaviors at work. To advance research on leadership and gratitude, we take a whole-person view of leaders to understand the interpersonal crossover and intrapersonal spillover of gratitude. By integrating the moral affect theory of gratitude and savoring interventions research, we investigate how an intervention involving reflecting on gratitude received from family members at home motivates leaders to be more helpful and empowering toward their followers at work. We studied these ideas across three daily field experiments with 103 full-time managers from high schools, 116 leader-follower dyads from a variety of industries, and 109 leaders across various industries. Our findings demonstrate that when leaders reflected on receiving gratitude from family members at home, they felt higher prosocial impact at home, which in turn fulfilled their basic daily needs, consequently motivating them to engage in more helping and empowering behavior toward their followers at work. We also found some evidence that leaders higher in trait negative affect benefited the least from reflecting on receiving gratitude at home. We discuss how our findings provide extensions to literatures on gratitude, leadership, and work-family issues. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Corrigendum: Electrically-evoked responses for retinal prostheses are differentially altered depending on ganglion cell types in outer retinal neurodegeneration caused by Crb1 gene mutation.

[This corrects the article DOI: 10.3389/fncel.2023.1115703.].

A Rare Case of Giant Bilateral Adrenal Myelolipomas in a Patient With Classical Congenital Hyperplasia.

Congenital adrenal hyperplasia (CAH) is caused by genetic defects in the enzymes involved in cortisol biosynthesis in the adrenal gland and, in more than 90% of cases, due to a deficiency in the 21-hydroxylase enzyme. Classical CAH due to 21-hydroxylase deficiency is a severe form of the disease that presents with cortisol deficiency and is further categorized into salt-wasting or simple-virilizing types. Appropriate steroid replacement has been shown to effectively treat patients with classical CAH and prevent complications. Individuals who receive inadequate treatment or fail to comply with their prescribed steroid hormone regimen are susceptible to the development of adrenal myelolipomas. Myelolipomas are benign tumors composed of both adipose and hematopoietic tissues. While documented cases of adrenal myelolipomas exist in medical literature, instances of large bilateral myelolipomas remain exceedingly rare. This case report highlights a 40-year-old female patient with a known history of classical congenital adrenal hyperplasia who presented with unusually large bilateral adrenal myelolipomas. A diagnostic CT scan of the abdomen and pelvis revealed a 13.4 x 10.8 cm myelolipoma on the left adrenal gland and a 10 x 8.6 cm myelolipoma on the right adrenal gland. Prior to her presentation, the patient experienced recurrent nausea and vomiting, along with left upper quadrant pain, over five months. Hormonal assessments indicated significantly elevated serum androgen levels, suggesting inadequate management of her CAH. In this report, we present a rare case of symptomatic bilateral large adrenal myelolipomas, underscoring the significance of adhering to treatment regimens, diagnostic assessments, and management for adrenal myelolipomas in individuals diagnosed with CAH.

Corrigendum: Localization of hyperpolarization-activated cyclic nucleotide-gated channels in the vertebrate retinas across species and their physiological roles.

[This corrects the article DOI: 10.3389/fnana.2024.1385932.].