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Summary: In the melanocortin pathway, melanocortin-4 receptor (MC4R) functions to control energy homeostasis. MC4R is expressed in a sub-population of Sim1 neurons (Sim1/MC4R neurons) and functions in hypothalamic paraventricular nuclei (PVN) to control food intake. Mapping sites of hypothalamic injury in obesity is essential to counteract the disease. In the PVN of male and female mice with diet-induced obesity (DIO) there is neuronal loss. However, the existing subpopulation of PVN Sim1/MC4R neurons is unchanged, but has a loss of mitochondria and MC4R protein. In mice of both sexes with DIO, dietary intervention to re-establish normal weight restores abundance of MC4R protein in Sim1/MC4R neurons and neurogenesis in the PVN. However, the number of non-Sim1/MC4R neurons in the PVN continues to remain decreased. Selective survival and recovery of Sim1/MC4R neurons after DIO suggests these neurons as preferential target to restore energy homeostasis and of therapy against obesity.

This scoping review summarizes existing approaches, benefits, and barriers to shared decision-making (SDM) in the context of sports cardiology. Among 6,058 records screened, 37 articles were included in this review. Most included articles defined SDM as an open dialogue between the athlete, healthcare team, and other stakeholders. The benefits and risks of management strategies, treatment options, and return-to-play were the focus of this dialogue. Key components of SDM were described through various themes, such as emphasizing patient values, considering nonphysical factors, and informed consent. Benefits of SDM included enhancing patient understanding, implementing a personalized management plan, and considering a holistic approach to care. Barriers to SDM included pressure from institutions, consideration of multiple perspectives in decision-making, and the potential liability of healthcare providers. The use of SDM when discussing management, treatment, and lifestyle modification for athletes diagnosed with a cardiovascular condition is necessary to ensure patient autonomy and engagement., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy)., Methods: A total of 74 families with diverse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases., Results: Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with samples from ≥2 affected individuals or heterozygotes and 10 cases with ≥2 biospecimens. PCR amplicons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing., Conclusion: RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long amplicons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data., Competing Interests: Conflict of Interest Sandra T. Cooper is director of Frontier Genomics Pty Ltd (Australia). Sandra T. Cooper currently receives no consultancy fees or other remuneration for this role. Frontier Genomics Pty Ltd (Australia) has no existing financial relationships that will benefit from publication of these data. Samuel P. Strom is an employee and shareholder of Fulgent Genetics. Michael F. Buckley is an employee and shareholder of Invitae. The remaining coauthors declare no conflicts of interest., (Copyright © 2021. Published by Elsevier Inc.)

As our understanding of the complications of coronavirus disease-2019 (COVID-19) evolve, subclinical cardiac pathology such as myocarditis, pericarditis, and right ventricular dysfunction in the absence of significant clinical symptoms represents a concern. The potential implications of these findings in athletes are significant given the concern that exercise, during the acute phase of viral myocarditis, may exacerbate myocardial injury and precipitate malignant ventricular arrhythmias. Such concerns have led to the development and publication of expert consensus documents aimed at providing guidance for the evaluation of athletes after contracting COVID-19 in order to permit safe return to play. Cardiac imaging is at the center of these evaluations. This review seeks to evaluate the current evidence regarding COVID-19-associated cardiovascular disease and how multimodality imaging may be useful in the screening and clinical evaluation of athletes with suspected cardiovascular complications of infection. Guidance is provided with diagnostic "red flags" that raise the suspicion of pathology. Specific emphasis is placed on the unique challenges posed in distinguishing athletic cardiac remodeling from subclinical cardiac disease. The strengths and limitations of different imaging modalities are discussed and an approach to return to play decision making for athletes post-COVID-19, as informed by multimodality imaging, is provided., Competing Interests: Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: Cost-effectiveness evaluations of first-line genomic sequencing (GS) in the diagnosis of children with genetic conditions are limited by the lack of well-defined comparative cohorts. We sought to evaluate the cost-effectiveness of early GS in pediatric patients with complex monogenic conditions compared with a matched historical cohort., Methods: Data, including investigation costs, were collected in a prospective cohort of 92 pediatric patients undergoing singleton GS over an 18-month period (2016-2017) with two of the following: a condition with high mortality, multisystem disease involving three or more organs, or severe limitation of daily function. Comparative data were collected in a matched historical cohort who underwent traditional investigations in the years 2012-2013., Results: GS yielded a diagnosis in 42% while traditional investigations yielded a diagnosis in 23% (p = 0.003). A change in management was experienced by 74% of patients diagnosed following GS, compared with 32% diagnosed following traditional investigations. Singleton GS at a cost of AU$3100 resulted in a mean saving per person of AU$3602 (95% confidence interval [CI] AU$2520-4685). Cost savings occurred across all investigation subtypes and were only minimally offset by clinical management costs., Conclusion: GS in complex pediatric patients saves significant costs and doubles the diagnostic yield of traditional approaches.

Objectives: This study sought to investigate the regional uptake of technetium 99m-pyrophosphate (TcPYP) in transthyretin cardiac amyloidosis (ATTR) and its association with mortality., Background: TcPYP nuclear scintigraphy is a diagnostic and prognostic tool in ATTR. Echocardiography has identified a pattern of regional variation in longitudinal strain (LS) with a gradient of improved strain from base to apex in ATTR., Methods: Consecutive patients with ATTR were evaluated who underwent TcPYP nuclear scintigraphy with planar and attenuation corrected single-photon emission computed tomography (SPECT). Heart-to-contralateral lung (H/CL) ratio was calculated on planar images, and left ventricular (LV) uptake was determined in each of the 17 segments using SPECT. A measure of apical-sparing of myocardial TcPYP uptake, termed the apical-sparing ratio (ASR), was calculated as basal + mid / apical counts., Results: Overall, 54 patients with ATTR (age 78 ± 9 years, 76% male, 31% hereditary ATTR) were analyzed. There was increased TcPYP uptake in basal and mid relative to apical LV segments, and an apical-sparing LS pattern on echocardiography. The right ventricle similarly showed greater uptake in basal segments. There were 26 deaths over 1.8 years median follow-up. The ASR of TcPYP uptake was associated with age-adjusted all-cause mortality (p = 0.013) with worse prognosis seen at levels <2.75. Global LS was also prognostic (p = 0.01), whereas H/CL ratio and total LV uptake indexed to blood pool were not (p = 0.772 and p = 0.850, respectively). The prognostic utility of the ASR persisted in multivariable modeling (p = 0.003), whereas global LS did not., Conclusions: There is decreased TcPYP uptake in apical as compared to mid and basal segments in the LV, mimicking apical-sparing LS seen on echocardiography. Regional distribution of LV TcPYP uptake is associated with mortality, whereas overall amount of uptake as measured by H/CL ratio and indexed LV SPECT uptake is not., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Antibodies (Abs) to donor HLA (donor-specific antibodies [DSA]) have been associated with transplant glomerulopathy (TG) following kidney transplantation (KTx). Immune responses to tissue-restricted self-antigens (self-Ags) have been proposed to play a role in chronic rejection. We determined whether KTx with TG have immune responses to self-Ags, Collagen-IV (Col-IV) and fibronectin (FN). DSA were determined by solid phase assay, Abs against Col-IV and FN by enzyme-linked immunosorbent assay and CD4+ T cells secreting interferon gamma (IFN-γ), IL-17 or IL-10 by ELISPOT. Development of Abs to self-Ags following KTx increased the risk for TG with an odds ratio of 22 (p-value = 0.001). Abs to self-Ags were IgG and IgM isotypes. Pretransplant Abs to self-Ags increased the risk of TG (22% vs. 10%, p < 0.05). Abs to self-Ags were identified frequently in KTx with DSA. TG patients demonstrated increased Col-IV and FN specific CD4+ T cells secreting IFN-γ and IL-17 with reduction in IL-10. We conclude that development of Abs to self-Ags is a risk factor and having both DSA and Abs to self-Ags increases the risk for TG. The increased frequency of self-Ag-specific IFN-γ and IL-17 cells with reduction in IL-10 demonstrate tolerance breakdown to self-Ags which we propose play a role in the pathogenesis of TG., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: To compare the incidence of anterior capsular tears after femtosecond laser-assisted cataract surgery (FLACS) versus phacoemulsification cataract surgery (PCS) and to assess the ultrastructural features of anterior capsulotomy specimens (FLACS and PCS) using electron microscopy., Design: Prospective, multicenter, comparative cohort case series., Participants: Consecutive patients undergoing FLACS or PCS., Methods: A prospective cohort study of all patients (n = 1626) undergoing FLACS or PCS by 2 surgeons from centers A and B was undertaken to compare the incidence of anterior capsule tears. Anterior lens capsules were collected by 4 surgeons from centers A, B, C, and D using 3 different commercially available femtosecond platforms, each with latest version upgrades. Lens capsule tissue was prepared for scanning electron microscopy (SEM) using a total of 10 samples for patients undergoing PCS, and 40 samples for patients undergoing FLACS., Main Outcome Measures: Incidence of anterior capsule tear and comparative ultrastructural features of capsular samples from both PCS and FLACS cases., Results: There was a significantly increased rate of anterior capsule tears in the FLACS group (15/804 [1.87%]) when compared with the PCS group (1/822 [0.12%]; P = 0.0002, Fisher exact test). In 7 cases, the anterior capsule tear extended to the posterior capsule. Because all cases had occurred in complete capsulotomy, the integrity of the anterior capsule was questioned in the FLACS group. Subsequent SEM sampling showed irregularity at the capsule margin, as well as multiple apparently misplaced laser pits in normal parts of the tissue. Aberrant pits were approximately 2 to 4 μm apart and occurred at a range of 10 to 100 μm radially from the capsule edge., Conclusions: Laser anterior capsulotomy integrity seems to be compromised by postage-stamp perforations and additional aberrant pulses, possibly because of fixational eye movements. This can lead to an increased rate of anterior capsule tears, and extra care should be taken during surgery after femtosecond laser pretreatment has been performed. A learning curve may account for some of the increased complication rate with FLACS. However, the SEM features raise safety concerns for capsular integrity after FLACS and warrant further investigation., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Surgical stabilization of flail chest injury with generic osteosynthesis implants remains challenging. A novel implant system comprising anatomic rib plates and intramedullary splints may improve surgical stabilization of flail chest injuries. This observational study evaluated our early clinical experience with this novel implant system to document if it can simplify the surgical procedure while providing reliable stabilization., Methods: Twenty consecutive patients that underwent stabilization of flail chest injury with anatomic plates and intramedullary splints were prospectively enrolled at two Level I trauma centres. Data collection included patient demographics, injury characterization, surgical procedure details and post-operative recovery. Follow-up was performed at three and six months to assess pulmonary function, durability of implants and fixation and patient health., Results: Patients had an Injury Severity Score of 28±10, a chest Abbreviated Injury Score of 4.2±0.4 and 8.5±2.9 fractured ribs. Surgical stabilization was achieved on average with five plates and one splint. Intra-operative contouring was required in 14% of plates. Post-operative duration of ventilation was 6.4±8.6 days. Total hospitalization was 15±10 days. At three months, patients had regained 84% of their expected forced vital capacity (%FVC). At six months, 7 of 15 patients that completed follow-up had returned to work. There was no mortality. Among the 91 rib plates, 15 splints and 605 screws in this study there was no hardware failure and no loss of initial fixation. There was one incidence of wound infection. Implants were removed in one patient after fractures had healed., Conclusions: Anatomic plates eliminated the need for extensive intraoperative plate contouring. Intramedullary rib splints provided a less-invasive fixation alternative for single, non-comminuted fractures. These early clinical results indicate that the novel implant system provides reliable fixation and accommodates the wide range of fractures encountered in flail chest injury., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: The role of non-complement activating antibodies (ncAbs) to mismatched donor human leukocyte antigen (HLA) in the pathogenesis of chronic lung rejection is not known. We used a murine model of obliterative airway disease (OAD) induced by Abs to major histocompatibility major histocompatibility complex (MHC) class I and serum from donor-specific Abs developed in human lung transplant (LTx) recipients to test the role of ncAbs in the development of OAD and bronchiolitis obliterans syndrome (BOS)., Methods: Anti-MHC ncAbs were administered intrabronchially in B.10 mice or in C3 knockout (C3KO) mice. Lungs were analyzed by histopathology. Lymphocytes secreting interleukin (IL)-17, interferon-γ, or IL-10 to collagen V and K-α1 tubulin (Kα1T) were enumerated by enzyme-linked immunospot assay. Serum antibodies to collagen V and Kα1T were determined by enzyme-linked immunosorbent assay. Cytokine and growth factor expression in lungs was determined by real-time polymerase chain reaction. Donor-specific Abs from patients with BOS and control BOS-negative LTx recipients were analyzed by C1q assay., Results: Administration of ncAbs in B.10 mice or C3KO resulted in OAD lesions. There were significant increases in IL-17- and interferon-γ-secreting cells to collagen V and Kα1T, along with serum Abs to these antigens. There was also augmented expression of monocyte chemotactic protein-1, IL-6, IL-1β, vascular endothelial growth factor, transforming growth factor-β, and fibroblastic growth factor in mice administered ncAbs by Day 3. Among 5 LTx recipients with BOS, only 1 had C1q binding donor-specific Abs., Conclusion: Complement activation by Abs to MHC class I is not required for development of OAD and human BOS. Therefore, anti-MHC binding to epithelial and endothelial cells can directly activate pro-fibrotic and pro-inflammatory cascades leading to immune response to self-antigens and chronic rejection., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Decisions regarding surgery for mitral regurgitation (MR) are predicated on the accurate quantification of MR severity. Quantitative parameters, including vena contracta width, regurgitant volume and fraction, and effective regurgitant orifice area have prognostic significance and are recommended to be obtained from patients with more than mild MR. New tools for MR quantification have been provided by 3-dimensional echocardiography, cardiac magnetic resonance, and cardiac computed tomography, but limited guidance on appropriate image acquisition and post-processing techniques has hindered their clinical application and reproducibility. This review describes optimal image acquisition and post-processing methods for quantification of MR., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Bronchiolitis obliterans syndrome (BOS) is a major cause of morbidity and mortality after lung transplantation (LTx). We sought to better understand the relationship between alloimmune responses and autoimmunity and, subsequently, how autoimmunity leads to chronic rejection., Methods: We analyzed the development of donor-specific antibodies (Abs) in LTx by flow PRA and the development of Abs to K-α1 tubulin (K-α1T) and collagen V (ColV) by ELISA. The frequency of K-α1T- and ColV-specific T cells that secrete IFN-γ, IL-17 and IL-10 in LTx recipients was measured by ELISPOT., Results: In a retrospective analysis of 42 LTx recipients, we demonstrated a strong correlation between development of donor-specific anti-HLA Abs, Abs to self-antigens and BOS (p < 0.05). To test the hypothesis that alloimmunity is related to an immune response to self-antigens, we analyzed 103 LTx patients prospectively for the development of donor-specific Abs (DSA) and Abs to self-antigens. A total of 42.7% of recipients developed DSA and 30.1% developed Abs to K-α1T and ColV. Development of DSA preceded development of Abs to self-antigens. BOS(+) patients had higher frequency of T cells secreting IL-17 (p < 0.01) and IFN-γ (p < 0.05) with decreased IL-10 (p < 0.05) when compared with BOS(-) patients., Conclusions: Based on these results we propose that alloimmune responses to donor HLA can induce autoimmune responses to airway epithelial self-antigens, characterized by activation of the IL-17 pathway. These immune responses to self-antigens along with alloimmunity contribute to the pathogenesis of BOS. Strategies to prevent development of autoimmunity may be play a key role in preventing the development of chronic rejection., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Herein we study the role of donor-specific antibodies (DSA) to mismatched human leukocyte antigen (HLA) and antibodies (Abs) to the cardiac self-antigens myosin (MYO) and vimentin (VIM) in the pathogenesis of acute antibody-mediated rejection (AMR) in the early post-transplant period (EP, <12 months) and cardiac allograft vasculopathy (CAV) in the late post-transplant period (LP, >12 months) after heart transplantation (HTx)., Methods: One hundred forty-eight HTx recipients (65 in EP, 83 in LP) were enrolled in the study. Development of DSA was determined by Luminex. Circulating Abs against MYO and VIM in sera were measured using enzyme-linked immunoassay (ELISA). Frequency of CD4+ T-helper cells (CD4+ Th) secreting interferon (IFN)-γ, interleukin (IL)-17, IL-10 or IL-5 specific to either MYO or VIM were analyzed in vitro using ELISpot assays., Results: AMR patients were more likely DSA positive (AMR-: 15%; AMR+: 70%; p = 0.03) and demonstrated increased Abs to MYO (AMR-: 144 ± 115 μg/ml; AMR+: 285 ± 70 μg/ml; p = 0.033) and VIM (AMR-: 37 ± 19 μg/ml; AMR+: 103 ± 43 μg/ml; p = 0.014). AMR patients demonstrated increased IL-5 CD4+ Th cells specific to MYO (5.2 ± 0.9 fold, p = 0.003) and VIM (7.3 ± 2.9-fold, p = 0.004) and decreased IL-10 CD4+ Th cells specific to MYO (2.2 ± 0.4-fold, p = 0.009) and VIM (1.7 ± 0.2-fold, p = 0.03). CAV patients were more likely DSA positive (CAV-): 25%; CAV+: 79%; p = 0.03) and demonstrated increased Abs to MYO (CAV-: 191 ± 120 μg/ml; CAV+: 550 ± 98 μg/ml; p = 0.025) and VIM (CAV-: 55 ± 25 μg/ml; CAV+: 255 ± 49 μg/ml; p = 0.001). CAV patients demonstrated increased IL-17 CD4+ Th cells specific to MYO (10.5 ± 7.3-fold, p = 0.002) and VIM (7.0 ± 3.9-fold, p = 0.003)., Conclusions: The presence of DSA in AMR and CAV is significantly associated with development of Abs to MYO and VIM in post-HTx patients. Induction of high CD4+ Th cells specific to cardiac self-antigens that secrete predominantly IL-5 and IL-17 plays a significant role in the development of Abs to self-antigens leading to AMR and CAV, respectively., (Copyright © 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Immune responses to mismatched donor human leukocyte antigens (HLA) are important in the pathogenesis of chronic rejection. This study evaluated whether erythrocyte-bound C4d (E-C4d) is associated with known alloimmune and autoimmune markers of antibody-mediated rejection after human lung transplantation (LTx)., Methods: Flow cytometry was used to analyze 22 LTx recipients and 15 healthy individuals for E-C4d. Development of antibodies to donor-mismatched HLA (donor-specific antibody [DSA]) and antibodies to HLA were determined using the solid-phase method by Luminex. Development of antibodies to self-antigens, K-alpha-1-tubulin (KA1T) and collagen V (Col-V), were measured by enzyme-linked immunosorbent assay. C3d deposition in lung biopsy specimens was determined by immunohistochemical staining., Results: Percent E-C4d (%E-C4d) levels were 19.9% in LTx patients vs 3.7% in healthy individuals (p = 0.02). DSA+ patients had higher E-C4d levels than DSA- patients (34.1% vs 16.7%, p = 0.02). In 5 patients with preformed anti-HLA, E-C4d levels were not significantly different vs 13 patients without detectable anti-HLA (p = 0.1). E-C4d levels were higher in patients who developed antibodies to KA1T (p = 0.02) and Col-V (p = 0.03). Recipients with C3d-positive tissue deposition had higher E-C4d levels than patients with C3d-negative biopsy results (p = 0.01)., Conclusions: Increased %E-C4d levels are found in patients with positive DSA, high antibody titers to KA1T and Col-V, and have C3d+ lung biopsy findings. Therefore, %E-C4d can serve as a potential marker for antibody-mediated rejection after LTx.

Knowing the etiology of hearing loss in a person has implications for counseling and management of the condition. More than 50% of cases of early onset, nonsyndromic sensorineural hearing loss are attributable to genetic factors. However, deafness is a genetically heterogeneous condition and it is therefore currently not economically and practically feasible to screen for mutations in all known deafness genes. We have developed a microarray-based hybridization biochip assay for the detection of known mutations. The current version of the hearing loss biochip detects nine common mutations in the connexin 26 gene, four mutations in the pendrin gene, one mutation in the usherin gene, and one mutation in mitochondrial DNA. The biochip was validated using DNA from 250 people with apparent nonsyndromic, moderate to profound sensorineural hearing loss. The hearing loss biochip detected with 100% accuracy the mutations it was designed for. No false-positives or false-negative results were seen. The biochip can easily be expanded to test for additional mutations in genes associated with hearing impairment or other genetic conditions.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates many of the biological and toxicological actions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and related chemicals. Although no endogenous physiological ligand for the AhR has yet been described, persistent expression of hepatic CYP1A1 gene expression (an AhR-dependent response) in congenitally jaundiced Gunn rats indirectly supports the existence of such a ligand(s) in these animals. High plasma levels of the heme degradation product bilirubin (BR) in these animals prompted us to evaluate whether BR is an endogenous AhR agonist. Expression of dioxin responsive element (DRE)-driven luciferase gene expression in stably transfected mouse, guinea pig, rat, and human cells was induced by treatment with physiological concentrations of BR. Biliverdin (BV), the metabolic precursor of bilirubin, also induced luciferase activity in all species. BR and BV not only stimulated AhR transformation and DRE binding in vitro andin cells in culture, but competitive inhibition of [3H]TCDD-specific binding to the cytosolic AhR revealed that these chemicals are AhR ligands. The significantly greater inducing potency of these chemicals in intact cells, compared to their ligand binding and AhR transformation potency in vitro, suggests that BR and BV may also be converted within the cell to a more potent activator(s). Our results demonstrate that the heme degradation products BR and BV are AhR ligands which can regulate the AhR-dependent gene expression pathway., (Copyright 1998 Academic Press.)