Citations

» Fibrodysplasia ossificans progressiva (FOP), the most severe form of heterotopic ossification (HO) in humans, may lead to severe thoracic deformity (TD) and thoracic insufficiency syndrome (TIS), the most common cause of mortality in individuals with FOP. » In this study, we examine the multiple causes of TD in FOP and propose a dynamic model for the development and evolution of TD that can be used to guide clinical care. This model posits that multiple factors, all originating from the causative gain-of-function mutation in activin receptor A, type 1, lead to TD in FOP. » Factors that lead to TD in FOP include early developmental costovertebral and facet joint arthropathy and joint ankylosis, progressive episodic flare-ups (both trauma induced or spontaneous) and subsequent HO, dysregulated soft tissue sensitivity to mechanical stimuli, growth plate dysregulation, and congenital rib fusions. These factors contribute to TD in FOP through a combination of intra-articular and extra-articular mechanisms, all amplified by growth. » Although FOP is a rare condition, it is illustrative of how a mutation in a critical receptor in the bone morphogenetic protein signaling pathway can cause a litany of musculoskeletal dysfunction that can lead to life-threatening consequences. Clinicians caring for individuals who have FOP must be aware of the occurrence, evolution, and implications of progressive TD and resultant TIS so that appropriate preventive measures such as avoidance of pulmonary infections, incentive spirometry, and diaphragmatic strengthening can be instituted.

Managing persistent atrial fibrillation (AF) remains challenging due to its complex arrhythmic substrate, and pulmonary vein isolation through catheter ablation remains the primary treatment. This meta-analysis aims to compare the efficacy and safety outcomes of cryoballoon ablation (CBA) and radiofrequency ablation (RFA) in patients with persistent AF to provide evidence-based insights for clinical decision-making. A systematic search of PubMed, Embase, and Cochrane Central was conducted following PRISMA guidelines. Randomized controlled trials (RCTs) comparing CBA and RFA in persistent AF were included. Data on efficacy, safety, and procedural outcomes were pooled in the form of odds ratios (ORs) or mean differences (MDs) with corresponding 95% confidence intervals (CIs) using the random effects model in the Review Manager (RevMan) software. Four RCTs comprising 899 patients were included in our analysis. There were no significant differences between CBA and RFA in terms of AF recurrence, atrial tachycardia/flutter recurrence, or any arrhythmia recurrence during a mean follow-up period of 18 months after ablation. Procedure time was significantly shorter with CBA (MD: −44.85 minutes, 95% CI: −56.46 to −32.24, P < 0.01), while fluoroscopy time was comparable between the 2 groups (MD: 4.31 minutes, 95% CI: −1.79 to 10.40, P = 0.17). Safety outcomes, including overall complications, phrenic nerve palsy, access-site complications, and pericardial effusion, showed no significant differences between the 2 groups. CBA and RFA show similar rates of atrial arrhythmia recurrence and periprocedural complications in the treatment of persistent AF, while CBA offers the advantage of a shorter procedure time.

Hypoplastic left heart syndrome (HLHS) is the most lethal congenital heart disease (CHD) whose genetic basis remains elusive, likely due to oligogenic complexity. To identify regulators of cardiomyocyte (CM) proliferation relevant to HLHS, we performed a genome-wide siRNA screen in human iPSC-derived CMs, revealing ribosomal protein (RP) genes as the most prominent effectors of CM proliferation. Whole-genome sequencing of 25 HLHS proband–parent trios similarly showed enrichment of rare RP gene variants, including a damaging RPS15A promoter variant shared in a familial CHD case. Cross-species functional analyses demonstrated that perturbation of RP genes impairs cardiac growth: knockdown of RPS15A, RPS17, RPL26L1, RPL39, or RPS15 reduced CM proliferation, caused cardiac malformations in Drosophila , and produced hypoplastic or dysfunctional hearts in zebrafish. Genetic interactions between RP genes and key cardiac transcription factors (TBX5 and NKX2–7) further support their developmental role. Importantly, p53 suppression or Hippo activation partially rescued RP deficiency phenotypes. Together, these findings implicate RP genes as critical regulators of cardiogenesis and candidate contributors to HLHS.

Abstract Hypoplastic left heart syndrome (HLHS) is the most lethal congenital heart disease (CHD). The pathogenesis of HLHS is poorly understood, and due to the likely oligogenic complexity of the disease, definitive HLHS-causing genes have not yet been identified. Postulating impaired cardiomyocyte proliferation as a likely important contributing mechanism to HLHS pathogenesis, and we conducted a genome-wide siRNA screen to identify genes affecting proliferation of human iPSC-derived cardiomyocytes (hPSC-CMs). This yielded ribosomal protein (RP) genes as the most prominent class of effectors of CM proliferation. In parallel, whole genome sequencing and rare variant filtering of a cohort of 25 HLHS proband-parent trios with poor clinical outcome revealed enrichment of rare variants of RP genes. In addition, in a familial CHD case we identified a rare, predicted-damaging promoter variant affecting RPS15A that was shared between the HLHS proband and a distant relative with CHD. Functional testing with an integrated multi-model system approach reinforced the idea that RP genes are major regulators of cardiac growth and proliferation, thus potentially contributing to the hypoplastic phenotype observed in HLHS patients. Cardiac knockdown (KD) of RP genes with promoter or coding variants (RPS15A, RPS17, RPL26L1, RPL39, RPS15) reduced proliferation in generic hPSC-CMs and caused malformed hearts, heart-loss or even lethality in Drosophila. In zebrafish, diminished rps15a function caused reduced CM numbers, heart looping defects, or weakened contractility, while reduced rps17 or rpl39 function caused reduced ventricular size or systolic atrial dysfunction of the atrium, respectively. Importantly, genetic interactions between RPS15A and core cardiac transcription factors TBX5 in CMs, Drosocross, pannier and tinman in flies, and tbx5 and nkx2-7 (nkx2-5 paralog) in fish, support a specific role for RP genes in heart development. Furthermore, RPS15A KD-induced heart/CM proliferation defects were significantly attenuated by p53 KD in both hPSC- CMs and zebrafish, and by Hippo activation (YAP/yorkie overexpression) in developing fly hearts. Based on these findings, we conclude that RP genes play novel critical roles in cardiogenesis and constitute an emerging class of gene candidates likely involved in HLHS and other CHDs.

ImportanceSurvivors of thyroid cancer represent 10% of all cancer survivors in the US, yet their unmet care needs remain unexplored. Understanding the unmet care needs of survivors of thyroid cancer could help develop targeted interventions to enhance their quality of life and overall well-being.ObjectiveTo summarize the unmet care needs of survivors of thyroid cancer and programs to address them and to summarize the reporting and patterns of sociodemographic factors influencing these needs across studies.Evidence ReviewA systematic review and meta-narrative synthesis on studies published from January 2000 to September 2023 that evaluated the unmet needs of survivors of thyroid cancer or clinical programs to address them. The review included quantitative, qualitative, and mixed-methods studies. Two reviewers independently identified relevant articles and extracted data using standardized forms. Unmet care needs were summarized using the Supportive Care Framework for Cancer, whereas sociodemographic characteristics were evaluated according to the PROGRESS-Plus framework. A narrative synthesis was performed for quantitative studies, and a meta-narrative was created for qualitative studies. The risk of bias in the included studies was also assessed.FindingsWe included 14 quantitative studies (n = 8930) and 9 qualitative studies (n = 166) evaluating unmet care needs. Reported participant demographics were female (7653/9034 [85%]), White (2497/2986 [84%]), 40 years or older (2497/2986 [58%]), well-educated (1493/2124 [70%]), married or in stable relationships (1445/2114 [68%]), and English-speaking (1815/1915 [95%]). Quantitative studies primarily assessed and demonstrated unmet psychological and informational needs among survivors of thyroid cancer. Qualitative synthesis highlighted the negative impact of thyroid cancer’s perception as a “good cancer,” unmet informational and emotional support needs throughout survivorship stages, and practical hindrances in daily life. Sociodemographic data reporting was limited to a few factors influencing thyroid cancer care (eg, age, sex reported in &amp;gt;90% vs socioeconomic status &amp;lt;10%). One interventional study evaluating a patient navigation program was identified.Conclusions and RelevanceThis systematic review found that adult survivors of thyroid cancer report unmet informational, psychological, emotional, and practical support needs, which may be influenced by the good cancer label. Although patient demographics shape thyroid cancer care experiences and needs, population description is primarily limited to age and sex, overlooking other important variables that can affect care.

ImportanceThe De-escalated Adjuvant Radiation Therapy (DART) phase 3 randomized clinical trial (RCT) showed that in patients with human papillomavirus (HPV)−associated oropharyngeal squamous cell carcinoma, postoperative minimal residual disease (MRD), detected through circulating tumor HPV DNA (ctHPVDNA), was associated with a higher risk of disease progression. When considered along with pathologic factors, postoperative ctHPVDNA assessment may improve patient selection for adjuvant treatment de-escalation; however, more data are needed to demonstrate how it may be used in personalizing treatment intensity.ObjectiveTo determine the association of postoperative MRD status with progression-free survival (PFS) after surgery for HPV-associated oropharyngeal squamous cell carcinoma.Design, Setting, and ParticipantsThis was a secondary analysis of the DART RCT, which was conducted from October 2016 to August 2020 in multiple sites in the US. Participants from the de-escalated adjuvant radiation therapy group and the standard of care group with available blood specimen data were included. Reports from 3-month posttreatment surveillance visits were used to assess associations and outcomes. Data analyses were performed from March 2023 to March of 2025.InterventionsThe DART group received 30 to 36 Gy of radiation therapy in 1.5 to 1.8 Gy twice daily, plus docetaxel, 15 mg/m2, on days 1 and 8. The standard of care group received 60 Gy with or without weekly cisplatin, 40 mg/m2.Main Outcome and MeasurePFS.ResultsThe analysis included 140 patients (mean [SD] age, 59.1 [8.4] years; 12 [8.6%] females and 128 [91.4%] males; 97 [69.3%] with no smoking history); characteristics were similar to the overall DART RCT population. Of these, 17 patients (12.1%) had postoperative MRD (13 of 96 [13.5%] receiving DART and 4 of 44 [9.1%] receiving standard of care). For all patients, postoperative MRD positivity was strongly associated with worsened PFS at 24 months (MRD positivity, 69.5%; MRD negativity, 95.9%; hazard ratio [HR], 0.19; 95% CI, 0.06-0.59). MRD positivity was associated with PFS when evaluating only those patients in the DART group, where 24-month PFS was 68.4% compared to 92.6% for MRD-negative patients (HR, 0.28; 95% CI, 0.08-0.93). Three months after completion of all treatment, 8 of 117 patients (6.8%) had detectable ctHPVDNA, whereas 109 of 117 (93.2%) did not, and detection was highly associated with PFS (HR, 20.48; 95% CI, 6.91-60.67).Conclusions and RelevanceThis secondary analysis of the DART RCT found that patients with detectable ctHPVDNA after surgery had a higher risk of disease progression. When added to the pathologic factors considered, ctHPVDNA assessment may improve selection of patients for treatment de-escalation. In addition, the 3-month posttreatment time point, early in surveillance, may identify a sizable portion of patients with progression and may guide intervention and surveillance after surgery for HPV-associated oropharyngeal squamous cell carcinoma.Trial RegistrationClinicalTrials.gov Identifier: NCT02908477

Background Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV‐targeted therapies.