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Introduction: This article politicizes a reimbursement model proposed by some professional nursing associations that aim to better align the price of nursing labor (nurses' pay) to the value of nursing and make nurses' contributions more visible. Methods: Using the concept of "missing care," the critique reveals how professionalization directs attention to individual-level interactions between care seekers and practitioners while obscuring from view the harm inflicted by social institutions and structures constitutive of a capitalist political economy and the related carceral state. Results: Direct reimbursement models render practitioners complicit in the harms perpetrated and perpetuated by the health care industrial complex while professionalization processes are deployed to reduce cognitive dissonance (and moral injury) produced by combining harm with nursing's normative principles. Discussion: We describe and trace the complementary capitalist imperatives of extraction-based profit maximization and efficiency through the health care industrial complex to demonstrate how formative those imperatives are of the health care system, care-seekers' outcomes, nurses' experiences, nonconsensual modes of data collection, and surveillance. Conclusion: The naturalization of racial capitalism and the precarity and violence it entails foreclose the creation of ethical alternatives that prioritize well-being instead of the pursuit of profit that could bring the provision of and payment for care closer to the normative principles held by practitioners.
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PURPOSE: The best possible outcomes in infantile epileptic spasms syndrome require electroclinical remission; however, determining electrographic remission is not straightforward. Although the determination of hypsarrhythmia has inadequate interrater reliability (IRR), the Burden of AmplitudeS and Epileptiform Discharges (BASED) score has shown promise for the reliable interictal assessment of infantile epileptic spasms syndrome. Our aim was to develop a BASED training program and assess the IRR among learners. We hypothesized moderate or better IRR for the final BASED score and the presence or absence of epileptic encephalopathy (+/-EE). METHODS: Using a web-based application, 31 learners assessed 12 unmarked EEGs (length 1-6 hours) from children with infantile epileptic spasms syndrome. RESULTS: For all readers, the IRR was good for the final BASED score (intraclass correlation coefficient 0.86) and +/-EE (Marginal Multirater Kappa 0.63). For all readers, the IRR was fair to good for all individual BASED score elements. CONCLUSIONS: These findings support the use of our training program to quickly learn the BASED scoring method. The BASED score may be a valuable clinical and research tool. Given that the IRR for the determination of epileptic encephalopathy is not perfect, clinical acumen remains paramount. Additional experience with the BASED scoring technique among learners and advances in collaborative EEG evaluation platforms may improve IRR.
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Background & Objective: Congenital brain malformations and neurodevelopmental disorders (NDDs) are common pediatric neurological disorders and result in chronic disability. With the expansion of genetic testing, new etiologies for NDDs are continually uncovered, with as many as one third attributable to single-gene pathogenic variants. While our ability to identify pathogenic variants has continually improved, we have little understanding of the underlying cellular pathophysiology in the nervous system that results from these variants. We therefore integrated phenotypic information from subjects with monogenic diagnoses with two large, single-nucleus RNA-sequencing (snRNAseq) datasets from human cortex across developmental stages in order to investigate cell-specific biases in gene expression associated with distinct neurodevelopmental phenotypes. Methods: Phenotypic data was gathered from 1) a single-institution cohort of 84 neonates with pathogenic single-gene variants referred to Duke Pediatric Genetics, and 2) a cohort of 4,238 patients with neurodevelopmental disorders and pathogenic single-gene variants enrolled in the Deciphering Developmental Disorders (DDD) study. Pathogenic variants were grouped into genesets by neurodevelopmental phenotype and geneset expression across cortical cell subtypes was compared within snRNAseq datasets from 86 human cortex samples spanning the 2nd trimester of gestation to adulthood. Results: We find that pathogenic variants associated with speech/cognitive delay or seizures involve genes that are more highly expressed in cortical excitatory neurons than variants in genes not associated with these phenotypes (Speech/cognitive: p=2.25×10-7; Seizures: p=7.97×10-12). A separate set of primarily rare variants associated with speech/cognitive delay or seizures, distinct from those with excitatory neuron expression biases, demonstrated expression biases in microglia. We also found that variants associated with speech/cognitive delay and an excitatory neuron expression bias could be further parsed by the presence or absence of comorbid seizures. Variants associated with speech/cognitive delay without seizures tended to involve calcium regulatory pathways and showed greater expression in extratelencephalic neurons, while those associated with speech/cognitive delay with seizures tended to involve synaptic regulatory machinery and an intratelencephalic neuron expression bias (ANOVA by geneset p<2×10-16). Conclusions: By combining extensive phenotype datasets from subjects with neurodevelopmental disorders with massive human cortical snRNAseq datasets across developmental stages, we identified cell-specific expression biases for genes in which pathogenic variants are associated with speech/cognitive delay and seizures. The involvement of genes with enriched expression in excitatory neurons or microglia highlights the unique role both cell types play in proper sculpting of the developing brain. Moreover, this information begins to shed light on distinct cortical cell types that are more likely to be impacted by pathogenic variants and that may mediate the symptomatology of resulting neurodevelopmental disorders.
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Small RNA pathways regulate eukaryotic antiviral defense. Many of the Caenorhabditis elegans mutations that were identified based on their enhanced RNAi, the synMuv B genes, also emerged from unrelated genetic screens for increased growth factor signaling. The dozen synMuv B genes encode homologues of the mammalian dREAM complex found in nearly all animals and plants, which includes the lin-35/retinoblastoma oncogene. We show that a set of highly induced mRNAs in synMuv B mutants is congruent with mRNAs induced by Orsay RNA virus infection of C. elegans. In wild type animals, a combination of a synMuv A mutation and a synMuv B mutation are required for the Muv phenotype of increased growth factor signaling. But we show that Orsay virus infection of a single synMuv A mutant can induce a Muv phenotype, unlike the uninfected single synMuv A mutant. This suggests that decreased synMuv B activity, which activates the antiviral RNAi pathway, is a defense response to viral infection. Small RNA deep sequencing analysis of various dREAM complex mutants uncovers distinct siRNA profiles indicative of such an siRNA response. We conclude that the synMuv B mutants maintain an antiviral readiness state even in the absence of actual infection. The enhanced RNAi and conservation of the dREAM complex mutants suggests new therapeutic avenues to boost antiviral defenses.
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Assessment of pulmonary regurgitation (PR) guides treatment for patients with congenital heart disease. Quantitative assessment of PR fraction (PRF) by echocardiography is limited. Cardiac MRI (cMRI) is the reference-standard for PRF quantification. We created an algorithm to predict cMRI-quantified PRF from echocardiography using machine learning (ML). We retrospectively performed echocardiographic measurements paired to cMRI within 3 months in patients with ≥ mild PR from 2009 to 2022. Model inputs were vena contracta ratio, PR index, PR pressure half-time, main and branch pulmonary artery diastolic flow reversal (BPAFR), and transannular patch repair. A gradient boosted trees ML algorithm was trained using k-fold cross-validation to predict cMRI PRF by phase contrast imaging as a continuous number and at > mild (PRF ≥ 20%) and severe (PRF ≥ 40%) thresholds. Regression performance was evaluated with mean absolute error (MAE), and at clinical thresholds with area-under-the-receiver-operating-characteristic curve (AUROC). Prediction accuracy was compared to historical clinician accuracy. We externally validated prior reported studies for comparison. We included 243 subjects (median age 21 years, 58% repaired tetralogy of Fallot). The regression MAE = 7.0%. For prediction of > mild PR, AUROC = 0.96, but BPAFR alone outperformed the ML model (sensitivity 94%, specificity 97%). The ML model detection of severe PR had AUROC = 0.86, but in the subgroup with BPAFR, performance dropped (AUROC = 0.73). Accuracy between clinicians and the ML model was similar (70% vs. 69%). There was decrement in performance of prior reported algorithms on external validation in our dataset. A novel ML model for echocardiographic quantification of PRF outperforms prior studies and has comparable overall accuracy to clinicians. BPAFR is an excellent marker for > mild PRF, and has moderate capacity to detect severe PR, but more work is required to distinguish moderate from severe PR. Poor external validation of prior works highlights reproducibility challenges.
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Pembrolizumab has received approval in the UK as first-line monotherapy for recurrent and/or metastatic HNSCC (R/M HNSCC) following the results of the KEYNOTE-048 trial, which demonstrated a longer overall survival (OS) in comparison to the EXTREME chemotherapy regimen in patients with a combined positive score (CPS) ≥1. In this article, we provide retrospective real-world data on the role of pembrolizumab monotherapy as first-line systemic therapy for HNSCC across 18 centers in the UK from March 20, 2020 to May 31, 2021. 211 patients were included, and in the efficacy analysis, the objective response rate (ORR) was 24.7%, the median progression-free survival (PFS) was 4.8 months (95% confidence interval [CI]: 3.6-6.1), and the median OS was 10.8 months (95% CI 9.0-12.5). Pembrolizumab monotherapy was well tolerated, with 18 patients having to stop treatment owing to immune-related adverse events (irAEs). 53 patients proceeded to second-line treatment with a median PFS2 of 10.2 months (95% CI: 8.8-11.5). Moreover, patients with documented irAEs had a statistically significant longer median PFS (11.3 vs. 3.3 months; log-rank p value = <.001) and median OS (18.8 vs. 8.9 months; log-rank p value <.001). The efficacy and safety of pembrolizumab first-line monotherapy for HNSCC has been validated using real-world data.
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Anticorpos Monoclonais Humanizados , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Masculino , Feminino , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Reino Unido/epidemiologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/mortalidade , Adulto , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: Adolescents and young adults (AYAs) diagnosed with cancer experience physical, cognitive, and psychosocial effects from cancer treatment that can negatively affect their ability to remain engaged in education or work through cancer treatment and in the long term. Disengagement from education or work can have lasting implications for AYAs' financial independence, psychosocial well-being, and quality of life. Australian AYAs with cancer lack access to adequate specialist support for their education and work needs and report a preference for web-based support that they can access from anywhere, in their own time. However, it remains unclear what web-based resources exist that are tailored to support AYAs with cancer in reaching their educational or work goals. OBJECTIVE: This study aimed to determine what web-based resources exist for Australian AYAs with cancer to (1) support return to education or work and (2) identify the degree to which existing resources are age-specific, cancer-specific, culturally inclusive, and evidence-based; are co-designed with AYAs; use age-appropriate language; and are easy to find. METHODS: We conducted an environmental scan by searching Google with English search terms in August 2022 to identify information resources about employment and education for AYAs ever diagnosed with cancer. Data extraction was conducted in Microsoft Excel, and the following were assessed: understandability and actionability (using the Patient Education and Materials Tool), readability (using the Sydney Health Literacy Laboratory Health Literacy Editor), and whether the resource was easy to locate, evidence-based, co-designed with AYAs, and culturally inclusive of Aboriginal and Torres Strait Islander peoples. The latter was assessed using 7 criteria previously developed by members of the research team. RESULTS: We identified 24 web-based resources, comprising 22 written text resources and 12 video resources. Most resources (21/24, 88%) were published by nongovernmental organizations in Australia, Canada, the United States, and the United Kingdom. A total of 7 resources focused on education, 8 focused on work, and 9 focused on both education and work. The evaluation of resources demonstrated poor understandability and actionability. Resources were rarely evidence-based or co-designed by AYAs, difficult to locate on the internet, and largely not inclusive of Aboriginal and Torres Strait Islander populations. CONCLUSIONS: Although web-based resources for AYAs with cancer are often available through the websites of hospitals or nongovernmental organizations, this environmental scan suggests they would benefit from more evidence-based and actionable resources that are available in multiple formats (eg, text and audio-visual) and tailored to be age-appropriate and culturally inclusive.
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CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an embryonic role of CELSR3 in CNS and urinary tract formation.
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PURPOSE: This paper examines the prevalence of long COVID across different demographic groups in the US and the extent to which workers with impairments associated with long COVID have engaged in pandemic-related remote work. METHODS: We use the US Household Pulse Survey to evaluate the proportion of all adults who self-reported to (1) have had long COVID, and (2) have activity limitations due to long COVID. We also use data from the US Current Population Survey to estimate linear probability regressions for the likelihood of pandemic-related remote work among workers with and without disabilities. RESULTS: Findings indicate that women, Hispanic people, sexual and gender minorities, individuals without 4-year college degrees, and people with preexisting disabilities are more likely to have long COVID and to have activity limitations from long COVID. Remote work is a reasonable arrangement for people with such activity limitations and may be an unintentional accommodation for some people who have undisclosed disabilities. However, this study shows that people with disabilities were less likely than people without disabilities to perform pandemic-related remote work. CONCLUSION: The data suggest this disparity persists because people with disabilities are clustered in jobs that are not amenable to remote work. Employers need to consider other accommodations, especially shorter workdays and flexible scheduling, to hire and retain employees who are struggling with the impacts of long COVID.
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COVID-19 , Pessoas com Deficiência , Humanos , COVID-19/epidemiologia , Feminino , Pessoas com Deficiência/estatística & dados numéricos , Masculino , Adulto , Prevalência , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , SARS-CoV-2 , Teletrabalho/estatística & dados numéricos , Síndrome de COVID-19 Pós-Aguda , Adulto Jovem , Adolescente , IdosoRESUMO
CONTEXT: Children with cancer are at risk of poor nutritional status during treatment and into survivorship. Objectively measured taste perception and self-reported food hedonics are 2 factors that may influence food intake. OBJECTIVE: This 2-armed systematic review examined whether chemotherapy and radiotherapy affect (1) taste perception and (2) hedonic experiences of children and survivors of childhood cancer. DATA SOURCE: A 2-armed systematic literature search was conducted in the Medline, CINAHL, Embase, and PsychInfo database until June 2022. The effects of cancer treatment on objective taste perception or food hedonics (ie, food liking or aversion and appetite) were examined. DATA EXTRACTION: Peer-reviewed articles published in English of studies that included children (aged <18 years) or survivors of childhood cancer (any age) were reviewed. Risk of bias was determined using the Evidence Analysis Library by the Academy of Nutrition and Dietetics. DATA ANALYSIS: A total of 1417 articles in the taste search arm and 3862 articles in the hedonics search arm were identified. Of these, 9 and 4 articles were eligible for review, respectively. Cancer treatment had highly variable effects on taste perception during treatment and into survivorship. Learned food aversions were experienced by children receiving chemotherapy treatment and liking of meats and salty foods by children with cancer was affected. The impact of treatment on appetite varied. CONCLUSIONS: Cancer treatment did not uniformly affect taste perception. Food liking may be negatively affected, and learned food aversions may develop during cancer treatment. To establish the clinical relevance of childhood cancer treatment on taste perception and food hedonics, more research is required. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no.CRD42020207127.
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BACKGROUND: Long COVID symptoms - which include brain fog, depression, and fatigue - are mild at best and debilitating at worst. Some U.S. health surveys have found that women, lower income individuals, and those with less education are overrepresented among adults with long COVID, but these studies do not address intersectionality. To fill this gap, we conduct an intersectional analysis of the prevalence and outcomes of long COVID in the U.S. We posit that disparities in long COVID have less to do with the virus itself and more to do with social determinants of health, especially those associated with occupational segregation and the gendered division of household work. METHODS: We use 10 rounds of Household Pulse Survey (HPS) data collected between June 2022 and March 2023 to perform an intersectional analysis using a battery of descriptive statistics that evaluate (1) the prevalence of long COVID and (2) the interference of long COVID symptoms with day-to-day activities. We also use the HPS data to estimate a set of multivariate logistic regressions that relate the odds of having long COVID and activity limitations due to long COVID to a set of individual characteristics as well as intersections by sex, race/ethnicity, education, and sexual orientation and gender identity. RESULTS: Findings indicate that women, some people of color, sexual and gender minorities, and people without college degrees are more likely to have long COVID and to have activity limitations from long COVID. Women have considerably higher odds of developing long COVID compared to men, a disparity exacerbated by having less education. Intersectional analysis by gender, race, ethnicity, and education reveals a striking step-like pattern: college-educated men have the lowest prevalence of long COVID while women without college educations have the highest prevalence. Daily activity limitations are more evenly distributed across demographics, but a different step-like pattern is present: fewer women with degrees have activity limitations while limitations are more widespread among men without degrees. Regression results confirm the negative association of long COVID with being a woman, less educated, Hispanic, and a sexual and gender minority, while results for the intersectional effects are more nuanced. CONCLUSIONS: Results point to systematic disparities in health, highlighting the urgent need for policies that increase access to quality healthcare, strengthen the social safety net, and reduce economic precarity.
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COVID-19 , Síndrome de COVID-19 Pós-Aguda , Adulto , Humanos , Feminino , Masculino , Identidade de Gênero , Prevalência , Enquadramento Interseccional , COVID-19/epidemiologiaRESUMO
Lysosomal storage disorders (LSDs) are a group of monogenic condition, with many characterized by an enzyme deficiency leading to the accumulation of an undegraded substrate within the lysosomes. For those LSDs, postnatal enzyme replacement therapy (ERT) represents the standard of care, but this treatment has limitations when administered only postnatally because, at that point, prenatal disease sequelae may be irreversible. Furthermore, most forms of ERT, specifically those administered systemically, are currently unable to access certain tissues, such as the central nervous system (CNS), and furthermore, may initiate an immune response. In utero enzyme replacement therapy (IUERT) is a novel approach to address these challenges evaluated in a first-in-human clinical trial for IUERT in LSDs (NCT04532047). IUERT has numerous advantages: in-utero intervention may prevent early pathology; the CNS can be accessed before the blood-brain barrier forms; and the unique fetal immune system enables exposure to new proteins with the potential to prevent an immune response and may induce sustained tolerance. However, there are challenges and limitations for any fetal procedure that involves two patients. This article reviews the current state of IUERT for LSDs, including its advantages, limitations, and potential future directions for definitive therapies.
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Terapia de Reposição de Enzimas , Doenças por Armazenamento dos Lisossomos , Gravidez , Feminino , Humanos , Terapia de Reposição de Enzimas/métodos , Doenças por Armazenamento dos Lisossomos/terapia , Doenças por Armazenamento dos Lisossomos/complicações , Sistema Nervoso Central , LisossomosRESUMO
Some types of collagens, including transmembrane MACIT collagens and C. elegans cuticle collagens, are N-terminally cleaved at a dibasic site that resembles the consensus for furin or other proprotein convertases of the subtilisin/kexin (PCSK) family. Such cleavage may release transmembrane collagens from the plasma membrane and affect extracellular matrix assembly or structure. However, the functional consequences of such cleavage are unclear and evidence for the role of specific PCSKs is lacking. Here, we used endogenous collagen fusions to fluorescent proteins to visualize the secretion and assembly of the first collagen-based cuticle in C. elegans and then tested the role of the PCSK BLI-4 in these processes. Unexpectedly, we found that cuticle collagens SQT-3 and DPY-17 are secreted into the extraembryonic space several hours before cuticle matrix assembly. Furthermore, this early secretion depends on BLI-4/PCSK; in bli-4 and cleavage-site mutants, SQT-3 and DPY-17 are not efficiently secreted and instead form large intracellular puncta. Their later assembly into cuticle matrix is reduced but not entirely blocked. These data reveal a role for collagen N-terminal processing in intracellular trafficking and the control of matrix assembly in vivo. Our observations also prompt a revision of the classic model for C. elegans cuticle matrix assembly and the pre-cuticle-to-cuticle transition, suggesting that cuticle layer assembly proceeds via a series of regulated steps and not simply by sequential secretion and deposition.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Subtilisina , Animais , Sequência de Aminoácidos , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Colágeno/genética , Colágeno/metabolismo , Pró-Proteína Convertases/genética , Pró-Proteína Convertases/metabolismo , Subtilisina/genética , Subtilisina/metabolismoRESUMO
Food restriction augments drug seeking in abstinent rats. The underlying motivational mechanisms, however, remain unclear. We hypothesized that caloric restriction enhances the incentive value attributed to drug-associated cues and, in turn, augments drug seeking. Male rats were trained to lever-press for heroin, and then moved to the animal colony for a forced-abstinence period. Rats were maintained on free access to food (Sated) or subjected to 14 days of food restriction (FDR). In a series of experiments, we assessed the effect of food-restriction on the incentive value of heroin-associated cues. Tests included performance under a progressive ratio (PR) schedule of reinforcement maintained by heroin-associated cues, acquisition of a novel operant response reinforced by drug-associated cues, effect of food-restriction on operant response reinforced by neutral cues, acquisition of a novel operant response reinforced by drug-associated or neutral cues, and the effect of food-restriction on operant response reinforced by drug-associated or neutral cues, under a discrete choice procedure. Food-restriction did not change breakpoints in PR maintained by heroin-associated cues. FDR rats acquired the novel response at a greater level compared to the Sated group. Food-restriction-induced increase in novel-response rate was observed for both heroin-paired and the neutral cue. Responding for a heroin-associated cue was greater than for the neutral cue in both Sated and FDR groups. Response rate for the neutral cue, however, was greater in the FDR versus Sated group. Our findings suggest that food restriction increases the conditioned motivational properties of environmental stimuli, including, but not exclusive to, heroin-paired cues.
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Oculogastrointestinal neurodevelopmental syndrome has been described in seven previously published individuals who harbor biallelic pathogenic variants in the CAPN15 gene. Biallelic missense variants have been reported to demonstrate a phenotype of eye abnormalities and developmental delay, while biallelic loss of function variants exhibit phenotypes including microcephaly and craniofacial abnormalities, cardiac and genitourinary malformations, and abnormal neurologic activity. We report six individuals from three unrelated families harboring biallelic deleterious variants in CAPN15 with phenotypes overlapping those previously described for this disorder. Of the individuals affected, four demonstrate radiographic evidence of the classical triad of Dandy-Walker malformation including hypoplastic vermis, fourth ventricle enlargement, and torcular elevation. Cerebellar anomalies have not been previously reported in association with CAPN15-related disease. Here, we present three unrelated families with findings consistent with oculogastrointestinal neurodevelopmental syndrome and cerebellar pathology including Dandy-Walker malformation. To corroborate these novel clinical findings, we present supporting data from the mouse model suggesting an important role for this protein in normal cerebellar development. Our findings add six molecularly confirmed cases to the literature and additionally establish a new association of Dandy-Walker malformation with biallelic CAPN15 variants, thereby expanding the neurologic spectrum among patients affected by CAPN15-related disease.
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Vermis Cerebelar , Síndrome de Dandy-Walker , Microcefalia , Animais , Camundongos , Humanos , Síndrome de Dandy-Walker/diagnóstico , Síndrome de Dandy-Walker/genética , Cerebelo/anormalidades , Microcefalia/complicações , Fenótipo , Calpaína/genéticaRESUMO
PURPOSE OF REVIEW: The aim of this study was to provide pediatric providers with a review of the diagnosis and management of fetal cardiac disease in the current era. RECENT FINDINGS: Prenatal detection of congenital heart disease (CHD) has improved but is still imperfect. In experienced hands, fetal echocardiography can detect severe CHD as early as the first trimester and a majority of more subtle conditions in the second and third trimesters. Beyond detection, a prenatal diagnosis allows for lesion-specific counseling for families as well as for development of a multidisciplinary perinatal management plan, which may involve in-utero treatment. Given the diversity of cardiac diagnoses and the rarity of some, collaborative multicenter fetal cardiac research has gained momentum in recent years. SUMMARY: Accurate diagnosis of fetal cardiac disease allows for appropriate counseling, pregnancy and delivery planning, and optimization of immediate neonatal care. There is potential for improving fetal CHD detection rates. Fetal interventions are available for certain conditions, and fetal and pediatric cardiac centers have developed management plans specific to the expected postnatal physiology.
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Doenças Fetais , Cardiopatias Congênitas , Gravidez , Feminino , Recém-Nascido , Humanos , Criança , Ultrassonografia Pré-Natal , Feto , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/terapia , Diagnóstico Pré-Natal , Estudos Multicêntricos como AssuntoRESUMO
BACKGROUND: 1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor PRDM16. Early studies suggest that deletion of PRDM16 may underlie cardiomyopathy in patients with 1p36 deletion; however, the prognostic impact of PRDM16 loss is unknown. METHODS: This retrospective cohort included subjects with 1p36 deletion syndrome from 4 hospitals. Prevalence of cardiomyopathy and freedom from death, cardiac transplantation, or ventricular assist device were analyzed. A systematic review cohort was derived for further analysis. A cardiac-specific Prdm16 knockout mouse (Prdm16 conditional knockout) was generated. Echocardiography was performed at 4 and 6 to 7 months. Histology staining and qPCR were performed at 7 months to assess fibrosis. RESULTS: The retrospective cohort included 71 patients. Among individuals with PRDM16 deleted, 34.5% developed cardiomyopathy versus 7.7% of individuals with PRDM16 not deleted (P=0.1). In the combined retrospective and systematic review cohort (n=134), PRDM16 deletion-associated cardiomyopathy risk was recapitulated and significant (29.1% versus 10.8%, P=0.03). PRDM16 deletion was associated with increased risk of death, cardiac transplant, or ventricular assist device (P=0.04). Among those PRDM16 deleted, 34.5% of females developed cardiomyopathy versus 16.7% of their male counterparts (P=0.2). We find sex-specific differences in the incidence and the severity of contractile dysfunction and fibrosis in female Prdm16 conditional knockout mice. Further, female Prdm16 conditional knockout mice demonstrate significantly elevated risk of mortality (P=0.0003). CONCLUSIONS: PRDM16 deletion is associated with a significantly increased risk of cardiomyopathy and cardiac mortality. Prdm16 conditional knockout mice develop cardiomyopathy in a sex-biased way. Patients with PRDM16 deletion should be assessed for cardiac disease.
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Cardiomiopatias , Proteínas de Ligação a DNA , Animais , Feminino , Humanos , Masculino , Camundongos , Cardiomiopatias/genética , Proteínas de Ligação a DNA/genética , Fibrose , Camundongos Knockout , Estudos Multicêntricos como Assunto , Estudos Retrospectivos , Fatores de Transcrição/genéticaRESUMO
Some types of collagens, including transmembrane MACIT collagens and C. elegans cuticle collagens, are N-terminally cleaved at a dibasic site that resembles the consensus for furin or other proprotein convertases of the subtilisin/kexin (PCSK) family. Such cleavage may release transmembrane collagens from the plasma membrane and affect extracellular matrix assembly or structure. However, the functional consequences of such cleavage are unclear and evidence for the role of specific PCSKs is lacking. Here, we used endogenous collagen fusions to fluorescent proteins to visualize the secretion and assembly of the first collagen-based cuticle in C. elegans and then tested the role of the PCSK BLI-4 in these processes. Unexpectedly, we found that cuticle collagens SQT-3 and DPY-17 are secreted into the extraembryonic space several hours before cuticle matrix assembly. Furthermore, this early secretion depends on BLI-4/PCSK; in bli-4 and cleavage-site mutants, SQT-3 and DPY-17 are not efficiently secreted and instead form large intracellular aggregates. Their later assembly into cuticle matrix is reduced but not entirely blocked. These data reveal a role for collagen N-terminal processing in intracellular trafficking and in the spatial and temporal restriction of matrix assembly in vivo . Our observations also prompt a revision of the classic model for C. elegans cuticle matrix assembly and the pre-cuticle-to-cuticle transition, suggesting that cuticle layer assembly proceeds via a series of regulated steps and not simply by sequential secretion and deposition.
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Background Fetal diagnosis of congenitally corrected transposition of the great arteries (ccTGA) has been increasingly reported; however, predictors of clinical outcomes remain underexplored. We undertook a multicenter, retrospective study to investigate natural history, associated anomalies, and outcomes of fetal ccTGA. Methods and Results Fetuses with ccTGA diagnosed from January 2004 to July 2020 within 20 North American programs were included. Fetuses with severe ventricular hypoplasia thought to definitively preclude biventricular repair were excluded. We included 205 fetuses diagnosed with ccTGA at a median gestational age of 23 (interquartile range, 21-27) weeks. Genetic abnormalities were found in 5.9% tested, with extracardiac anomalies in 6.3%. Associated cardiac defects were diagnosed in 161 (78.5%), with atrioventricular block in 23 (11.3%). On serial fetal echocardiogram, 39% demonstrated a functional or anatomic change, most commonly increased tricuspid regurgitation (6.7%) or pulmonary outflow obstruction (11.1%). Of 194 fetuses with follow-up, 26 were terminated, 3 experienced fetal death (2 with atrioventricular block), and 165 were live-born. Of 158 with postnatal data (median follow-up 3.7 years), 10 (6.6%) had death/transplant before 1 year. On univariable analysis, fetal factors associated with fetal death or death/transplant by 1 year included ≥ mild tricuspid regurgitation, pulmonary atresia, aortic obstruction, fetal arrhythmia, and worsening hemodynamics on serial fetal echocardiogram (defined as worse right ventricular function, tricuspid regurgitation, or effusion). Conclusions Associated cardiac lesions and arrhythmias are common in fetal ccTGA, and functional changes commonly occur through gestation. Worse outcomes are associated with fetal tricuspid regurgitation (≥mild), any arrhythmia, pulmonary atresia, aortic obstruction, and worsening hemodynamics on serial echocardiograms. These findings can inform prenatal counseling and perinatal management planning.