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INTRODUCTION: The diagnosis of acute myocarditis (AM) is complex due to its heterogeneity and typically is defined by either Electronic Healthcare Records (EHRs) or advanced imaging and endomyocardial biopsy, but there is no consensus. We aimed to investigate the diagnostic accuracy of these approaches for AM. METHODS: Data on ICD 10th Revision(ICD-10) codes corresponding to AM were collected from two hospitals and compared to CMR-confirmed or clinically suspected(CS) AM cases with respect to diagnostic accuracy, clinical characteristics, and all-cause mortality. Next, we performed a review of published AM studies according to inclusion criteria. RESULTS: We identified 291 unique admissions with ICD-10 codes corresponding to AM in the first three diagnostic positions. The positive predictive value(PPV) of ICD-10 codes for CMR-confirmed or CS-AM was 36%, and patients with CMR-confirmed or CS AM had a lower all-cause mortality than those with a refuted diagnosis (P = 0.019). Using an unstructured approach, patients with CMR-confirmed and CS AM had similar demographics, comorbidity profiles and survival over a median follow-up of 52 months (P = 0.72). Our review of the literature confirmed our findings. Outcomes for patients included in studies using CMR-confirmed criteria were favourable compared to studies with EMB-confirmed AM cases. CONCLUSION: ICD-10 codes have poor accuracy in identification of AM cases and should be used with caution in clinical research. There are important differences in management and outcomes of patients according to the selection criteria used to diagnose AM. Potential selection biases must be considered when interpreting AM cohorts and requires standardisation of inclusion criteria for AM studies.
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Background: Out-of-hospital cardiac arrest is a common cause of morbidity and mortality, and ethnic variation in outcomes is recognised. We investigated ethnic and socioeconomic differences in arrest circumstances, rates of coronary artery disease, treatment, and outcomes in resuscitated OOHCA. Methods: Patients with resuscitated OOHCA of suspected cardiac aetiology were included in the King's Out-of-Hospital Cardiac Arrest Registry between 1-May-2012 and 31-December-2020. Results: Of 526 patients (median age 62.0 years, IQR 21.1, 74.1% male), 414 patients (78.7%) were White, 35 (6.7%) were Asian, and 77 (14.6%) were Black. Black patients had more co-existent hypertension (p = 0.007) and cardiomyopathy (p = 0.003), but less prior coronary revascularisation (p = 0.026) compared with White/Asian patients. There were no ethnic differences in location, witnesses, or bystander CPR, but Black patients had more non-shockable rhythms (p < 0.001). Black patients received less immediate coronary angiography (p < 0.001) and percutaneous coronary intervention (p < 0.001) but had lower rates of CAD (p = 0.004) than White/Asian patients. All-cause mortality at 12 months was highest amongst Black patients, followed by Asian and then White patients (57.1% vs 48.6% vs 41.3%, p = 0.032). In Black patients, excess mortality was driven by higher rates of multi-organ dysfunction but lower cardiac death than White/Asian patients, with cardiac death highest amongst Asian patients (p = 0.009). Socioeconomic status had no effect on mortality, and in a multivariable logistic regression, age, location, witnesses, and Black compared to White ethnicity were independent predictors of mortality, whilst social deprivation was not. Conclusion: In this single-centre study, Black patients had higher mortality after resuscitated OOHCA than White/Asian patients. This may be in part due to differing underlying aetiology rather than differences in arrest circumstances or social deprivation.
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Introduction Paroxysmal supraventricular tachycardia (PSVT) is an often-recurring tachyarrhythmia that frequently results in emergency department visits and is commonly treated using intravenous adenosine. Given the anecdotal variable success of adenosine, the question arose of which patient factors may affect its success. This retrospective cohort analysis seeks to test the hypothesis that adult patients who receive adenosine at doses of ≥0.1mg/kg will have greater rates of successful conversion upon receipt of the first dose of adenosine. Methods This retrospective cohort analysis examines the charts from patients with known paroxysmal supraventricular tachycardia from November 1, 2015, through March 31, 2020, who were treated with intravenous adenosine. The primary outcome was the first-dose success of adenosine when stratified by patient weight (greater than 0.1mg/kg or less than 0.1mg/kg). Baseline characteristics and adverse effects were also collected. Results Seventy-six patients were included in the analysis. Patients who received adenosine at doses greater than or equal to 0.1mg/kg were more likely to convert to sinus rhythm than those who received doses less than 0.1mg/kg (p=0.006). No difference in adverse effects was noted between the groups (p=0.75). Conclusion This retrospective cohort analysis found that patients who received adenosine at doses greater than or equal to 0.1mg/kg for the treatment of PSVT were more likely to convert to sinus rhythm than those who received lower doses, with no difference in adverse effects. This hypothesis-generating finding provides the basis for a subsequent randomized, controlled trial to investigate the effectiveness and safety of weight-based adenosine.
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The caudolenticular (or transcapsular) gray bridges (CLGBs) connect the caudate nucleus (CN) and putamen across the internal capsule. The CLGBs function as the main efferent terminus from premotor and supplementary motor area cortex to the basal ganglia (BG). We conjectured if inherent variations in numbers and sizes of CLGBs could contribute to abnormal cortical-subcortical connectivity in Parkinson's disease (PD), a neurodegenerative disorder featuring a hindrance of BG processing. However, there are no literature accounts of normative anatomy and morphometry of CLGBs. We therefore retrospectively analyzed axial and coronal 3T fast spoiled gradient-echo magnetic resonance images (MRIs) of 34 healthy individuals for bilateral CLGBs symmetry, their numbers, dimensions of thickest and longest bridge, and axial surface areas of CN head and putamen. We calculated Evans' index (EI) to account for any brain atrophy. We statistically tested associations between sex or age and measured dependent variables, and linear correlations between all measured variables (significance at p < 0.05). Study subjects were F:M = 23:11 with mean age 49.9 years. All EI's were normal (<0.3). All but three CLGBs were bilaterally symmetrical with a mean 7.4 CLGBs per side. Mean CLGBs thickness and lengths were 1.0 and 4.6 mm, respectively; CN head and putamen areas were 205 and 382.0 mm2 , respectively. Females had thicker CLGBs (p = 0.02) but we found no significant interactions between sex or age and measured dependent variables, and no correlations between CN head or putamen areas and CLGBs dimensions. These normative MRI dimensions of the CLGBs will help guide future studies on the possible role of CLGBs morphometry in PD predisposition.
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Encéfalo , Enfermedad de Parkinson , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Encéfalo/diagnóstico por imagen , Enfermedad de Parkinson/patología , Ganglios Basales/diagnóstico por imagen , Ganglios Basales/patología , Imagen por Resonancia Magnética/métodosRESUMEN
Background An increasing number of nonbinary patients are receiving gender-affirming procedures due to improved access to care. However, the preferred treatments for nonbinary patients are underdescribed. The purpose of this study was to investigate the goals and treatments of nonbinary patients. Methods A retrospective study of patients who self-identified as nonbinary from our institutional Gender Health Program was conducted. Patient demographics, clinical characteristics, surgical goals, and operative variables were analyzed. Results Of the 375 patients with gender dysphoria, 67 (18%) were nonbinary. Over half of the nonbinary patients were assigned male at birth ( n = 57, 85%) and nearly half preferred the gender pronoun they/them/theirs ( n = 33, 49%). A total of 44 patients (66%) received hormone therapy for an average of 2.5 ± 3.6 years, primarily estrogen ( n = 39). Most patients ( n = 46, 69%) received or are interested in gender-affirming surgery, of which, almost half were previously on hormone therapy ( n = 32, 48%). The most common surgeries completed or desired were facial feminization surgery ( n = 15, 22%), vaginoplasty ( n = 15, 22%), mastectomy ( n = 11, 16%), and orchiectomy ( n = 9, 13%). Nonbinary patients who were assigned male at birth (NB-AMAB) were more often treated with hormones compared to nonbinary patients assigned female at birth (NB-AFAB) (72% vs. 30%, p = 0.010). Conversely, patients who were AFAB were more likely to complete or desire surgical intervention than those who were AMAB (100% vs. 63.0%, p < 0.021). Conclusion Majority of nonbinary patients were assigned male at birth. NB-AFAB patients all underwent surgical treatment, whereas NB-AMAB patients were predominantly treated with hormone therapy.
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Clustered regularly interspaced short palindromic repeats (CRISPR)-based genomic disruption of vascular endothelial growth factor A (Vegfa) with a single gRNA suppresses choroidal neovascularization (CNV) in preclinical studies, offering the prospect of long-term anti-angiogenesis therapy for neovascular age-related macular degeneration (AMD). Genome editing using CRISPR-CRISPR-associated endonucleases (Cas9) with multiple guide RNAs (gRNAs) can enhance gene-ablation efficacy by augmenting insertion-deletion (indel) mutations with gene truncations but may also increase the risk of off-target effects. In this study, we compare the effectiveness of adeno-associated virus (AAV)-mediated CRISPR-Cas9 systems using single versus paired gRNAs to target two different loci in the Vegfa gene that are conserved in human, rhesus macaque, and mouse. Paired gRNAs increased Vegfa gene-ablation rates in human cells in vitro but did not enhance VEGF suppression in mouse eyes in vivo. Genome editing using paired gRNAs also showed a similar degree of CNV suppression compared with single-gRNA systems. Unbiased genome-wide analysis using genome-wide unbiased identification of double-stranded breaks (DSBs) enabled by sequencing (GUIDE-seq) revealed weak off-target activity arising from the second gRNA. These findings suggest that in vivo CRISPR-Cas9 genome editing using two gRNAs may increase gene ablation but also the potential risk of off-target mutations, while the functional benefit of targeting an additional locus in the Vegfa gene as treatment for neovascular retinal conditions is unclear.
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Objectives: Medication errors represent a significant threat to patient safety. Pharmacotherapy is one of the 23 Accreditation Council of Graduate Medical Education milestones for emergency medicine, yet there is minimal understanding of what content should be prioritized during training. The study aim was to develop objectives for a patient-safety focused pharmacology curriculum for emergency medicine residents. Methods: We incorporated data from a de-identified safety event database and survey responses of 30 faculty and clinical pharmacists at a single-site suburban university hospital with 24-hour emergency medicine pharmacists and an annual volume of approximately 70,000. We reviewed the database to quantify types and severity of medication errors over a 5-year period for a total of 370 errors. Anonymous surveys included categorical items that we analyzed with descriptive statistics and short answer questions that underwent thematic analysis by 2 coders. We summarized all data sources to identify curriculum gaps. Results: Common medication errors reported in our database were wrong dose (43%) and computer order entry errors (14%). Knowledge gaps were medication cost (63%), pregnancy risk information (60%), antibiotic stewardship (53%), interactions (47%), and side effects (47%). Qualitative analysis revealed the need to optimize computer order entry, understand the scope of critical medications, use references, and consult pharmacists. Integration of data suggested specific medications should be covered in curricular efforts, including antibiotics, analgesics, sedatives, and insulin. Conclusion: We developed objectives of pharmacology topics to prioritize during emergency medicine training to enhance prescribing safety. This study is limited due to its small sample and single institution source of data. Future studies should investigate the impact of pharmacology curriculum on minimizing clinical errors.
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Facial feminization surgery (FFS) refers to a set of procedures aimed at altering the features of a masculine face to achieve a more feminine appearance. In the second part of this twopart series, assessment and operations involving the midface, mandible, and chin, as well as soft tissue modification of the nasolabial complex and chondrolaryngoplasty, are discussed. Finally, we provide a review of the literature on patient-reported outcomes in this population following FFS and suggest a path forward to optimize care for FFS patients.
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BACKGROUND: Late childhood (8 to 10 years of age) has emerged as a vulnerable period in children with cleft and craniofacial anomalies such that increased interventions during this period are associated with worse long-term patient-reported anxiety and depressive symptoms. These findings suggest that one possible practice change may be to consider changes in timing for surgical treatment algorithms. In this work, the authors investigated outcomes in altering the timing of the most common operation in late childhood for cleft lip and palate patients, alveolar bone grafting. METHODS: A two-part, multi-institutional cohort study was conducted. To understand the feasibility of changing alveolar bone graft timing with respect to surgical success, reoperation rates were retrospectively compared among patients grafted at different ages (4 to 7, 8 to 10, and 11 to 13 years of age). To understand the long-term effect of changing alveolar bone graft timing on psychosocial outcomes, the psychosocial suite of the Patient-Reported Outcomes Measurement Information System was prospectively administered to teenagers and adults with cleft lip and palate. RESULTS: Among the three age groups, early grafting (4 to 7 years of age) demonstrated the lowest regraft rates compared with the other groups. As these results suggested that early grafting is a viable alternative to standard timing, we next compared the differences in long-term psychosocial outcomes. Patients who were grafted early reported lower levels of anxiety and depressive symptoms as teenagers and adults. CONCLUSION: Altering timing of one stage in cleft lip and palate reconstruction to an earlier age decreases regraft rates and improves long-term patient-reported anxiety and depressive symptoms. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.
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Injerto de Hueso Alveolar/métodos , Ansiedad/diagnóstico , Labio Leporino/cirugía , Fisura del Paladar/cirugía , Depresión/diagnóstico , Adolescente , Adulto , Factores de Edad , Injerto de Hueso Alveolar/estadística & datos numéricos , Ansiedad/etiología , Ansiedad/psicología , Niño , Preescolar , Labio Leporino/complicaciones , Labio Leporino/psicología , Fisura del Paladar/complicaciones , Fisura del Paladar/psicología , Depresión/etiología , Depresión/psicología , Estudios de Seguimiento , Humanos , Masculino , Medición de Resultados Informados por el Paciente , Estudios Prospectivos , Reoperación/estadística & datos numéricos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Tiempo de Tratamiento/estadística & datos numéricos , Resultado del Tratamiento , Adulto JovenRESUMEN
Despite improved insurance coverage for gender confirmation surgeries in the United States, coverage for facial feminization surgery (FFS) continues to be difficult. Here, we describe our institutional experience on navigation, time, and costs of the FFS insurance authorization process. METHODS: FFS consults (n = 40) at the University of California, Los Angeles (2018-2020) were reviewed for time and cost to definitive insurance authorization decision. Patients were stratified into 3 groups based on authorization process: Group A (standard approval, n = 26, 65.0%) including public and private insurances; Group B (extended approval, n = 10, 25.0%) consisting of private insurance plans that initially denied and required multi-level appeals for denial overturn; and Group C (denial, n = 4, 10.0%), including private insurance plans that denied even after multi-level appeals. RESULTS: An estimated 90% of all patient consults were approved for FFS under insurance. Group A averaged 1.1 months for approval, requiring 1.4 hours of administrative time translating to $38.18 per patient. The addition of multi-level appeals in Groups B and C increased the total time for a definitive decision (7.0 and 5.1 months, respectively) and required both surgeon and administrative time to navigate the process (10.8 and 12.0 hours, respectively). The time spent on the presurgical authorization process for Groups B and C translated to an over 20-fold increase in cost ($855.00 and $988.38, respectively) compared with Group A. CONCLUSION: Navigation of the insurance process for FFS is challenging and time-consuming; however, coverage is a reality in California provided that multi-level appeals are exhausted.
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ABSTRACT: The purpose of this study was to analyze the prevalence, diagnosis, and management of velopharyngeal insufficiency (VPI) in patients with craniofacial microsomia (CFM).Craniofacial microsomia patients 13âyears of age and above treated at 2 centers from 1997 to 2019 were reviewed retrospectively for demographics, prevalence of VPI, and management of VPI. Patients with isolated microtia were excluded. Comparisons were made between patients with and without VPI using chi-square and independent samples t tests.Among 68 patients with CFM (63.2% male, mean 20.7âyears of age), VPI was diagnosed in 19 patients (27.9%) at an average age of 7.2âyears old. Among the total cohort, 61 patients had isolated CFM, of which 12 (19.6%) were diagnosed with VPI. Of the patients with isolated CFM and VPI, 8 patients (66.7%) were recommended for nasoendoscopy, of which only 2 patients completed. Seven isolated CFM patients (58.3%) underwent speech therapy, whereas none received VPI surgery. In contrast, 7 patients were diagnosed with both CFM and cleft lip and/or palate (CL/P), all of whom had VPI and were recommended for nasoendoscopy, with 5 (71.4%) completing nasoendoscopy, 6 (85.7%) undergoing speech therapy, and 6 (85.7%) undergoing corrective VPI surgery. Overall, we demonstrated that VPI was present in 27.9% of all CFM patients. On subset analysis, VPI was diagnosed in 20% of patients with isolated CFM and 100% of patients with CFM and CL/P. In addition, despite clinical diagnosis of VPI, a sizeable proportion of isolated CFM patients did not undergo therapy or surgical interventions.
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Labio Leporino , Fisura del Paladar , Síndrome de Goldenhar , Insuficiencia Velofaríngea , Niño , Fisura del Paladar/complicaciones , Fisura del Paladar/diagnóstico , Fisura del Paladar/epidemiología , Femenino , Síndrome de Goldenhar/complicaciones , Síndrome de Goldenhar/diagnóstico , Síndrome de Goldenhar/epidemiología , Humanos , Masculino , Prevalencia , Estudios Retrospectivos , Resultado del Tratamiento , Insuficiencia Velofaríngea/diagnóstico , Insuficiencia Velofaríngea/epidemiología , Insuficiencia Velofaríngea/terapiaRESUMEN
Importance: Quality of care of young adults with acute myocardial infarction (AMI) may depend on health care systems in addition to individual-level factors such as biological sex and social determinants of health (SDOH). Objective: To examine whether the quality of in-hospital and postacute care among young adults with AMI differs between the US and Canada and whether female sex and adverse SDOH are associated with a low quality of care. Design, Setting, and Participants: This retrospective cohort analysis used data from 2 large cohorts of young adults (aged ≤55 years) receiving in-hospital and outpatient care for AMI at 127 centers in the US and Canada. Data were collected from August 21, 2008, to April 30, 2013, and analyzed from July 12, 2019, to March 10, 2021. Exposures: Sex, SDOH, and health care system. Main Outcomes and Measures: Opportunity-based quality-of-care score (QCS), determined by dividing the total number of quality indicators of care received by the total number for which the patient was eligible, with low quality of care defined as the lowest tertile of the QCS. Results: A total of 4048 adults with AMI (2345 women [57.9%]; median age, 49 [interquartile range, 44-52] years; 3004 [74.2%] in the US) were included in the analysis. Of 3416 patients with in-hospital QCS available, 1061 (31.1%) received a low QCS, including more women compared with men (725 of 2007 [36.1%] vs 336 of 1409 [23.8%]; P < .001) and more patients treated in the US vs Canada (962 of 2646 [36.4%] vs 99 of 770 [12.9%]; P < .001). Conversely, low quality of post-AMI care (748 of 2938 [25.5%]) was similarly observed for both sexes, with a higher prevalence in the US (678 of 2346 [28.9%] vs 70 of 592 [11.8%]). In adjusted analyses, female sex was not associated with low QCS for in-hospital (odds ratio [OR], 1.05; 95% CI, 0.87-1.28) and post-AMI (OR, 1.07; 95% CI, 0.88-1.30) care. Conversely, being treated in the US was associated with low in-hospital (OR, 2.93; 95% CI, 2.16-3.99) and post-AMI (OR, 2.67; 95% CI, 1.97-3.63) QCS, regardless of sex. Of all SDOH, only employment was associated with higher quality of in-hospital care (OR, 0.72; 95% CI, 0.59-0.88). Finally, only in the US, low quality of in-hospital care was associated with a higher 1-year cardiac readmissions rate (234 of 962 [24.3%]). Conclusions and Relevance: These findings suggest that beyond sex, health care systems and SDOH that depict social vulnerability are associated with quality of AMI care. Taking into account SDOH among young adults with AMI may improve quality of care and reduce readmissions, especially in the US.
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Infarto del Miocardio/psicología , Calidad de la Atención de Salud/normas , Factores Sexuales , Determinantes Sociales de la Salud/normas , Adulto , Canadá/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Calidad de la Atención de Salud/estadística & datos numéricos , Estudios Retrospectivos , Factores de Riesgo , Determinantes Sociales de la Salud/estadística & datos numéricos , Estados Unidos/epidemiologíaRESUMEN
Facial feminization surgery (FFS) incorporates aesthetic and craniofacial surgical principles and techniques to feminize masculine facial features and facilitate gender transitioning. A detailed understanding of the defining male and female facial characteristics is essential for success. In this first part of a two-part series, we discuss key aspects of the general preoperative consultation that should be considered when evaluating the prospective facial feminization patient. Assessment of the forehead, orbits, hairline, eyebrows, eyes, and nose and the associated procedures, including scalp advancement, supraorbital rim reduction, setback of the anterior table of the frontal sinus, rhinoplasty, and soft tissue modifications of the upper and midface are discussed. In the second part of this series, bony manipulation of the midface, mandible, and chin, as well as soft tissue modification of the nasolabial complex and chondrolaryngoplasty are discussed. Finally, a review of the literature on patient-reported outcomes in this population following FFS is provided.
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SUMMARY: The intermediate cleft tip rhinoplasty is frequently performed during childhood to address nasal tip anomalies in cleft patients before the most critical period of psychosocial development. The authors previously described the component restoration intermediate cleft tip rhinoplasty technique for the unilateral cleft nose, which was developed to systematically address the lining deficiency, cleft lower lateral cartilage malpositioning, and cleft lateral cartilage weakness using a combination of lower lateral cartilage release, lateral cartilage repositioning, and placement of an auricular composite chondrocutaneous graft. In this work, the authors evaluate the utility of this technique to the bilateral cleft nose. Preoperative and postoperative (mean ± SD, 18.6 ± 10.8 months) photographs of bilateral cleft patients treated with the component restoration intermediate cleft tip rhinoplasty (n = 7) were evaluated using photogrammetric measurements and aesthetic assessments. From preoperatively to postoperatively, the columella length-to-alar width ratio on basal photographs increased (0.19 ± 0.05 versus 0.28 ± 0.05; p = 0.001). On lateral view, the columella-labial angle decreased from preoperatively to postoperatively [138 degrees (interquartile range, 132 to 144 degrees) versus 123 degrees (interquartile range, 122 to 139 degrees); p = 0.04]. Aesthetic ratings performed by four blinded observers also improved from preoperatively to postoperatively (1.6 ± 0.8 versus 2.4 ± 0.7; p = 0.004). As a comparison, bilateral cleft nose patients who did not undergo intermediate cleft tip rhinoplasty (n = 3) of similar ages were subjected to the same photogrammetric and aesthetic analyses, which showed no differences from preoperatively to postoperatively. In combination, the current work suggests that the component restoration technique in the bilateral intermediate cleft tip rhinoplasty improves nasal tip support and aesthetic outcomes.
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Labio Leporino/complicaciones , Fisura del Paladar/complicaciones , Nariz/anomalías , Rinoplastia/métodos , Niño , Preescolar , Labio Leporino/cirugía , Fisura del Paladar/cirugía , Estética , Femenino , Humanos , Masculino , Nariz/diagnóstico por imagen , Nariz/cirugía , Fotograbar , Tiempo de Tratamiento , Resultado del TratamientoRESUMEN
Crossing over is essential for chromosome segregation during meiosis. Protein modification by SUMO is implicated in crossover control, but pertinent targets have remained elusive. Here we identify Msh4 as a target of SUMO-mediated crossover regulation. Msh4 and Msh5 constitute the MutSγ complex, which stabilizes joint-molecule (JM) recombination intermediates and facilitates their resolution into crossovers. Msh4 SUMOylation enhances these processes to ensure that each chromosome pair acquires at least one crossover. Msh4 is directly targeted by E2 conjugase Ubc9, initially becoming mono-SUMOylated in response to DNA double-strand breaks, then multi/poly-SUMOylated forms arise as homologs fully engage. Mechanistically, SUMOylation fosters interaction between Msh4 and Msh5. We infer that initial SUMOylation of Msh4 enhances assembly of MutSγ in anticipation of JM formation, while secondary SUMOylation may promote downstream functions. Regulation of Msh4 by SUMO is distinct and independent of its previously described stabilization by phosphorylation, defining MutSγ as a hub for crossover control.
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Intercambio Genético , Proteínas de Unión al ADN/metabolismo , Meiosis , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/metabolismo , Sumoilación , Núcleo Celular/genética , Segregación Cromosómica , ADN/genética , Daño del ADN , Reparación del ADN , Proteínas de Unión al ADN/genética , Saccharomyces cerevisiae/crecimiento & desarrollo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/genética , Enzimas Ubiquitina-Conjugadoras/genética , Enzimas Ubiquitina-Conjugadoras/metabolismoRESUMEN
Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I-dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I-expressing tumors by reinvigorated CD8+ CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had "epigenetically down-regulated," but had not permanently lost MHC-I AgPP activity.
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Presentación de Antígeno/inmunología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antígenos de Histocompatibilidad Clase I/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , FN-kappa B/metabolismo , Neoplasias/tratamiento farmacológico , Factores de Transcripción p300-CBP/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Linfocitos T CD8-positivos , Proliferación Celular , Quimioterapia Combinada , Humanos , Inmunoterapia/métodos , Ratones , FN-kappa B/genética , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patología , Oxaliplatino/farmacología , Pronóstico , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Factores de Transcripción p300-CBP/genéticaRESUMEN
Post-transplant lymphoproliferative disorders (PTLD) are a group of lesions that can complicate solid organ or hematopoietic stem cell transplantation and are often associated with Epstein-Barr virus (EBV). The treatment of PTLD is dependent on the type of lesion and includes a wide range of therapies, but chimeric antigen receptor (CAR) T-cell therapy has not previously been reported as a treatment option for PTLD. We present a patient who developed refractory PTLD in her right retroperitoneum, right inguinal and iliac chains, and right axillary region shortly after heart transplantation and was treated with CAR T-cell therapy. She could not tolerate complete discontinuation of immunosuppression due to the risk of rejection of a life-supporting graft. The patient's PTLD responded to CAR T-cell therapy, and her heart was monitored throughout the treatment course without any signs of rejection or ventricular dysfunction. CAR T-cell therapy may be a viable treatment option in patients who develop PTLD after a solid organ transplant.
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Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Trasplante de Corazón , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/terapia , Complicaciones Posoperatorias/inmunología , Complicaciones Posoperatorias/terapia , Receptores Quiméricos de Antígenos/inmunología , Adolescente , Femenino , HumanosRESUMEN
INTRODUCTION: sickle cell disease (SCD) has significant pediatric morbidity and mortality in sub-Saharan Africa, where access to therapies such as hydroxyurea and opioids is often limited. Poor disease control and Pain management adversely affects the well-being and mental health of affected children. Questionnaires have been utilized in other regions to report the quality of life (QOL) in children with SCD, but assessments from Africa are lacking. METHODS: children age 2-14 years with SCD presenting for routine outpatient consultations at Hospital Central de Maputo from June-August 2017 were offered participation. After informed consent, the Pediatric QOL Inventory (PedsQL) SCD Module was administered to all caregivers and children > 5 years. Responses were scored from 0-100, with higher scores representing better QOL. RESULTS: a total of 14 children were included, with six (43%), four (29%), two (14%), and two (14%) from the age groups of 2-4, 5-7, 8-12, and 13-14 years, respectively. Mean overall patient QOL was 65.3 and 56.0 in child and caregiver respondents. In patients > 5 years, the difference in mean overall QOL for those on/not on hydroxyurea was 0.6 (66.5-64.9) in child respondents and 15.8 (68.4-52.6) in caregiver respondents. Domains related to worry/emotions and communication scored lower in QOL than Pain-related domains for both patient and caregiver respondents. CONCLUSION: SCD has a negative impact on QOL as reported by this cohort of Mozambican pediatric patients and caregivers, with Pain being less of a concern than emotional and interpersonal issues. A comprehensive, child-focused care approach with robust psychosocial support is needed.
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Anemia de Células Falciformes/fisiopatología , Accesibilidad a los Servicios de Salud , Manejo del Dolor/métodos , Calidad de Vida , Adolescente , Analgésicos Opioides/administración & dosificación , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/psicología , Cuidadores/estadística & datos numéricos , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Hidroxiurea/administración & dosificación , Masculino , Mozambique , Dolor/etiología , Apoyo Social , Encuestas y CuestionariosRESUMEN
Pediatric recipients of HCT may have a high susceptibility for overweight and obesity, and obesity may negatively impact post-transplant mortality and survival. This is a single-center retrospective analysis of 297 pediatric patients who received HCT between 2005 and 2018. Patients were classified as UW, NW, OW, or OB based on age-adjusted BMI. A mixed-effects linear regression model controlling for patient, disease, and transplant-related characteristics was used to trend weight longitudinally. Comparisons were made between weight category and post-transplant outcomes. In the pretransplant period, 5.4%, 54.5%, 22.2%, and 17.8% of patients were UW, NW, OW, and OB, respectively. Five years post-transplantation, those numbers were 10.6%, 48.2%, 16.5%, and 24.7%. Overall, BMI increased 0.00094 ± 0.0001 kg/m2 each day post-transplant (P < .001), with older individuals demonstrating greater rates of increase. Further, there was a larger BMI increase in patients without TBI compared with those who received TBI (1.29 ± 0.49, P = .008). Rates of acute GVHD, chronic GVHD, and viral infections, in addition to time to platelet and neutrophil engraftment and 5-year survival estimates, were not significantly different based on pretransplant BMI. Overweight and obese individuals had poorer 5-year survival based on 100-day post-transplant BMI (P = .02). Overall, pediatric HCT recipients are at risk of developing obesity, which is associated with decreased survival. Adolescents and young adults demonstrate the highest risk of weight gain, representing a vulnerable population that requires close monitoring, additional interventions, and further research.
Asunto(s)
Índice de Masa Corporal , Predicción , Enfermedad Injerto contra Huésped/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Obesidad/etiología , Sobrepeso/etiología , Receptores de Trasplantes , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Masculino , Obesidad/epidemiología , Sobrepeso/epidemiología , Estudios Retrospectivos , Medición de Riesgo/métodos , Factores de Riesgo , Resultado del Tratamiento , Estados Unidos/epidemiología , Adulto JovenRESUMEN
The complex cellular mechanisms and inter-related pathways of cancer proliferation, evasion, and metastasis remain an emerging field of research. Over the last several decades, nutritional research has prominent role in identifying emerging adjuvant therapies in our fight against cancer. Nutritional and dietary interventions are being explored to improve the morbidity and mortality for cancer patients worldwide. In this review, we examine several dietary interventions and their proposed mechanisms against cancer as well as identifying limitations in the currently available literature. This review provides a comprehensive review of the cancer metabolism, dietary interventions used during cancer treatment, anti metabolic drugs, and their impact on nutritional deficiencies along with a critical review of the following diets: caloric restriction, intermittent fasting, ketogenic diet, Mediterranean diet, Japanese diet, and vegan diet.