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Coordination polymers derived from 5-benzyloxy isophthalic acid (H2BzOip) are rare, with only three reported that do not contain additional bridging ligands, of which two M2(BzOip)2(H2O) (M = Co and Zn) are isomorphous. It was hoped that by varying the solvent system in a reaction between H2BzOip and M(OAc)2 (M = Co and Zn), from water to a water/alcohol mixture, coordination polymers of different topology could be formed. Instead, two polymorphs of the existing M2(BzOip)2(H2O) (M = Co and Zn) were isolated from aqueous methanol and aqueous ethanol, in which a small number of guest solvent molecules are present in the crystals. These guest water molecules disrupt the hexaphenyl embrace motif, leading to varying degrees of disorder of the benzyl groups.

The topology of coordination polymers containing 5-alkoxy isophthalic acids and first row transition metals was found to be dependent on the combination of solvent system used and length of the alkyl chain. Four different framework types were identified: Phase A, M6(ROip)5(OH)2(H2O)4·xH2O (M = Co and R = Et, Pr, or nBu, or M = Zn and R = Et); Phase B, M2(ROip)2(H2O) (M = Co or Zn and R = Et, Pr, nBu, or iBu, or M = Mn and R = nBu or iBu); Phase C, Zn3(EtOip)2(OH)2; and Phase D, Zn2(EtOip)2(H2O)3. Preliminary screening of the NO storage and release capabilities of the Co-containing materials is also reported.

Background: Although transcatheter pulmonary valve replacement (TPVR) with Melody and Sapien valves has been shown to be safe and effective, infective endocarditis (IE) of the valve remains a significant risk. The goal of this study is to assess how different immunocompromised states influence the likelihood of developing IE in our congenital heart disease population with these valves. Methods: A chart review was conducted of all patient who underwent TPVR at UCLA. Various risk factors including age, transcatheter valve type, and type of immunocompromised state were analyzed as possible risk factors for IE. CART analysis was used to create a visual representation of the interplay of various risk factors. Results: The incidence of IE at our institution was approximately 8% (26 events in 339 valve implants), over a median follow up of 2.92 (0.07–9.71) years. All but one event occurred in patients with Melody valves. Patients with any immunocompromised condition were more likely to develop IE (P = 0.01). Presentation severity and outcome of IE was similar for immunocompromised and non-immunocompromised patients. Patients with DiGeorge syndrome and those taking oral immunosuppressants for autoimmune conditions or asthma were at highest risk for developing IE. Conclusions: The relatively high rate of endocarditis in TPVR patients, particularly in those with Melody valves, is a concerning development. A subset of immunocompromised patients appears to be at higher risk, and it may be beneficial for providers to be especially vigilant with these patients. Further research is needed to assess long-term risk of IE in all TPVR patients.

Objective: The current literature on propofol infusion as a bridge to extubation in critically ill children is limited to children with burns and congenital cardiac disease. We hypothesize that propofol infusion is a feasible bridge to extubation in mechanically ventilated, critically ill children.Design: Retrospective chart review.Setting: Pediatric intensive care unit of a tertiary care teaching hospital.Patients: Children < 21 years, admitted to our Pediatric intensive care unit (PICU), requiring mechanical ventilation (MV) for at least 48 h and at least two sedative infusions and who received propofol infusion for 4 to 24 h during anticipated extubation from January 2014 to May 2017.Interventions: None.Measurements and Main Results: We assessed extubation success as primary outcome. We defined extubation success as no re-intubation within 24 h after extubation. We also assessed for occurrence of adverse effects of propofol infusion (1) hemodynamic instability [more than 10% change from pre-propofol baseline heart rate (HR) and mean arterial pressure (MAP) measured 4 h before and during propofol infusion, need for any inotrope and/or fluid bolus] and (2) occurrence of lactic acidosis in absence of any documented sepsis. We compared hemodynamic parameters before and during infusion using Wilcoxon Rank Sum Test (significant p-value ≤ 0.05). We evaluated 35 critically ill, mechanically ventilated children. The median age, weight and duration of MV were 3.8 (IQR: 1.25–10.5) years, 12 (IQR: 6–16.2) kilograms and 111 (IQR: 78–212) h, respectively. Of the 35 patients, 15 (43%) were post-surgical (10 general and 5 cardiac) and the remaining 20 (57%) were non-surgical respiratory failure cases. The median (IQR) propofol infusion dose and duration were 64.7 (53.2-81.1) mcg/kg/min and 7.8 h respectively. Only one patient got re-intubated within 24 h of extubation and was later diagnosed with vascular ring. During propofol infusion, 7/35 (20%) patients exhibited transient drop in MAP > 10% from baseline, but none had lactic acidosis or required an inotrope or fluid bolus.Conclusions: In critically ill, mechanically ventilated patients, propofol infusion used over a short duration (

Background: Recombinant human parathyroid hormone (1-84) (PTH) increases bone mass and strength and improves bone quality by stimulating new bone formation.Objective: To determine the safety of PTH and its effect on the incidence of vertebral fractures in postmenopausal women with osteoporosis.Design: 18-month, randomized, double-blind, placebo-controlled, parallel-group study.Setting: 168 centers in 9 countries.Patients: 2532 postmenopausal women with low bone mineral density at the hip or lumbar spine.Interventions: Women received 100 mug of recombinant human PTH or placebo daily by subcutaneous injection. All received calcium, 700 mg/d, and vitamin D3, 400 U/d.Measurements: New or worsened vertebral fractures (primary outcome) and changes in bone mineral density and safety (secondary outcomes).Results: 67.2% of patients who received at least 1 dose of the study drug completed the study. Parathyroid hormone reduced the risk for new or worsened vertebral fractures, but in sensitivity analyses, the magnitude of the reduction was changed with assumptions about fracture incidence in patients who did not complete the study (relative risk assuming no fractures, 0.42 [95% CI, 0.24 to 0.72] [P = 0.001]; relative risk assuming fracture incidence observed in all patients who completed the trial, 0.60 [CI, 0.36 to 1.00] [P = 0.05]; relative risk assuming fracture incidence observed in the placebo group, 0.62 [CI, 0.37 to 1.04] [P = 0.07]). Compared with placebo, mean bone mineral density increased at the spine by 6.9% (CI, 6.4% to 7.4%) and at the hip by 2.1% (CI, 1.7% to 2.5%) but decreased at the forearm in the PTH-treated group. Parathyroid hormone treatment increased the percentage of participants with hypercalciuria, hypercalcemia, and nausea by 24% (CI, 20% to 27%), 23% (CI, 21% to 26%), and 14% (CI, 11% to 16%), respectively, compared with placebo.Limitations: Baseline serum PTH and vitamin D levels were not measured. Many patients discontinued the trial prematurely.Conclusions: Parathyroid hormone (1-84) reduced the overall risk for new or worsened vertebral fracture in postmenopausal women with osteoporosis. Hypercalciuria, hypercalcemia, and nausea were more common in women who took the drug. Although the magnitude of the reduction was sensitive to assumptions about fracture incidence in patients who did not complete the study, the findings suggest that PTH provides an alternative therapeutic option for fracture prevention. [ABSTRACT FROM AUTHOR]

Digoxin therapy has long been used to treat heart failure; however, its effectiveness was not completely known until recently. Results of the Digitalis Investigation Group trial showed that adding digoxin to standard heart failure therapy had no effect on mortality. However, adding digoxin decreased hospitalizations related to heart failure and improved symptoms in patients treated for heart failure. Reanalyses of the trial's findings have raised new questions about the role of digoxin in heart failure treatment. These new analyses showed that low serum digoxin concentrations used in patients with more severe disease offered the most benefit. Digoxin use in women was associated with increased mortality risk. This finding should be interpreted with caution, however, because it was based on retrospective data, and the cause of this phenomenon has not been fully elucidated. Prospective clinical trials are needed to determine the serum digoxin concentration that is associated with the most clinical benefit and to determine the role of digoxin therapy for women. Digoxin generally does not have a role in the treatment of diastolic heart failure and is not a first-line therapy for managing atrial fibrillation in patients with heart failure. [ABSTRACT FROM AUTHOR]

Background: Dependency in activities of daily living (ADLs) is a reality within nursing homes, and we describe ADL measurement strategies based on items in the Minimum Data Set (MDS) and the creation and distributional properties of three ADL self-performance scales and their relationship to other measures.Methods: Information drawn from four data sets for a multistep analysis was guided by four study objectives: (1) to identify the subcomponents of ADLs that are present in the MDS battery; (2) to demonstrate how these items could be aggregated within hierarchical and additive ADL summary scales; (3) to describe the baseline and longitudinal distributional properties of these scales in a large, seven-state MDS database; and (4) to evaluate how these scales relate to two external criteria.Results: Prevalence and factor structure findings for seven MDS ADL self-performance variables suggest that these items can be placed into early, middle, and late loss ADL components. Two types of summary ADL self-performance measures were created: additive and hierarchical. Distributional properties of these scales are described, as is their relationship to two external ADL criteria that have been reported in prior studies: first as an independent variable predicting staff time involved in resident care; second as a dependent variable in a study of the efficacy of two programs to improve resident functioning.Conclusions: The new ADL summary scales, based on readily available MDS data, should prove useful to clinicians, program auditors, and researchers who use the MDS functional self-performance items to determine a resident's ADL status. [ABSTRACT FROM AUTHOR]

ObjectivesThis study aimed to assess factors related to adherence to the Pediatric Advanced Life Support guidelines for severe sepsis and septic shock in an emergency room (ER) of a tertiary care children’s hospital.MethodsThis was a retrospective, observational study of children (0–18 years old) in The Children’s Hospital of San Antonio ER over 1 year with the International Consensus Definition Codes, version-9 (ICD-9) diagnostic codes for “severe sepsis” and “shocks.” Patients in the adherent group were those who met all three elements of adherence: (1) rapid vascular access with at most one IV attempt before seeking alternate access (unless already in place), (2) fluids administered within 15 min from sepsis recognition, and (3) antibiotic administration started within 1 h of sepsis recognition. Comparisons between groups with and without sepsis guideline adherence were performed using Student’s t-test (the measurements expressed as median values). The proportions were compared using chi-square test. p-Value ≤0.05 was considered significant.ResultsA total of 43 patients who visited the ER from July 2014 to July 2015 had clinically proven severe sepsis or SS ICD-9 codes. The median age was 5 years. The median triage time, times from triage to vascular access, fluid administration and antibiotic administration were 26, 48.5, 76, and 135 min, respectively. Adherence to vascular access, fluid, and antibiotic administration guidelines was 21, 26, and 34%, respectively. Appropriate fluid bolus (20 ml/kg over 15–20 min) was only seen in 6% of patients in the non-adherent group versus 38% in the adherent group (p = 0.01). All of the patients in the non-adherent group used an infusion pump for fluid resuscitation. Hypotension and ≥3 organ dysfunction were more commonly observed in patients in adherent group as compared to patients in non-adherent group (38 vs. 14% p = 0.24; 63 vs. 23% p = 0.03).ConclusionOverall adherence to sepsis guidelines was low. The factors associated with non-adherence to sepsis guidelines were >1 attempt at vascular access, delay in antibiotic ordering, fluid administration using infusion pump, absence of hypotension, and absence of three or more organs in dysfunction at ER presentation.

Kasabach-Merritt Syndrome (KMS) is an uncommon phenomenon characterized by the presence of a vascular tumor in association with thrombocytopenia, consumption coagulopathy and hemodynamic instability. Typically presents in infancy and involve the skin and deep soft tissues of the arms and legs. Treatment options vary with clinical presentation, and ranges from medical management to immediate surgical intervention. We present an unusual case of a newborn with KMS and fatal hemodynamic collapse imminent, which was successfully treated with surgical resection at our institution.

Chylothorax is an uncommon condition which is potentially life-threatening if untreated. The following case study of a 75-year-old man with chyle leak following surgery shows how prompt dietetic action prevented further compromise in immune function and nutritional status. Dietetic recommendation to minimize enteral intake rapidly stopped chyle flow and promoted wound closure. Peripheral parenteral nutrition (PPN) was administered in order to prevent malnutrition. There is limited literature available for evidence of best practice for cases of chyle leakage, however, this particular case demonstrates PPN should be considered despite the potential risks. [ABSTRACT FROM AUTHOR]

BACKGROUND: In Central America, there has been a marked increase in obesity in the last 30 years. Over this time frame, in Panama, there have been lifestyle changes associated with economic development and urbanization that may have facilitated increases in body weight. The aim of the study is to describe the change in the prevalence of obesity in the country since 1982 and to analyze the association of obesity with gender, place of residence and socioeconomic factors. METHODS: We analyzed three nationally representative cross-sectional studies and one sub-national study of Panamanian adults that evaluated anthropometric and socioeconomic variables; ENPA-1982 (n = 11 611), ENV-II 2003 (n = 14 737), ENV-III 2008 (n = 15 484), PREFREC-2010 (n = 3 590). We also evaluated one nationally representative study that evaluated people's perception of their body weight, ENSCAVI-2007 (n = 25 748). RESULTS: In 1982, the prevalence in males of a body mass index (BMI) ≥ 30 kg/m2 was 3.8% (3.3-4.2) and in females 7.6% (6.9-8.2). In 2003, the prevalence in males increased to 14.4% (13.6-15.2) and in females to 21.8% (20.8-22.7). In 2008, the prevalence in males was 16.9% (16.0-17.7) and in females it was 23.8% (22.8-24.7). Nevertheless, in 2007, the national perception of being obese was only 4% among males and 6.7% among females. The highest prevalence of obesity was noted in urban areas. Female gender and higher income were found to be positively associated with obesity. Income level was positively associated with abdominal obesity in men but not in women. CONCLUSIONS: There has been a marked increase of obesity in Panama in the last 3 decades. Initiatives to control this problem will have to take into consideration the observed gender difference and the lifestyle changes that have contributed to the rise of this problem.

Epidemiological publications on the relationship of caffeine to birth weight and duration of human pregnancy, from 1966 to 1995, were searched through Medline. Each study was treated as the stratification variable, and its weight in the weighted average was proportional to the inverse of its variance. Twenty-six studies were located. Among the twenty-two studies on birth weight, eleven were on mean birth weight, nine on low birth weight (LBW), and four on intrauterine growth retardation (IUGR). Combined analysis of mean birth weigh study results showed a significant decrease in birth weight of nearly 43g among newborns of the heaviest caffeine-consuming mothers. LBW, IUGR, and preterm delivery displayed significant homogeneity in the test results, indicating that a pooled estimate should not be taken as an adequate measure. The high heterogeneity of the available literature on the effects of caffeine on LBW, IUGR, and preterm delivery prevents estimation of reliable pooled estimates through meta-analysis. Further assessment of caffeine intake during pregnancy is needed in future research.

O objetivo desta investigação foi identificar a prevalência da anemia e alguns de seus potenciais determinantes em 754 crianças de áreas urbanas de sete municípios na região do semi-árido baiano. Hemoglobina foi determinada em 745 crianças de um a 72 meses de idade. Para o grupo etário de seis a 72 meses um valor de hemoglobina < 11,0 g/dl identifica a anemia segundo recomendação da OMS enquanto o valor

Foram estudados 754 pré-escolares de áreas urbanas de sete municípios do semi-árido do Estado Bahia, Brasil, com o objetivo de determinar a prevalência da hipovitaminose A e sua associação com a idade, sexo, renda em salário-mínimo, escolaridade materna e adequação dietética em vitamina A. Na amostra estudada não se registrou nenhum caso de sinais e/ou sintomas de xeroftalmia durante o exame clínico-oftalmológico. Em 563 crianças foi possível a coleta de sangue para determinação de retinol sérico; encontrou-se um valor médio de 20,3 µg/dl (DP=10,8µg/dl) e uma prevalência de 15,3% de níveis deficientes (abaixo de 10,0 µg/dl). Em todos os sete municípios estudados a prevalência de retinol sérico deficiente foi superior a 5,0% que é nível crítico proposto pela OMS para considerar a hipovitaminose A como problema de saúde pública. A distribuição de retinol sérico encontrada não teve relação com o sexo das crianças, mas com a idade, diminuindo a prevalência de níveis deficientes e baixos na medida em que a idade aumenta. Não se encontrou associação entre renda familiar per capita ou escolaridade materna e a prevalência de níveis de retinol deficiente. Os resultados de consumo alimentar provenientes do inquérito recordatório de 24h mostraram que apenas 8% das crianças consumiram quantidades adequadas de retinol ou de seus precursores; 66% ingeriam abaixo da metade e quase 35% delas não chegaram a ingerir nem um quarto da quantidade recomendada para sua faixa etária. A carência de vitamina A deve ser considerada como problema de saúde pública severo, tanto pela alta prevalência de níveis deficientes de retinol em todos os municípios como também pela dimensão da inadequação dietética.

Foram estudados 754 pré-escolares de áreas urbanas de sete municípios do semi-árido da Bahia, Brasil. Os objetivos foram determinar a prevalência de déficit ponderal e estatural, indicativos de desnutrição atual e/ou pregressa e sua associação com a idade, sexo, renda em salário-mínimo (SM), escolaridade materna e adequação do consumo alimentar. Encontrou-se 22,9% de crianças com altura/idade abaixo de -2,0 DP (desnutrição pregressa), 19,1% com peso/idade e 3,6% com peso/altura abaixo de -2,0 DP (desnutrição atual). Em relação ao inquérito dietético somente 6,8% das crianças haviam consumido no dia anterior uma dieta que suprisse os requerimentos energéticos para sua faixa etária. Houve forte associação entre os indicadores A/l e P/l inadequados com renda familiar per capita (p=0,001 e p=0,000, respectivamente); crianças de famílias com renda per capita < 1/4 SM tinham duas vezes mais chance de estar desnutridas se comparadas com as do estrato de renda >1/2 SM. Em relação ao P/A como também P/l, os pré-escolares estudados no semi-árido apresentaram prevalências significativamente superiores às encontradas por pesquisa nacional realizada na mesma época (p=0,047 e p=0,000, respectivamente). Esses achados surpreendem, já que nas últimas décadas tem sido demonstrada no Brasil uma melhoria signifivativa na desnutrição e mortalidade infantil e parecem indicar que as crianças do semi-árido não lograram ainda alcançar os mesmos benefícios que o restante da população infantil brasileira.

Publishers are making great efforts to find out what their customers - authors, readers and librarians - need, and their publishing practices are changing in response to what they hear. Much has already been achieved in making more content available to more people (for not much more money) and in adopting more liberal licensing policies towards both authors and users. Alternative publishing models, such as Open Access, are of great interest to publishers but present difficult economic challenges which need to be carefully investigated if we are not to throw the baby out with the bathwater.

Abstract Background Geometric morphometric methods of capturing information about curves or outlines of organismal structures may be used in conjunction with canonical variates analysis (CVA) to assign specimens to groups or populations based on their shapes. This methodological paper examines approaches to optimizing the classification of specimens based on their outlines. This study examines the performance of four approaches to the mathematical representation of outlines and two different approaches to curve measurement as applied to a collection of feather outlines. A new approach to the dimension reduction necessary to carry out a CVA on this type of outline data with modest sample sizes is also presented, and its performance is compared to two other approaches to dimension reduction. Results Two semi-landmark-based methods, bending energy alignment and perpendicular projection, are shown to produce roughly equal rates of classification, as do elliptical Fourier methods and the extended eigenshape method of outline measurement. Rates of classification were not highly dependent on the number of points used to represent a curve or the manner in which those points were acquired. The new approach to dimensionality reduction, which utilizes a variable number of principal component (PC) axes, produced higher cross-validation assignment rates than either the standard approach of using a fixed number of PC axes or a partial least squares method. Conclusion Classification of specimens based on feather shape was not highly dependent of the details of the method used to capture shape information. The choice of dimensionality reduction approach was more of a factor, and the cross validation rate of assignment may be optimized using the variable number of PC axes method presented herein.

Pharmacogenomic testing has emerged as an aid in clinical decision making for psychiatric providers, but more data is needed regarding its utility in clinical practice and potential impact on patient care. In this cross-sectional study, we determined the real-world prevalence of pharmacogenomic actionability in patients receiving psychiatric care. Potential actionability was based on the prevalence of CYP2C19 and CYP2D6 phenotypes, including CYP2D6 allele-specific copy number variations (CNVs). Combined actionability additionally incorporated CYP2D6 phenoconversion and the novel CYP2C-TG haplotype in patients with available medication data. Across 15,000 patients receiving clinical pharmacogenomic testing, 65% had potentially actionable CYP2D6 and CYP2C19 phenotypes, and phenotype assignment was impacted by CYP2D6 allele-specific CNVs in 2% of all patients. Of 4114 patients with medication data, 42% had CYP2D6 phenoconversion from drug interactions and 20% carried a novel CYP2C haplotype potentially altering actionability. A total of 87% had some form of potential actionability from genetic findings and/or phenoconversion. Genetic variation detected via next-generation sequencing led to phenotype reassignment in 22% of individuals overall (2% in CYP2D6 and 20% in CYP2C19). Ultimately, pharmacogenomic testing using next-generation sequencing identified potential actionability in most patients receiving psychiatric care. Early pharmacogenomic testing may provide actionable insights to aid clinicians in drug prescribing to optimize psychiatric care., (© 2024. The Author(s).)

Background: Event monitors are being increasingly used in pediatric and adult congenital heart disease (ACHD) patients for arrhythmia evaluation. Data on their diagnostic yield are limited., Objectives: To evaluate the diagnostic yield of event monitors, patient characteristics associated with critical events, and clinical response to events., Methods: We retrospectively assessed event monitors prescribed to patients at our institution's Heart Center from 2017 to 2020. Thirty-day event monitor tracings were reviewed by an electrophysiologist (EP) to identify critical events defined as supraventricular tachycardia (SVT, re-entrant, atrial tachycardia, atrial flutter, and atrial fibrillation), ventricular tachycardia (VT), atrioventricular block, and pauses greater than 3 s. Patient characteristics and treatment data were collected. Characteristics associated with events were assessed using multivariable logistic regression. Trends in monitor prescription over time, diagnostic yield, and clinical response to events were analyzed., Results: 204/2330 (8.8%) event monitors had EP-confirmed critical events. Critical events included SVT (51.5%), VT (38.5%), atrioventricular block (4%), and pauses (6%). 129/198 (65%) patients with critical events underwent treatment. Event monitoring usage increased by 52% between 2017 and 2020 (p < 0.0001). Complex CHD (OR 2.1, 95% CI 1.3-3.4, p = 0.004), cardiomyopathy (OR 2.9, 95% CI 1.5-4.8, p < 0.001), and EP-ordered monitors (OR 1.6, 95% CI 1.2-2.1, p = 0.001) were more highly associated with critical events., Conclusion: Event monitor use is common, and critical events were captured in 8.8% of patients. The majority of patients with critical events underwent treatment. Factors associated with critical events include EPs as ordering providers, complex CHD, and cardiomyopathy., (© 2024 Wiley Periodicals LLC.)

Heterotaxy is a disorder characterized by severe congenital heart defects (CHDs) and abnormal left-right patterning in other thoracic or abdominal organs. Clinical and research-based genetic testing has previously focused on evaluation of coding variants to identify causes of CHDs, leaving non-coding causes of CHDs largely unknown. Variants in the transcription factor zinc finger of the cerebellum 3 (ZIC3) cause X-linked heterotaxy. We identified an X-linked heterotaxy pedigree without a coding variant in ZIC3. Whole-genome sequencing revealed a deep intronic variant (ZIC3 c.1224+3286A>G) predicted to alter RNA splicing. An in vitro minigene splicing assay confirmed the variant acts as a cryptic splice acceptor. CRISPR-Cas9 served to introduce the ZIC3 c.1224+3286A>G variant into human embryonic stem cells demonstrating pseudoexon inclusion caused by the variant. Surprisingly, Sanger sequencing of the resulting ZIC3 c.1224+3286A>G amplicons revealed several isoforms, many of which bypass the normal coding sequence of the third exon of ZIC3, causing a disruption of a DNA-binding domain and a nuclear localization signal. Short- and long-read mRNA sequencing confirmed these initial results and identified additional splicing patterns. Assessment of four isoforms determined abnormal functions in vitro and in vivo while treatment with a splice-blocking morpholino partially rescued ZIC3. These results demonstrate that pseudoexon inclusion in ZIC3 can cause heterotaxy and provide functional validation of non-coding disease causation. Our results suggest the importance of non-coding variants in heterotaxy and the need for improved methods to identify and classify non-coding variation that may contribute to CHDs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Bicuspid aortic valve (BAV) is the most common congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that specific gene variants predispose to early-onset complications of BAV (EBAV). We analyzed whole-exome sequences (WESs) to identify rare coding variants that contribute to BAV disease in 215 EBAV-affected families. Predicted damaging variants in candidate genes with moderate or strong supportive evidence to cause developmental cardiac phenotypes were present in 107 EBAV-affected families (50% of total), including genes that cause BAV (9%) or heritable thoracic aortic disease (HTAD, 19%). After appropriate filtration, we also identified 129 variants in 54 candidate genes that are associated with autosomal-dominant congenital heart phenotypes, including recurrent deleterious variation of FBN2, MYH6, channelopathy genes, and type 1 and 5 collagen genes. These findings confirm our hypothesis that unique rare genetic variants drive early-onset presentations of BAV disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies., (© 2024 Wiley Periodicals LLC.)

Aortopathy encompasses a spectrum of conditions predisposing to dilation, aneurysm, dissection, or rupture of the aorta and other blood vessels. Aortopathy is diagnosed commonly in children, from infancy through adolescence, primarily affecting the thoracic aorta, with variable involvement of the peripheral vasculature. Pathogeneses include connective tissue disorders, smooth muscle contraction disorders, and congenital heart disease, including bicuspid aortic valve, among others. The American Heart Association has published guidelines for diagnosis and management of thoracic aortic disease. However, these guidelines are predominantly focused on adults and cannot be applied adeptly to growing children with emerging features, growth and developmental changes, including puberty, and different risk profiles compared with adults. Management to reduce risk of progressive aortic dilation and dissection or rupture in children is complex and involves genetic testing, cardiovascular imaging, medical therapy, lifestyle modifications, and surgical guidance that differ in many ways from adult management. Pediatric practice varies widely, likely because aortopathy is pathogenically heterogeneous, including genetic and nongenetic conditions, and there is limited published evidence to guide care in children. To optimize care and reduce variation in management, experts in pediatric aortopathy convened to generate this scientific statement regarding the cardiovascular care of children with aortopathy. Available evidence and expert consensus were combined to create this scientific statement. The most common causes of pediatric aortopathy are reviewed. This document provides a general framework for cardiovascular management of aortopathy in children, while allowing for modification based on the personal and familial characteristics of each child and family.

Pharmacogenetics promises to optimize treatment-related outcomes by informing optimal drug selection and dosing based on an individual's genotype in conjunction with other important clinical factors. Despite significant evidence of genetic associations with drug response, pharmacogenetic testing has not been widely implemented into clinical practice. Among the barriers to broad implementation are limited guidance for how to successfully integrate testing into clinical workflows and limited data on outcomes with pharmacogenetic implementation in clinical practice. The Pharmacogenomics Global Research Network Implementation Working Group seeks to engage institutions globally that have implemented pharmacogenetic testing into clinical practice or are in the process or planning stages of implementing testing to collectively disseminate data on implementation strategies, metrics, and health-related outcomes with the use of genotype-guided drug therapy to ultimately help advance pharmacogenetic implementation. This paper describes the goals, structure, and initial projects of the group in addition to implementation priorities across sites and future collaborative opportunities., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Data on mitral annular disjunction (MAD) in children with Marfan syndrome (MFS) are sparse. To investigate the diagnostic yield of MAD by echocardiography and cardiac magnetic resonance imaging (CMR), its prevalence and progression during childhood., Methods and Results: We included patients <21 years old with MFS, defined by 2010 Ghent criteria and a pathogenic FBN1 variant or ectopia lentis. Two readers measured systolic separation between the mitral valve (MV) posterior hinge point and left ventricular (LV) myocardium on initial and subsequent imaging. MAD was defined as MV-LV separation ≥2 mm, MV prolapse (MVP) as atrial displacement ≥2 mm. Kappa coefficients evaluated echocardiogram-CMR agreement. Bland-Altman and intraclass correlation coefficients (ICCs) assessed inter-rater and inter-modality reliability. Univariable mixed-effects linear regression was used to evaluate longitudinal changes of MAD. MAD was detected in 60% (110/185) eligible patients. MVP was present in 48% (53/110) of MAD and MAD in 90% (53/59) of MVP. MAD detection by CMR and echocardiography had 96% overall agreement (Kappa = 0.89, P < 0.001) and a 0.32 mm estimate bias (95% CI 0.00, 0.65). ICC by echocardiography, CMR, and between modalities were 0.97 (95% CI 0.93, 0.98), 0.92 (95% CI 0.79, 0.97), and 0.91 (95% CI 0.85, 0.94), respectively. MAD was associated with aortic root dilation (P < 0.001). MAD was found in children of all ages, increased +0.18 mm/year (95% CI +0.14, +0.22) during a median duration of 5.5 years (IQR 3.1, 7.5 years). MAD indexed by height yielded a constant value +0.0002 mm/m/year (95% CI -0.0002, +0.0005 mm/m/year)., Conclusion: MAD was common in pediatric MFS and was associated with aortic root dilation. MAD detection by echocardiography and CMR was highly reliable, suggesting that routine assessment in MFS is feasible. MAD was present in neonates and progressed over time but remained constant when indexing by height. Further studies are needed to evaluate MAD as a biomarker for clinical outcomes in pediatric MFS., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Influenza is associated with adverse outcomes in children, although modification by additional medical conditions is not well-documented. We aimed to compare outcomes in children with versus without congenital heart defects (CHDs) who were hospitalized for influenza. We retrospectively evaluated patients 1-18y hospitalized for influenza in the Pediatric Health Information (PHIS) database from 2004 to 2019. Outcomes were compared by CHD presence and then by CHD severity (minor biventricular, major biventricular, and single ventricle disease) using log-binomial regression adjusted for propensity scores accounting for age at admission, sex, and history of asthma. Outcomes included inpatient mortality, intensive care unit (ICU) admission, mechanical ventilation, and length of stay (LOS) > 12 days. To evaluate for effect modification by genetic diagnoses, analyses were repeated stratified by CHD and genetic diagnosis. Among 55,161 children hospitalized for influenza, 2369 (4.3%) had CHDs, including 963 with minor biventricular, 938 with major biventricular, and 468 with single ventricle CHDs. Adjusting for propensity scores, children with CHDs had higher mortality (4.1% versus 0.9%) compared to those without CHDs (risk ratio [RR] 2.5, 95% confidence interval [CI] 1.9-3.4). Children with CHDs were at higher risk of mechanical ventilation (RR 1.6, 95% CI 1.6-1.7), ICU admission (RR 1.9, 95% CI 1.8-2.1), and LOS > 12 days (RR 2.2, 95% CI 2.0-2.3). Compared to those with neither CHD nor genetic condition, children with both had significantly higher risk of all outcomes, with the largest difference for LOS > 12 days (RR 2.3, 95% CI 2.0-2.7). Children with CHDs hospitalized for influenza are particularly susceptible to adverse outcomes compared to those without CHDs. Future studies are needed to corroborate findings in light of influenza vaccination., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Traditional strategies for grouping congenital heart defects (CHDs) using birth defect registry data do not adequately address differences in expected clinical consequences between different combinations of CHDs. We report a lesion-specific classification system for birth defect registry-based outcome studies., Methods: For Core Cardiac Lesion Outcome Classifications (C-CLOC) groups, common CHDs expected to have reasonable clinical homogeneity were defined. Criteria based on combinations of Centers for Disease and Control-modified British Pediatric Association (BPA) codes were defined for each C-CLOC group. To demonstrate proof of concept and retention of reasonable case counts within C-CLOC groups, Texas Birth Defect Registry data (1999-2017 deliveries) were used to compare case counts and neonatal mortality between traditional vs. C-CLOC classification approaches., Results: C-CLOC defined 59 CHD groups among 62,262 infants with CHDs. Classifying cases into the single, mutually exclusive C-CLOC group reflecting the highest complexity CHD present reduced case counts among lower complexity lesions (e.g., 86.5% of cases with a common atrium BPA code were reclassified to a higher complexity group for a co-occurring CHD). As expected, C-CLOC groups had retained larger sample sizes (i.e., representing presumably better-powered analytic groups) compared to cases with only one CHD code and no occurring CHDs., Discussion: This new CHD classification system for investigators using birth defect registry data, C-CLOC, is expected to balance clinical outcome homogeneity in analytic groups while maintaining sufficiently large case counts within categories, thus improving power for CHD-specific outcome association comparisons. Future outcome studies utilizing C-CLOC-based classifications are planned., (© 2024 Wiley Periodicals LLC.)

Although descended from orb weavers, spiders in the family Theridiidae spin cobwebs whose sticky prey capture gumfoot lines extend from a silk tangle to a surface below. When a crawling insect contacts glue droplets at the bottom of a gumfoot line, the line's weak pyriform anchor releases, causing the taut line to contract, pulling the insect from the surface and making its struggles to escape ineffective. To determine if this change in prey capture biomechanics was accompanied by a change in the material properties of theridiid glue, we characterized the elastic modulus and toughness of the glue droplet proteins of four theridiid species at 20-90 % relative humidity and compared their properties with those of 13 orb weaving species in the families Tetragnathidae and Araneidae. Compared to orb weavers, theridiid glue proteins had low extensions per protein volume and low elastic modulus and toughness values. These differences are likely explained by the loss of tension on a gumfoot line when its anchor fails, which may prioritize glue droplet adhesion rather than extension. Similarities in theridiid glue droplet properties did not reflect these species' evolutionary relationships. Instead, they appear associated with differences in web architecture. Two species that had stiffer gumfoot support lines and longer and more closely spaced gumfoot lines also had stiffer glue proteins. These lines may store more energy, and, when their anchors release, require stiffer glue to resist the more forceful upward thrust of a prey. STATEMENT OF SIGNIFICANCE: When a crawling insect contacts glue droplets on a theridiid cobweb's gumfoot line, this taut line's anchor fails and the insect is hoisted upward, rendering its struggles to escape ineffective. This strategy contrasts with that of orb weaving ancestors, which rely on more closely spaced prey capture threads to intercept and retain flying insects. A comparison of the elastic modulus and toughness of gumfoot and orb web glue proteins shows that this change in prey capture biomechanics is associated with reductions in the stiffness and toughness of cobweb glue. Unlike orb web capture threads, whose droplets extend in a coordinated fashion to sum adhesive forces, gumfoot lines become untethered, which prioritizes glue droplet adhesive contact over glue droplet extension., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

With the improvement in the detection of congenital heart disease in fetal life, fetal cardiac interventions are pushing the envelope in hopes of either altering the natural history of disease or improving survival in certain high-risk lesions. These interventions include fetal aortic valvuloplasty for evolving hypoplastic left heart syndrome, fetal atrial septoplasty with or without atrial septal stenting for hypoplastic left heart syndrome and variants with intact or severely restrictive atrial septum, and fetal pulmonary valvuloplasty for severe pulmonary stenosis or pulmonary atresia with intact ventricular septum. This review discusses their indications, technical aspects, and outcomes based on available literature., Competing Interests: Disclosure A.M. Qureshi: Consultant for W.L. Gore and Associates, Edwards Lifesciences, Medtronic Inc, B. Braun and Abiomed Inc, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Marfan syndrome (MFS)-associated cardiomyopathy, defined as ventricular dilation and dysfunction unexplained by volume loading, is not well defined in children. This study evaluated ventricular size and function in paediatric MFS using cardiac MRI (cMRI)., Methods: This retrospective cohort study examined patients with MFS <19 years old at first cMRI. Left ventricular (LV) ejection fraction (EF) <55% was considered abnormal, as were z-scores >2. Combined mitral and aortic regurgitation indexed to LV stroke volume <20% defined absent/mild volume load. Biventricular volumes and EF on serial cMRI studies were compared with normative paediatric cMRI values, with measures converted to z-scores as appropriate. Longitudinal changes in volumes and EF were evaluated by mixed linear regression. Associations between ventricular, aortic and mitral characteristics were evaluated., Results: 58 patients (60% male) were evaluated. Median age at initial cMRI was 13.6 years (IQR 10.0-15.8 years). Among patients with absent/mild LV volume load at initial cMRI (n=44, 76%), indexed LV end-diastolic volume (EDV) was significantly increased above normative values (median z-score 1.8, IQR 0.6-3.5, p<0.0001) and LVEF was abnormal in 48% (21/44). In the absence of volume loading, mitral valve prolapse (MVP) was associated with larger ventricular volumes and lower LVEF. Among those with serial cMRIs, LVEF and EDV z-scores did not significantly change over a mean follow-up time between cMRI studies of 1.5 years., Conclusion: Ventricular dilation and reduced EF are common in children with MFS and occur with no/mild LV volume load, suggesting intrinsic cardiomyopathy. MVP may be associated with cardiomyopathy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

To resist lineage-dependent therapies such as androgen receptor inhibition, prostate luminal epithelial adenocarcinoma cells often adopt a stem-like state resulting in lineage plasticity and phenotypic heterogeneity. Castrate-resistant prostate adenocarcinoma can transition to neuroendocrine (NE) and occasionally to amphicrine, co-expressed luminal and NE, phenotypes. We developed castrate-resistant prostate cancer (CRPC) patient-derived organoid models that preserve heterogeneity of the originating tumor, including an amphicrine model displaying a range of luminal and NE phenotypes. To gain biological insight and to identify potential treatment targets within heterogeneous tumor cell populations, we assessed the lineage hierarchy and molecular characteristics of various CRPC tumor subpopulations. Transcriptionally similar stem/progenitor (St/Pr) cells were identified for all lineage populations. Lineage tracing in amphicrine CRPC showed that heterogeneity originated from distinct subclones of infrequent St/Pr cells that produced mainly quiescent differentiated amphicrine progeny. By contrast, adenocarcinoma CRPC progeny originated from St/Pr cells and self-renewing differentiated luminal cells. Neuroendocrine prostate cancer (NEPC) was composed almost exclusively of self-renewing St/Pr cells. Amphicrine subpopulations were enriched for secretory luminal, mesenchymal, and enzalutamide treatment persistent signatures that characterize clinical progression. Finally, the amphicrine St/Pr subpopulation was specifically depleted with an AURKA inhibitor, which blocked tumor growth. These data illuminate distinct stem cell (SC) characteristics for subtype-specific CRPC in addition to demonstrating a context for targeting differentiation-competent prostate SCs., (Published by Oxford University Press 2024.)

Purpose: Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain DPYD genetic variants with standard dosing. We implemented DPYD genotyping at a multisite cancer center and evaluated its impact on dosing, toxicity, and hospitalization., Methods: In this prospective observational study, patients receiving (reactive) or planning to receive (pretreatment) fluoropyrimidine-based chemotherapy were genotyped for five DPYD variants as standard practice per provider discretion. The primary end point was the proportion of variant carriers receiving fluoropyrimidine modifications. Secondary end points included mean relative dose intensity, fluoropyrimidine-related grade 3+ toxicities, and hospitalizations. Fisher's exact test compared toxicity and hospitalization rates between pretreatment carriers, reactive carriers, and wild-type patients. Univariable and multivariable logistic regression identified factors associated with toxicity and hospitalization risk. Kaplan-Meier methods estimated time to event of first grade 3+ toxicity and hospitalization., Results: Of the 757 patients who received DPYD genotyping (median age 63, 54% male, 74% White, 19% Black, 88% GI malignancy), 45 (5.9%) were heterozygous carriers. Fluoropyrimidine was modified in 93% of carriers who started treatment. In 442 patients with 3-month follow-up, 64%, 31%, and 30% of reactive carriers, pretreatment carriers, and wild-type patients had grade 3+ toxicity, respectively ( P = .085); 64%, 25%, and 13% were hospitalized ( P < .001). Reactive carriers had 10-fold higher odds of hospitalization compared with wild-type patients ( P = .001), whereas no significant difference was noted between pretreatment carriers and wild-type patients. Time-to-event of toxicity and hospitalization were significantly different between genotype groups ( P < .001), with reactive carriers having the earliest onset and highest incidence., Conclusion: DPYD genotyping prompted fluoropyrimidine modifications in most carriers. Pretreatment testing reduced toxicities and hospitalizations compared with reactive testing, thus normalizing the risk to that of wild-type patients, and should be considered standard practice.

Objectives: A subset of hypoplastic-left-heart-syndrome (HLHS) fetuses have a complex cor-triatriatum sinister that we named "labyrinthine-cor (L-cor)". We sought to determine the prevalence of L-cor in HLHS fetuses and hypothesized that it is associated with increased mortality., Methods: This single-center retrospective cohort study included all HLHS fetuses from January 2010-December 2020. Fetuses with other hypoplastic-left-heart variants, inadequate images, lack of follow-up and fetal atrial-septal interventions were excluded. RAS was defined as the ratio of pulmonary-vein forward-to-reverse velocity-time-integral (VTI) ≤ 5 and severe-RAS defined as VTI-ratio <3. Kaplan-Meier survival-analysis was performed for the primary outcome of transplant-free survival for 62 weeks after gestational-age of 30 weeks (∼1 year)., Results: Of the 156 consecutive fetuses with HLHS, 11 (7.7%) had L-cor and 8/11 (72.7%) of these had RAS. When compared to HLHS-RAS without L-cor, fetuses with HLHS-RAS and L-cor were less likely to survive to 28 days (87% vs. 62.5%, p = 0.017) and to 1 year (69.6% vs. 25%, p = 0.029). When comparing by survival analysis, fetuses with severe-RAS with L-cor had lower survival compared severe-RAS without L-cor (p = 0.020)., Conclusion: L-cor in fetal HLHS is associated with increased mortality. Recognition of this finding is important for prognostication and atrial-septal-intervention planning., (© 2024 John Wiley & Sons Ltd.)

Cardiovascular magnetic resonance (CMR) has become the reference standard for quantitative and qualitative assessment of ventricular function, blood flow, and myocardial tissue characterization. There is a preponderance of large CMR studies and registries in adults; However, similarly powered studies are lacking for the pediatric and congenital heart disease (PCHD) population. To date, most CMR studies in children are limited to small single or multicenter studies, thereby limiting the conclusions that can be drawn. Within the PCHD CMR community, a collaborative effort has been successfully employed to recognize knowledge gaps with the aim to embolden the development and initiation of high-quality, large-scale multicenter research. In this publication, we highlight the underlying challenges and provide a practical guide toward the development of larger, multicenter initiatives focusing on PCHD populations, which can serve as a model for future multicenter efforts., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Michael DiLorenzo reports a relationship with GE Healthcare that includes: funding grants. Mark Fogel reports a relationship with Rocket Pharmaceuticals Inc that includes: consulting or advisory. Mark Fogel reports a relationship with CMP Pharma that includes: funding grants. Andrew Powell reports a relationship with Siemens Medical Solutions USA Inc that includes: consulting or advisory. Shaine Morris reports a relationship with Aytu BioPharma Inc that includes: non-financial support. Kanwal Farooqi reports a relationship with Bristol-Myers Squibb Foundation that includes: funding grants. Jonathan Soslow reports a relationship with Pfizer Inc that includes: consulting or advisory. Jonathan Soslow reports a relationship with Sarepta Therapeutics Inc that includes: consulting or advisory. Jonathan Soslow reports a relationship with Immunoforge that includes: consulting or advisory. Heynric Grotenhuis serves as an associate editor for JCMR. Mark Fogel and Andrew Powell serve as members of the editorial board for JCMR. If there are other authors, they 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 © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Supravalvular aortic stenosis (SVAS) has been well described in Williams-Beuren Syndrome and non-syndromic elastin (ELN) mutations. Non-syndromic ELN mutations are inherited in an autosomal dominant pattern with incomplete penetrance and variable expressivity. ELN haploinsufficiency leads to progressive arteriopathy, typically affecting the aortic sinotubular junction. Multi-level pulmonary stenosis has also been reported and biventricular obstruction may portend a worse prognosis. Fetal presentation of ELN mutation with SVAS has not been previously reported in the literature. We present a case of fetal diagnosis of SVAS and multi-level pulmonary stenosis in a family with a known pathogenic ELN mutation (Exon 6, c.278del [p.Pro93Leufs*29]). On the fetus' initial fetal echo, there was only mild flow acceleration through the aortic outflow tract, however, she went on to develop progressive bilateral obstruction. In the early post-natal period, the child was clinically asymptomatic and showed similar mild SVAS and mild valvar and supravalvular pulmonary stenosis. Our case highlights the need for serial monitoring of fetuses with suspected or confirmed ELN arteriopathy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Complex gene regulatory mechanisms underlie differentiation and reprogramming. Contemporary single-cell lineage-tracing (scLT) methods use expressed, heritable DNA barcodes to combine cell lineage readout with single-cell transcriptomics. However, reliance on transcriptional profiling limits adaptation to other single-cell assays. With CellTag-multi, we present an approach that enables direct capture of heritable random barcodes expressed as polyadenylated transcripts, in both single-cell RNA sequencing and single-cell Assay for Transposase Accessible Chromatin using sequencing assays, allowing for independent clonal tracking of transcriptional and epigenomic cell states. We validate CellTag-multi to characterize progenitor cell lineage priming during mouse hematopoiesis. Additionally, in direct reprogramming of fibroblasts to endoderm progenitors, we identify core regulatory programs underlying on-target and off-target fates. Furthermore, we reveal the transcription factor Zfp281 as a regulator of reprogramming outcome, biasing cells toward an off-target mesenchymal fate. Our results establish CellTag-multi as a lineage-tracing method compatible with multiple single-cell modalities and demonstrate its utility in revealing fate-specifying gene regulatory changes across diverse paradigms of differentiation and reprogramming., (© 2023. The Author(s).)

Fetal cardiac intervention (FCI) is an emerging and rapidly advancing group of interventions designed to improve outcomes for fetuses with cardiovascular disease. Currently, FCI is comprised of pharmacologic therapies (e.g., trans-placental antiarrhythmics for fetal arrhythmia), open surgical procedures (e.g., surgical resection of pericardial teratoma), and catheter-based procedures (e.g., fetal aortic valvuloplasty for aortic stenosis). This review focuses on the rationale, criteria for inclusion, technical details, and current outcomes of the three most frequently performed catheter-based FCI procedures: (1) aortic valvuloplasty for critical aortic stenosis (AS) associated with evolving hypoplastic left heart syndrome (HLHS), (2) atrial septal intervention for HLHS with severely restrictive or intact atrial septum (R/IAS), and (3) pulmonary valvuloplasty for pulmonary atresia with intact ventricular septum (PA/IVS).