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Objectives: Our goal was to conduct a hemodynamic analysis of a novel animal model of Fontan physiology. Poor late-term outcomes in Fontan patients are believed to arise from Fontan-induced hemodynamics, but the mechanisms remain poorly understood. Recent advances in surgical experimentation have resulted in the development of a chronic sheep model of Fontan physiology; however, detailed analysis of this model is lacking. Methods: We created a single-stage Fontan model in juvenile sheep with normal biventricular circulation. The superior vena cava was anastomosed to the main pulmonary artery, and the inferior vena cava was connected to the main pulmonary artery using an expanded polytetrafluoroethylene conduit. Longitudinal hemodynamics, including catheterization and magnetic resonance imaging were evaluated. Results: Four out of 12 animals survived, with the longest surviving animal living 3 years after single-stage Fontan. We showed a significant era effect regarding survival (1 out of 8 and subsequently 3 out of 4 animals surviving beyond 2 months) attributed in large part to the procedural learning curve. Key characteristics of Fontan hemodynamics, namely systemic venous hypertension and low normal cardiac output, were observed. However, recapitulation of passive human Fontan hemodynamics is affected by volume loading of the right ventricle given an anatomic difference in sheep azygous venous anatomy draining to the coronary sinus. Conclusions: A significant learning curve exists to ensure long-term survival and future surgical modifications, including banding of the main pulmonary artery and ligation of the azygous to coronary sinus connection are promising strategies to improve the fidelity of model hemodynamics.

Chagas cardiomyopathy (CCC) is associated with coagulation disorders that frequently culminate in thrombotic events, contributing to increased mortality rates in this clinical condition. Considering the demonstrated effect that extracellular vesicles (EVs) have on regulating inflammatory processes, coagulation, and angiogenesis, the present study aims to characterize plasma EVs and their relationship with coagulation disorders in patients with CCC. A total of 78 patients were assessed with 46.1% (36/78) representing the CCC group, 8.9% (7/78) with cardiomyopathy unrelated to Chagas disease (CM group), and 44.8% (35/78) comprising the control group, which included individuals without cardiomyopathy and negative for T. cruzi infection. Plasma EVs concentration (EVs/mL) for each individual was evaluated by flow cytometry, along with the proportion of EVs expressing PSGL-1 (PSGL-1+ EVs), Tissue Factor (TF + EVs), and CD41a (CD41a + EVs). The ability of EVs to induce platelet aggregation was evaluated by spectrophotometry. We also evaluated other prothrombotic biomarkers, including platelet count, activated partial thromboplastin time (PTT), prothrombin time (PT), and D-dimer levels. The results revealed elevated D-dimer levels in the CCC group, accompanied by a decrease in the count of EVs per mL of plasma and a significant increase in the proportion of PSGL-1+ EVs ( P

Objective Brain tumors represent some of the most treatment refractory cancers, and there is a clinical need for additional treatments for these tumors. Domesticated dogs are the only other mammalian species which commonly develop spontaneous brain tumors, making them an ideal model for investigating novel therapies. Histotripsy is a non-thermal ultrasonic ablation method that emulsifies tissue through acoustic cavitation. The primary objectives of this prospective study were to assess the feasibility and safety of histotripsy to ablate naturally occurring canine brain tumors. Secondary endpoints included characterization of magnetic resonance imaging (MRI) responses to histotripsy treatment, and exploratory immunogenomic tumor response analyses. Methods The study design utilized a treat and resect paradigm, where tumors were approached using craniotomy, partially ablated with histotripsy delivered through the cranial defect, imaged with MRI, and then resected. Dogs were evaluated with clinical, brain MRI, immunopathologic, and genomic examinations before treatment, intraoperatively, and 1, 14, and 42 days post-treatment. Here we report the results of the three dogs with meningiomas, all of which were treated with a custom eight element 1 MHz histotripsy transducer at a pulse repetition frequency of 100 Hz and a treatment dosage of 400 pulses/point. Results Histotripsy was successfully delivered to all dogs, resulting in histopathologic evidence of ablations that were sharply demarcated from untreated tumor, with measured treatments approximating planned volumes in 2/3 dogs. One dog experienced an adverse event consisting of transient cerebral edema that was possibly attributable to histotripsy. Histotripsy ablations could be grossly visualized and identified on MRI, with features consistent with hemorrhage and necrosis. Significant expression or upregulation of the damage associated molecular pattern HMGB1, cytokine-cytokine receptor interaction, and NF-κb signaling pathways were observed in histotripsy treated tumors. Conclusion Ablation of canine meningiomas with histotripsy through an open cranial window was feasible and clinically well tolerated.

Background: Little is known about the effect of sex on functional status decline in aortic valve stenosis (AS) patients. Objectives: The purpose of this study was to examine the changes in functional status according to sex in patients with mild-to-moderate AS and its association with the composite of death or aortic valve replacement (AVR). Methods: We included patients with mild-to-moderate AS prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study (NCT01679431). Functional status was assessed using the New York Heart Association classification and the Duke Activity Status Index (DASI). Results: A total of 244 patients (mean age 64 ± 14 years, 29% women) were included. The mean follow-up was 4.3 ± 2.4 years. Women with intermediate-to-fast AS progression rate (median change in peak aortic jet velocity ≥0.11 m/s/year) had significantly faster decline in DASI score compared to men with similar progression rate (P

Background: In patients with low-gradient (LG) aortic stenosis (AS), confirming disease severity and indication of intervention often requires dobutamine stress echocardiography (DSE) or aortic valve calcium scoring by computed tomography. We hypothesized that the mean transvalvular pressure gradient to effective orifice area ratio (MG/EOA, in mm Hg/cm2) measured during rest echocardiography identifies true-severe AS (TSAS) and is associated with clinical outcomes in patients with low-flow, LG-AS. Objectives: The purpose of this study was to evaluate the diagnostic and prognostic value of MG/EOA ratio. Methods: The diagnostic accuracy of MG/EOA ratio to identify TSAS was retrospectively assessed in: 1) an in vitro data set obtained in a circulatory model including 93 experimental conditions; and 2) an in vivo data set of 188 patients from the TOPAS (True or Pseudo-Severe Aortic Stenosis) study (NCT01835028). Receiver operating characteristic curves were used to assess the diagnostic accuracy of MG/EOA ratio for identifying TSAS, and Cox proportional hazards regression analyses were performed to assess its association with clinical outcomes. Results: The optimal cutoff of MG/EOA ratio to identify TSAS in patients with low-flow, LG-AS was ≥25 mm Hg/cm2 (correct classification 85%), as well as in vitro (100%). During a median follow-up of 1.41 ± 0.75 years, 146 (78%) patients met the composite endpoint of aortic valve replacement or all-cause mortality. A MG/EOA ratio ≥25 mm Hg/cm2 was independently associated with an increased risk of the composite endpoint (adjusted HR: 2.36 [95% CI: 1.63-3.42], P

Background: Interbirth interval (IBI), the time between consecutive births, has been tied to perinatal outcomes. Objective: To analyze adverse perinatal events following short IBI in a large South American sample. Study design: Observational, retrospective, hospital-based study including malformed and nonmalformed live- and stillbirths. Outcomes were preterm birth (PTB), low birth weight (LBW), and specific birth defects. Logistic regressions were used to evaluate the risk of selected variables for short IBI and for adverse outcomes after short IBI, adjusting by confounders. Bayesian networks exhibited relationships among short IBI, outcomes, and variables. Results: Short IBI rate was 2%–3%. Maternal age and a previous abortion were the main confounders. A significant high risk for short IBI was found in mothers ≤19 years while mothers ≥30 were at low risk, mediated by a previous abortion. The risk of short IBI, adjusted by confounders, was significant for LBW but not for PTB. An unadjusted risk of short IBI was observed for gastroschisis, which disappeared after adjusting for confounders. Maternal age ≤19 and previous abortion were directly related with gastroschisis; the relationship between gastroschisis and short IBI occurred through any of these two variables. A direct relationship between gastroschisis and maternal age ≥30 was observed. Conclusions: Only young mothers were directly related with short IBI. In older mothers, a short IBI mainly occurred after a previous abortion. Short IBI was a risk factor only for LBW. The PTB and gastroschisis relationship with short IBI was indirect, mediated by young maternal age and/or a previous abortion.

Background: The association between sensitization to specific aeroallergens and outcomes in patients with asthma is well researched; however, the association between childhood-onset wheeze/asthma and sensitization to various aeroallergens and food allergens in the general pediatric population remains poorly understood. Objective: We sought to investigate the association between sensitization to common aeroallergens and food allergens with wheeze and type 2 (T2) inflammation in the general pediatric population. Methods: Specific IgEs against 9 aeroallergens and 4 food allergens were measured in the prospective Hokkaido birth cohort of 428 school-age children (age ∼10 years). Wheeze and other allergic symptoms were assessed using the International Study of Asthma and Allergies in Childhood questionnaire. Blood eosinophil count and fractional exhaled nitric oxide level were assessed as T2 biomarkers. The Isle of Wight birth cohort in the United Kingdom was used for replication analysis (n = 1032). Results: The prevalence of sensitization to at least 1 aeroallergen and food allergen was 70.5% and 22.3%, respectively. A significant association between wheeze and sensitization to aeroallergens such as ragweed, Japanese cedar, mugwort, and pet dander was found. However, the association between wheeze and wheat sensitization was highly significant (Hokkaido birth cohort: odds ratio, 4.67; 95% CI, 1.98-11.01; Isle of Wight birth cohort, odds ratio, 4.01; 95% CI, 1.78-9.07). Sensitization to most aeroallergens, though not any food allergen, was associated with the T2-high phenotype. Conclusions: Sensitization to wheat may be an important risk factor for wheeze/asthma development, especially the pathogenesis of T2-non/low asthma, independent of aeroallergens, in the general pediatric population.

Introduction: The primary objective of this study was to assess the feasibility of a 6-week internet-delivered Mantram Repetition Program (MRP) for women recently treated for breast cancer. A secondary objective explored changes in perceived stress, psycho-spiritual measures, and cytokines in the treatment group compared to a waitlist. Methods: A feasibility study (ORBIT model Phase IIa) with a randomized controlled trial pilot was conducted. Eligible women recently treated for breast cancer were randomized to the treatment group ( n = 14) or a waitlist group ( n = 12) and participated for 12 weeks. During weeks 1-6, the treatment group received the MRP intervention while the waitlisted group was inactive. During weeks 7-12, the treatment group was inactive while the waitlisted group received the MRP intervention. The primary outcomes were feasibility and acceptability of the internet-delivered MRP intervention protocol. Participants completed pre and post-intervention psycho-spiritual health assessments. A subset of participants provided serum for cytokine analyses at enrollment and week 6, coinciding with the period in which the treatment group receiving the MRP intervention. Results: Overall study attrition was 19.2%. MRP adherence for both groups was 86% at post-intervention and 90% in the treatment group at 6-week follow-up. Pre-to-post-intervention analyses pooling both groups’ data demonstrated decreased perceived stress ( p = .045) and increased spiritual well-being ( p =.004). IFN-γ and IL-17A were increased in the waitlisted group and decreased in the treatment group ( p = 0.048). Conclusion: Feasibility of a 6-week, internet-delivered MRP intervention for breast cancer survivors was established. Psycho-spiritual variables and serum cytokines are suitable clinical outcome measures for future MRP studies with breast cancer survivors. Data suggest MRP may reduce perceived stress and support spiritual well-being in women with breast cancer; however, additional studies are needed.

Background: Racial minorities are more likely to develop type 2 diabetes and experience associated microvascular complications. Non-Hispanic Blacks and Hispanics initially present with more severe diabetic foot ulcers (DFUs) and peripheral artery disease (PAD), with an associated 10-fold increase in risk for lower extremity amputation within the first year after diagnosis. This study was designed to determine if race is associated with a failure to refer to specialists for DFU treatment, and the severity of DFU at the time of initial presentation. Methods: Patients were identified from the medical record based on a diagnosis related to diabetic foot complications between January 1, 2018, and June 1, 2023, in the family medicine, endocrinology, orthopaedic, or emergency clinics at a Midwest Academic Hospital serving rural and urban populations. Patients self-reported race, demographics, severity of ulcer based on Wagner ulcer scale at time of referral, eventual amputation status, and measures of social determinants of health including the national Area Deprivation Index (ADI) and Rural-Urban Commuting Area (RUCA) codes were manually extracted and analyzed for correlations with referral status. Results: A total of 597 patients were eligible for inclusion. Race was not associated with lower referral rates ( P > .99) or source of referral ( P = .58) to specialty clinic and ulcer severity at initial examination ( P = .34). Patients who initially presented to the emergency department had more severe ulcers ( P = .016), and higher severity was significantly associated with lower limb amputation vs mild ulcers (odds ratio = 38.8, P = .02). No significant differences in referral source or severity of ulcer at presentation were seen for sex, age, marital status, insurance type, rural status, ADI, time from referral to appointment, or eventual amputation. Conclusion: In this study, we found that patient race was not associated with severity of DFU at presentation or subsequent referral to a Midwest academic specialty orthopaedic clinic for care. Level of Evidence: Level III, retrospective review.

Summary:. Acrodysostosis, a rare congenital syndrome, is characterized by peripheral dysostosis, nasal hypoplasia, mental retardation, and other skeletal deformities. Although severe saddle nose associated with midfacial hypoplasia causes great distress to patients, no studies have reported conducting rhinoplasty. In our experience, we suspected a boy with a significant saddle nose as having acrodysostosis and conducted genetic testing on the boy and his parents. Genetic analyses revealed that the patient had a deleterious mutation in the PDE4D gene that was not seen in either of his parents. Thus, the patient was diagnosed with de novo acrodysostosis. Rhinoplasty of the saddle nose using autogenous costal cartilage was planned; however, a major concern in using costal cartilage is the distortion caused by warping. To prevent this problem, a counterbalancing technique was used. After the surgery, no warping was observed during follow-up, and the patient and his family were satisfied with the outcomes. To our knowledge, we present the first case of surgical treatment of a patient with a saddle nose caused by acrodysostosis.

Objective. To evaluate the evidence regarding the association between iron deficiency anemia (IDA) and dental caries in children and adolescents. Methods. Searches were conducted in 4 international databases from the beginning of records until October 2023. Studies evaluating the association between IDA and dental caries in individuals aged 6 months to 18 years were included. Risk of bias was assessed using the Newcastle Ottawa Scale. Quantitative synthesis was performed using the inverse variance or Mantel-Haenzel method, depending on the type of outcome analyzed. Measures of association included odds ratios and mean differences, employing a random-effects model with a 95% confidence interval. Results. A total of 1161 studies were identified, of which 12 were selected for qualitative review and 9 for meta-analysis. A significant association was found between IDA and dental caries (odds ratio of 3.54; 95% CI: 2.54-4.94) and a higher rate of dental caries in the presence of IDA (mean difference of 1.96; 95% CI: 1.07-2.85). The certainty of evidence according to GRADE was rated as very low. Conclusions. Despite the limited certainty, the findings indicate a significant association between IDA and dental caries. It is prudent to interpret these results with caution, considering the methodological limitations of the studies. However, given the potential relevance of this association for public health, recommending oral health strategies, including preventive and corrective dental interventions, for anemia control programs underlines the importance of more rigorous future research to strengthen the certainty of the evidence and guide the implementation of these strategies.

There is a lack of stability in language difficulties across early childhood: most late talkers (LTs) resolve their difficulties by pre-school; and a significant number of children who were not LTs subsequently manifest language difficulties. Greater reliability in predicting individual outcomes is needed, which might be achieved by waiting until later in development when language is more stable. At 18 months, productive vocabulary scores on the Oxford Communicative Developmental Inventory were used to classify children as LTs or average talkers (ATs). Thirty matched-pairs of LTs and ATs were followed up at school-age (average age 7 years), when language and literacy outcomes were assessed. For 18 children, intermediate testing at age 4 had classified them as showing typical development (TD) or specific language impairment (SLI). After correcting for multiple comparisons, there were no significant differences between the LTs and ATs on any outcome measure, and the LTs were performing in the average range. However, there were large-sized effects on all outcomes when comparing the TD and SLI groups. LT status on its own is not determinative of language and literacy difficulties. It would therefore not be appropriate to use expressive vocabulary measures alone to screen for language difficulties at 18 months. However, children with language impairment at age 4 are at risk of enduring difficulties.