Angiogenic Biomarkers for Risk Stratification in Women with Preeclampsia.

BACKGROUND: Preeclampsia is a leading cause of maternal and neonatal mortality and morbidity worldwide. Diagnosis of the condition is currently limited to utilization of nonspecific signs and symptoms. However, identification of potential pathogenic biomarkers may support earlier diagnosis and ultimately improved prognosis. CONTENT: The current models of preeclampsia suggest that the disease has components of abnormal placentation, a degree of angiogenic imbalance and endothelial dysfunction. Angiogenic factors such as soluble fms-like tyrosine kinase-1 and soluble endoglin increase while placental growth factor concentrations decrease in the circulation weeks before the onset of the disease. Multiple studies have looked at the capacity of angiogenic factors for the prediction of preeclampsia and adverse pregnancy outcomes. SUMMARY: The goal of this review is to focus on the role of angiogenic factors in the pathogenesis of preeclampsia and use of angiogenic biomarkers for risk stratification, diagnosis, and prognosis of the disease.

FNPC-SAM: Uncertainty-Guided False Negative/Positive Control for SAM on Noisy Medical Images.

The Segment Anything Model (SAM) is a recently developed all-range foundation model for image segmentation. It can use sparse manual prompts such as bounding boxes to generate pixel-level segmentation in natural images but struggles in medical images such as low-contrast, noisy ultrasound images. We propose a refined test-phase prompt augmentation technique designed to improve SAM's performance in medical image segmentation. The method couples multi-box prompt augmentation and an aleatoric uncertainty-based false-negative (FN) and false-positive (FP) correction (FNPC) strategy. We evaluate the method on two ultrasound datasets and show improvement in SAM's performance and robustness to inaccurate prompts, without the necessity for further training or tuning. Moreover, we present the Single-Slice-to-Volume (SS2V) method, enabling 3D pixel-level segmentation using only the bounding box annotation from a single 2D slice. Our results allow efficient use of SAM in even noisy, low-contrast medical images. The source code has been released at: https://github.com/MedICL-VU/FNPC-SAM.

Open-source graphical user interface for the creation of synthetic skeletons for medical image analysis.

Purpose: Deformable medial modeling is an inverse skeletonization approach to representing anatomy in medical images, which can be used for statistical shape analysis and assessment of patient-specific anatomical features such as locally varying thickness. It involves deforming a pre-defined synthetic skeleton, or template, to anatomical structures of the same class. The lack of software for creating such skeletons has been a limitation to more widespread use of deformable medial modeling. Therefore, the objective of this work is to present an open-source user interface (UI) for the creation of synthetic skeletons for a range of medial modeling applications in medical imaging. Approach: A UI for interactive design of synthetic skeletons was implemented in 3D Slicer, an open-source medical image analysis application. The steps in synthetic skeleton design include importation and skeletonization of a 3D segmentation, followed by interactive 3D point placement and triangulation of the medial surface such that the desired branching configuration of the anatomical structure's medial axis is achieved. Synthetic skeleton design was evaluated in five clinical applications. Compatibility of the synthetic skeletons with open-source software for deformable medial modeling was tested, and representational accuracy of the deformed medial models was evaluated. Results: Three users designed synthetic skeletons of anatomies with various topologies: the placenta, aortic root wall, mitral valve, cardiac ventricles, and the uterus. The skeletons were compatible with skeleton-first and boundary-first software for deformable medial modeling. The fitted medial models achieved good representational accuracy with respect to the 3D segmentations from which the synthetic skeletons were generated. Conclusions: Synthetic skeleton design has been a practical challenge in leveraging deformable medial modeling for new clinical applications. This work demonstrates an open-source UI for user-friendly design of synthetic skeletons for anatomies with a wide range of topologies.

A Comparison of Obstetric Interventions and Outcomes Between Black and White Patients at an Urban Tertiary Medical Center.

The objective of the study is to evaluate whether rates of selected labor and delivery interventions and severe maternal morbidity (SMM) differ between Black and White pregnant patients. This retrospective observational cohort study included all Black or White pregnant patients who delivered at the University of Chicago Medical Center between January 2015 and December 2019. Data queried included demographic information, antepartum complications, preterm interventions, labor and delivery events, and neonatal outcomes. SMM was a composite outcome, including intensive care unit admission, blood transfusion, hysterectomy, eclampsia, cardiac arrest, or death. In total, 10,885 parturients (9001 Black and 1884 White) and 11,211 neonates (9254 born to Black and 1957 to White patients) were included in the study. Black patients were more likely to have preterm labor (3.51% vs. 1.86%, p = 0.0002) and no prenatal care (17.83% vs. 4.05%, p < 0.0001). There was no significant difference in the administration of magnesium sulfate for fetal neuroprotection (Black 44.78% vs. White 49.32%, p = 0.48) or antenatal corticosteroids (Black 67.83% vs. White 71.98%, p = 0.28) among those with preterm delivery. There was no significant difference in SMM (Black 2.24% vs. White 2.44%, p = 0.60), and SMM rates decreased over time (OR 0.79 per year, 95% CI: 0.72-0.87, p < 0.0001) for all patients. Black patients had more pregnancy complications, but their complications were addressed with similar rates of obstetrical interventions. In a high-resource setting, there was no difference in rates of SMM when compared to White patients.

Association of fetal sex with angiogenic factors in normotensive and hypertensive pregnancy states.

OBJECTIVES: With the incorporation of angiogenic biomarkers into clinical practice, identification of potential modifiers of the angiogenic profile, including fetal sex, is essential. STUDY DESIGN: In this retrospective cohort analysis, patients with hypertensive disorders of pregnancy (HDP) and normotensive pregnancies were enrolled upon admission to Labor and Delivery. Blood samples for angiogenic factors were assessed using an automated platform. Clinical and demographic information was abstracted from each patient's medical records. MAIN OUTCOME MEASURES: Soluble fms-like tyrosine kinase-1 (sFlt1) and placental growth factor (PlGF) levels and their ratio in relation to fetal sex in patients with normotensive pregnancies compared to those with HDP were evaluated. RESULTS: A total of 617 patients were analyzed (299 normotensive, 113 gestational hypertensive, 71 chronic hypertensive, and 134 preeclamptic patients). There was no difference between the number of patients who had a male fetus among preeclampsia and normotensive parturients (56.0 % vs 50.2 %, p = 0.26). Normotensive patients carrying a male fetus had significantly higher sFlt1 (pg/ml) (3168 [IQR: 2160-4945] vs 2678 [IQR: 1752-4271]; p = 0.01) and sFlt1/PlGF ratios (18 [IQR: 7-44] vs 12 [IQR: 5-30]; p = 0.01) in comparison to pregnant patients carrying a female fetus. This difference between fetal sexes was not observed in the angiogenic profile of patients with HDP. CONCLUSIONS: Our study of primarily Black, obese patients demonstrates that normotensive patients carrying a male fetus have a significantly higher sFlt1 and sFlt1/PlGF ratio as compared to those carrying a female fetus at term gestation. Fetal sex should be considered as a covariate when studying angiogenic factors in normotensive pregnant patients.

Prevalence and management of severe intrapartum hypertension in patients with preeclampsia at an urban tertiary care medical center.

OBJECTIVES: Data on management of severe intrapartum hypertension is lacking. The aim of this study is to explore the proportion of timely interventions in severe, persistent intrapartum hypertension treatment by exploring the prevalence and management of intrapartum hypertension trends. STUDY DESIGN: This was a retrospective case-control study of pregnant women who delivered at the University of Chicago between January 2015 and March 2017. Patients with severe preeclampsia who underwent labor (either induced or spontaneous) were stratified into two groups: severe intrapartum hypertension and no severe intrapartum hypertension. MAIN OUTCOME MEASURES: Type of treatment and timing to treatment of severe hypertensive episodes were explored as well as prevalence of maternal adverse outcomes. RESULTS: A total of 95 patients with severe preeclampsia in labor were identified. In patients with persistent severe intrapartum hypertension (n = 52), 15 (28.9%) received treatment. Patients experiencing greater than three episodes of blood pressure elevation were more likely to receive treatment as compared to those with fewer episodes. There was no significant difference in severe maternal morbidity (SMM) between those treated within 60 min compared to those untreated or treated after 60 min (16.7% vs 27.5%; p = 0.71). CONCLUSIONS: Management protocols of intrapartum hypertensive episodes are variable or not universally implemented. Inadequately treated episodes of severe intrapartum hypertension trend towards higher rates of SMM.

Women's perspectives and attitudes towards the utility of angiogenic biomarkers in preeclampsia.

OBJECTIVE: This study aimed to evaluate womens' perspectives about current and novel preeclampsia testing methods at an urban tertiary medical center. METHODS: This was an observational survey study conducted between October 1, 2020 and December 31, 2020. Subjects were eligible if they were ≥ 18 years of age and had a diagnosis of gestational hypertension, preeclampsia, or superimposed preeclampsia at the time of delivery. Informed consent was obtained, and the 26-question survey was administered after delivery. A detailed medical record review was completed for respondents (patients) and their neonates. RESULTS: A total of 100 women were included in the study. The majority of participants were Black (78%) and/or on Medicaid (51%). Most respondents agreed that they fully trust their doctor and medical team (96%) and that the newest medical tests, treatments, and technologies should always be used (91%). Most women (80%) at least somewhat agreed they have enough knowledge about preeclampsia and its complications. Over 90% of women agreed a test to predict complications of preeclampsia would be useful to them. Most women reported a rule out test would be useful to them because it would help them worry less (68%), reduce hospitalizations (32%) and reduce interventions (17%). CONCLUSION: There was majority support for novel methods such as biomarker testing among this cohort. Most patients reported the test would decrease worry associated with preeclampsia development and complications.

Use of the angiogenic biomarker profile to risk stratify patients with fetal growth restriction.

BACKGROUND: Novel angiogenic biomarker profiles have demonstrated emerging evidence for predicting preeclampsia onset, severity, and adverse outcomes. Limited data exist in screening patients with fetal growth restriction for preeclampsia development using angiogenic biomarkers. OBJECTIVE: The objective of this study was to risk stratify patients with fetal growth restriction using a soluble fms-like tyrosine kinase-1 to placental growth factor ratio. Previously published cutoff of 38 was used to predict preeclampsia development and severity as well as adverse maternal or neonatal outcomes within a 2-week time period. STUDY DESIGN: This was a prospective observational cohort study performed in a single tertiary hospital. Patients with a singleton fetal growth restriction pregnancy between 24 and 37 weeks' gestation were evaluated using serial 2-week encounters from the time of enrollment to delivery. Pregnancies with proven genetic or infectious etiology of fetal growth restriction or congenital anomalies were excluded. Ultrasound growth and Doppler measurements were obtained at the start of every encounter with routine preeclampsia laboratory tests and blood pressure checks when clinically indicated. Maternal serum was collected for all serial encounters and measured for soluble fms-like tyrosine kinase-1 and placental growth factor after delivery in a double-blinded fashion. Maternal charts were reviewed for baseline demographic characteristics, pregnancy diagnoses and outcomes, and neonatal outcomes. RESULTS: A total of 45 patients were enrolled for a total of 77 encounters, with the median (quartile 1, quartile 3) gestational age of the study enrolled at 31.43 (28.14-33.57) weeks. Patients were divided into low-risk (ratio of <38) and high-risk (ratio of ≥38) groups. Baseline characteristics of patients did not show any marked differences, including preeclampsia labs or ultrasound parameters, between the 2 groups. Systolic and diastolic blood pressures upon enrollment were statistically elevated when soluble fms-like tyrosine kinase-1 to placental growth factor ratio was ≥38 (P=.02 and P=.01, respectively). Compared to patients with a low ratio, patients with a high ratio had a greater proportion of preeclampsia diagnosis, higher rates of preterm delivery under 34 and 37 weeks gestation, smaller neonatal birthweight, and a shorter time to delivery from testing to delivery. CONCLUSION: Among patients with fetal growth restriction, the soluble fms-like tyrosine kinase-1 to placental growth factor ratio may serve as a potential biomarker for identifying at risk patients for developing preeclampsia and subsequently preterm delivery.

The Sibs Program: A Structured Peer-Mentorship Program to Reduce Burnout for First-Year Medical Students.

This article was migrated. The article was marked as recommended. First-year medical students are at risk for burnout despite resources available to help them manage stress. In 2015, a structured peer-mentorship program was created at our institution for incoming medical students (M1s) by second-year medical students (M2s) with a goal of reducing risk factors for burnout; a secondary goal was to improve the mentoring skills of M2s. Over the course of the year, we surveyed M1s about their anxiety, prioritization skills, and work-life balance; M2s from the previous year's unstructured peer-mentorship program served as a control group. 164 M1s and 164 M2s participated in this program. Among M1s, a structured peer-mentorship program significantly reduced anxiety levels (p=<0.01), improved prioritization skills (p=<0.01), and facilitated greater awareness of the importance of striving to maintain work-life balance (p=<0.01). M2s felt neutral-to-agreeable in their ability to provide guidance, refer students for help, and remain invested in their mentees. A structured peer-mentorship program, therefore, may reduce anxiety, improve prioritization skills, and emphasize the importance of work-life balance among M1s, elements that have been associated with reduced rates of burnout. Furthermore, this program can augment the professional development of M2s by motivating them to maintain longitudinal mentoring relationships with underclassmen.

Ultrasound Shear Wave Velocity Varies Across Anatomical Region in Ex Vivo Bovine Ovaries.

The physical properties of the ovarian extracellular matrix (ECM) regulate the function of ovarian cells, specifically the ability of the ovary to maintain a quiescent primordial follicle pool while allowing a subset of follicles to grow and mature in the estrous cycle. Design of a long-term, cycling artificial ovary has been hindered by the limited information regarding the mechanical properties of the ovary. In particular, differences in the mechanical properties of the two ovarian compartments, the cortex and medulla, have never been quantified. Shear wave (SW) ultrasound elastography is an imaging modality that enables assessment of material properties, such as the mechanical properties, based on the velocity of SWs, and visualization of internal anatomy, when coupled with B-mode ultrasound. We used SW ultrasound elastography to assess whole, ex vivo bovine ovaries. We demonstrated, for the first time, a difference in mechanical properties, as inferred from SW velocity, between the cortex and medulla, as measured along the length (cortex: 2.57 ± 0.53 m/s, medulla: 2.87 ± 0.77 m/s, p < 0.0001) and width (cortex: 2.99 ± 0.81 m/s, medulla: 3.24 ± 0.97 m/s, p < 0.05) and that the spatial distribution and magnitude of SW velocity vary between these two anatomical planes. This work contributes to a larger body of literature assessing the mechanical properties of the ovary and related cells and specialized ECMs and will enable the rational design of biomimetic tissue engineered models and durable bioprostheses. Impact Statement Shear wave (SW) ultrasound elastography can be used to simultaneously assess the material properties and tissue structures when accompanied with B-mode ultrasound. We report a quantitative difference in mechanical properties, as inferred from SW velocity, between the cortex and medulla, with SW velocity being 11.4% and 8.4% higher in the medulla than the cortex when measured along the length and width, respectively. This investigation into the spatial and temporal variation in SW velocity in bovine ovaries will encourage and improve design of more biomimetic scaffolds for ovarian tissue engineering.

Allogeneic Decellularized Muscle Scaffold Is Less Fibrogenic and Inflammatory than Acellular Dermal Matrices in a Rat Model of Skeletal Muscle Regeneration.

BACKGROUND: Skeletal muscle trauma can produce grave functional deficits, but therapeutic options remain limited. The authors studied whether a decellularized skeletal muscle scaffold would provide benefits in inducing skeletal muscle regeneration over acellular dermal matrices. METHODS: Eighty-two rat muscle defects were surgically created and assigned to no intervention or implantation of AlloDerm, Strattice, decellularized rat muscle, or decellularized rat dermis to 30 or 60 days. Decellularized rat muscle and dermis were prepared using a negative pressure-assisted protocol. Assessment for cellularity, neovascularization, myogenesis, inflammation and fibrosis were done histologically and by polymerase chain reaction. RESULTS: Histology showed relative hypercellularity of AlloDerm (p < 0.003); Strattice appeared encapsulated. Immunofluorescence for CD31 and myosin heavy chain in decellularized rat muscle revealed dense microvasculature and peripheral islands of myogenesis. MyoD expression in muscle scaffolds was 23-fold higher than in controls (p < 0.01). Decellularized rat muscle showed no up-regulation of COX-2 (p < 0.05), with less expression than decellularized rat dermis and Strattice (p < 0.002). Decellularized rat muscle scaffolds expressed tumor necrosis factor-α less than Strattice, AlloDerm, and decellularized rat dermis (p < 0.01); collagen-1a less than decellularized rat dermis and Strattice (p < 0.04); α-smooth muscle actin 7-fold less than AlloDerm (p = 0.04); and connective tissue growth factor less than Strattice, AlloDerm, and decellularized rat dermis (p < 0.02). CONCLUSION: Decellularized muscle matrix appears to reduce inflammation and fibrosis in an animal muscle defect as compared with dermal matrices and promotes greater expression of myocyte differentiation-inducing genes.

Residual sodium dodecyl sulfate in decellularized muscle matrices leads to fibroblast activation in vitro and foreign body response in vivo.

Detergents such as sodium dodecyl sulfate (SDS) are commonly used to extract cells from tissues in a process called "decellularization". Residual SDS is difficult to completely remove and may lead to an undesirable host response towards an implanted biomaterial. In this study, we developed a modification for SDS cell extraction from muscle equally efficient to previous methods but leading to significantly less residual SDS remnants in the matrices. Muscle-derived matrices were prepared via 2 SDS-based decellularization methods, which led to removal of either 81.4% or 98.4% of the SDS. In vitro, matrices were seeded with thp1 macrophages and primary human foreskin fibroblasts. By Day 2, both matrices demonstrated similar macrophage polarization; however, fibroblasts cultured on matrices with greater residual SDS expressed higher levels of mRNA associated with fibroblast activation: α-smooth muscle actin and connective tissue growth factor. In vivo, Collagen I gels spiked with increasing concentrations of SDS displayed a corresponding decrease in cell infiltration when implanted subcutaneously in rats after 4 days. Finally, as a model for muscle regeneration, matrices produced by each method were implanted in rat latissimus dorsi defects. At POD 30 greater levels of IL-1ß mRNA were present in defects treated with matrices containing higher levels of SDS, indicating a more severe inflammatory response. Although matrices containing higher levels of residual SDS became encapsulated by POD 30 and showed evidence of a foreign body response, matrices with the lower levels of SDS integrated into the defect area with lower levels of inflammatory and fibrosis-related gene expression.

Topical application of Dermatophagoides farinae or oxazolone induces symptoms of atopic dermatitis in the rabbit ear.

Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of the epidermis, and dermal infiltration of inflammatory cells. Appropriate animal models that recapitulate human AD and allow the analysis of disease processes in a reliable manner are essential to the study of AD. In this study, we established two AD models in rabbits by applying an allergen, Dermatophagoides farinae (Der f), or a hapten, oxazolone (OXZ). Application of the allergen or hapten induced a rapid onset and a chronically sustained AD-like skin lesion. The clinical symptoms, which include skin erythema, scaling, papula and edema, of AD-like rabbit skin were similar to those in human AD. Histological analysis showed that allergen- or hapten-treated rabbit skin showed increased epidermal thickening and inflammatory cell infiltration. Furthermore, PCNA and keratin 10 (K10) staining revealed excessive proliferation and insufficient differentiation of the epidermis in the rabbit AD-like skin. Western blot analysis showed decreased expression of thymic stromal lymphopoietin (TSLP), an AD cytokine, in the rabbit AD-like skin. Our results suggest that the allergen- or hapten-induced rabbit AD models have pathological features of human AD-like symptoms and will be useful for evaluating both pathogenic mechanisms and potential therapeutic agents for human AD.

El hábito tabáquico en un grupo de adolescentes de 12 a 16 años de edad y su repercusión en el aparato respiratorio / The smoke habit in teenagers between 12 and 16 years old and its consequences on the respiratory system

En un plantel escolar de nivel medio básico se estudiaron 634 alumnos (314 hombres y 320 mujeres) de 12 a 16 años de edad para conocer sus experiencias en el hábito de fumar tabaco y sus posibles consecuencias en el aparato respiratorio. Se investigaron antecedentes y patología respiratoria actual, presencia e intensidad del hábito de fumar y se realizaron estudios de función pulmonar, buscando alteraciones de la mecánica respiratoria compatibles con daño en las vías aéreas, atribuibles al tabaquismo. 167 alumnos (26.3 por ciento) aceptaron ser fumadores (110 hombres y 57 mujeres) de los cuales 45 (27 por ciento) consumían más de 5 cigarrillos al día desde dos años antes. Tanto en el número total de fumadores como en la intensidad del hábito hubo franco predominio de los hombres sobre las mujeres. Treinta y cinco de los más fumadores (25 hombres y 10 mujeres) aceptaron que se les realizaran pruebas de función pulmonar; se integró un grupo semejante de no fumadores como testigo. En los estudios de función pulmonar mostraron alteraciones en los flujos 50 por ciento y 75 por ciento de la Capacidad Vital en ambos grupos los que se relacionan con obstrucción de la vías aéreas de grueso calibre; como estos datos los presentaron los integrantes de los dos grupos de estudio, se deduce que posiblemente obedezcan a otro riesgo común y no sólo al hecho de fumar. El Volumen de Cierre mostró ser un parámetro útil ya que todos los grupos lo tuvieron alterado aunque de manera diferente; esta prueba identifica las lesiones de la vías aéreas más pequeñas. En el grupo de fumadoras los valores se corrigieron con la administración de broncodilatador no así en el grupo de varones fumadores, estos datos sugieren que en los varones predominan las alteraciones estructurales y en las mujeres las reactivas (p< 0.05)

Efecto de dos plaguicidas intramuros en la función respiratoria de una población mexicana / Effecto to respiratory function for insecticides in household in mexican population

Antecedentes: en las grandes ciudades la utilización de pesticidas ha ido en aumento. Existen pocos estudios que demuestren la existencia de repercusiones en el aparato respiratorio. Objetivo: determinar el tipo de las alteraciones respiratorias que se producen en una población sana de la Ciudad de México ante la exposición a dos productos comerciales para el control de plagas intramuros y conocer las manifestaciones clínicas y funcionales que su uso conlleva. Material y método: se incluyeron 70 individuos voluntarios sanos de la Ciudad de México que habitaban en un departamento de 100 metros cuadrados de construcción, sin antecedentes de tabaquismo y sin proceso infeccioso al momento del estudio. El total de individuos seleccionados se dividió en dos grupos, ambos expuestos a los insecticidas. El grupo A correspondió a los insecticidas por combustión y el grupo B al de combustión eléctrica. A todos los participantes se les efectuó un estudio espirométrico al inicio y cada hora durante el tiempo de exposición. El análisis se hizo mediante t de Student. Resultados: el grupo A tuvo disminución del VEF1 durante el tiempo de estudio, con una p < 0.01 en la primera hora y < 0.028 en las siguientes, con fenómenos colaterales como: irritación ocular (74 por ciento), tos (43 por ciento), disnea (57 por ciento) y cefalea (28 por ciento). El grupo B tuvo una pequeña diferencia (p< 0.03) durante la primera hora y ninguna en las dos siguientes; no se observaron fenómenos colaterales. El análisis intergrupal demostró una diferencia significativa de p < 0.004 en la primera hora. Conclusión: el uso de insecticidas puede ser dañino para la salud y su exposición puede producir obstrucción de la vía aérea y síntomas clínicos de tipo irritativo, en especial con los derivados químicos inorganicos.