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Adverse pregnancy outcomes (APOs) collectively represent the leading causes of maternal and neonatal morbidity and mortality. Beyond the potentially devastating impact of APOs during pregnancy and the puerperium, women diagnosed with APOs have a 2-fold to 4-fold increased risk of future cardiovascular disease. Fortunately, APOs occur at an opportune time, in early-adulthood to mid-adulthood, when primary and secondary prevention strategies can alter the disease trajectory and improve long-term health outcomes. This chapter takes a life-course approach to (1) the epidemiology of APOs, (2) evidence-based strategies for clinicians to manage APOs, and (3) future directions for APO research and clinical practice.

Given that eating disorders (EDs) are relatively common in college populations, it is important to have reliable and valid tools to identify students so that they can be referred to evidence-based care. Although research supports the psychometric properties of existing ED screens for identifying cases of EDs, most studies have been conducted in samples of young white-majority women or have not reported the psychometric properties of the screening tool in men.The purpose of the current study was to validate a brief, 10-item screening tool for the identification of EDs-the brief assessment of stress and eating (BASE).Participants were college students (N = 596; 68.2% cisgender women) from a large Midwestern university who completed the BASE and SCOFF. The Eating Disorders Diagnostic Survey was used to generate DSM-5 ED diagnoses. We evaluated area under the curve (AUC) for both receiver operating curves (ROC) and precision-recall curves (PRC).Both the BASE and SCOFF performed significantly better than chance at identifying probable EDs in cisgender women (BASE AUC: ROC = .787, PRC = .633, sensitivity = .733, specificity = .697; SCOFF AUC: ROC = .810, PRC = .684, sensitivity = .793, specificity = .701). However, the BASE (AUC: ROC = .821, PRC = .605, sensitivity = .966, specificity = .495) significantly outperformed the SCOFF (AUC: ROC = .710, PRC = .354, sensitivity = .828, specificity = .514) for identifying probable EDs in cisgender college men.The BASE is appropriate for student healthcare and college research settings. Because the BASE outperforms the SCOFF in college men, results from the current study are expected to contribute to improved identification of EDs on college campuses.The BASE is a new screening tool to identify eating disorders. The BASE performed as well as, if not better than, the SCOFF (particularly in men). Given the need for brief, psychometrically strong, and unbiased ED screening tools in college students, the current study helps address an unmet student healthcare need that we expect will contribute to improved identification of EDs on college campuses.

Treatment of small-caliber vessel lesions using flow diverters remains challenging because of vasculature's narrow luminal diameter and tortuosity. This in turn makes navigation and delivery of conventional devices with standard microcatheters more difficult. The Silk Vista Baby (SVB, Balt) flow diversion device was designed for ease of use in vessels with a smaller diameter, distal lesions, and 0.017 ″ microcatheter delivery systems.To report the outcomes of the SVB device on the treatment of posterior inferior cerebellar artery (PICA) aneurysms.Databases from different centers were retrospectively reviewed for PICA aneurysms treated with SVB. Demographic information, clinical presentation, radiographic characteristics, procedural complications, and immediate postprocedure outcomes were obtained.Fourteen patients harboring 15 true PICA aneurysms were treated between January 2019 and June 2021. Nine were female (n = 9/14; 64.2%), and the mean age was 51 ± 14.9 years. Most patients had previously ruptured aneurysms, treated by another endovascular technique. Six aneurysms were located distally (n = 6/15; 40%). The mean neck size was 3 mm (SD 1.35, range 2.5-5 mm), whereas the mean PICA diameter was 1.6 mm (SD 0.26, range 1.5-1.7 mm). The mean length of follow-up was 6 months (SD 8.28, range 4.5-16 months). Treatment-related adverse events included 1 case of transient hypoesthesia. Two additional events were reported, but adjudicated as unrelated to the procedure. Complete occlusion, measured as Raymond-Roy class I, was achieved in all cases.The SVB device was safely and effectively used in the treatment of PICA aneurysms. The smaller delivery system profile reduces the risk of procedure complications and creates new treatment options for distal lesions.

STUDY QUESTION Does having a male co-twin, older brothers, or sons lead to an increased probability of persistent male microchimerism in female members of twin pedigrees? SUMMARY ANSWER The presence of a male co-twin did not increase risk of male microchimerism and the prevalence of male microchimerism was not explained by having male offspring or by having an older brother. WHAT IS KNOWN ALREADY Microchimerism describes the presence of cells within an organism that originate from another zygote and is commonly described as resulting from pregnancy in placental mammals. It is associated with diseases with a female predilection including autoimmune diseases and pregnancy-related complications. However, microchimerism also occurs in nulliparous women; signifying gaps in the understanding of risk factors contributing to persistent microchimerism and the origin of the minor cell population. STUDY DESIGN, SIZE, DURATION This cross-sectional study composed of 446 adult female participants of the Netherlands Twin Register (NTR). PARTICIPANTS/MATERIALS, SETTING, METHODS Participants included in the study were female monozygotic (MZ) twins, female dizygotic same-sex twins and females of dizygotic opposite-sex twin pairs, along with the mothers and sisters of these twins. Peripheral blood samples collected from adult female participants underwent DNA extraction and were biobanked prior to the study. To detect the presence of male-origin microchimerism, DNA samples were tested for the relative quantity of male specific Y chromosome gene DYS14 compared to a common β-globin gene using a highly sensitive quantitative PCR assay. MAIN RESULTS AND THE ROLE OF CHANCE We observed a large number of women (26.9%) having detectable male microchimerism in their peripheral blood samples. The presence of a male co-twin did not increase risk of male microchimerism (odds ratio (OR) = 1.23: SE 0.40, P = 0.61) and the prevalence of male microchimerism was not explained by having male offspring (OR 0.90: SE 0.19, P = 0.63) or by having an older brother (OR = 1.46: SE 0.32, P = 0.09). The resemblance (correlation) for the presence of microchimerism was similar (P = 0.66) in MZ pairs (0.27; SE 0.37) and in first-degree relatives (0.091; SE 0.092). However, age had a positive relationship with the presence of male microchimerism (P = 0.02). LIMITATIONS, REASONS FOR CAUTION After stratifying for variables of interest, some participant groups resulted in a low numbers of subjects. We investigated microchimerism in peripheral blood due to the proposed mechanism of cell acquisition via transplacental blood exchange; however, this does not represent global chimerism in the individual and microchimerism may localize to numerous other tissues. WIDER IMPLICATIONS OF THE FINDINGS Immune regulation during pregnancy is known to mitigate allosensitization and support tolerance to non-inherited antigens found on donor cells. While unable to identify a specific source that promotes microchimerism prevalence within pedigrees, this study points to the underlying complexities of natural microchimerism in the general population. These findings support previous studies which have identified the presence of male microchimerism among women with no history of pregnancy, suggesting alternative sources of microchimerism. The association of detectable male microchimerism with age is suggestive of additional factors including time, molecular characteristics and environment playing a critical role in the prevalence of persistent microchimerism. The present study necessitates investigation into the molecular underpinnings of natural chimerism to provide insight into women’s health, transplant medicine and immunology. STUDY FUNDING/COMPETING INTEREST(S) This work is funded by Royal Netherlands Academy of Science Professor Award (PAH/6635 to D.I.B.); The Netherlands Organisation for Health Research and Development (ZonMw)—Genotype/phenotype database for behavior genetic and genetic epidemiological studies (ZonMw 911-09-032); Biobanking and Biomolecular Research Infrastructure (BBMRI–NL, 184.021.007; 184.033.111); The Netherlands Organisation for Scientific Research (NWO)—Netherlands Twin Registry Repository (NWO-Groot 480-15-001/674); the National Institutes of Health—The Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06), Grand Opportunity grants Integration of genomics and transcriptomics in normal twins and major depression (NIMH 1RC2 MH089951-01), and Developmental trajectories of psychopathology (NIMH 1RC2 MH089995); and European Research Council—Genetics of Mental Illness (ERC 230374). C.B.L. declares a competing interest as editor-in-chief of Human Reproduction and his department receives unrestricted research grants from Ferring, Merck and Guerbet. All remaining authors have no conflict-of-interest to declare in regards to this work. TRIAL REGISTRATION NUMBER N/A.

The majority of congenital cardiovascular disease including structural cardiac defects, abnormalities in cardiac function, and rhythm disturbances can be identified prenatally using screening obstetrical ultrasound with referral for fetal echocardiogram when indicated. Diagnosis of congenital heart disease in the fetus should prompt assessment for extracardiac abnormalities and associated genetic abnormalities once parental consent is obtained. Pediatric cardiologists, in conjunction with maternal-fetal medicine, neonatology, and cardiothoracic surgery subspecialists, should counsel families about the details of the congenital heart defect as well as prenatal and postnatal management. Prenatal diagnosis often leads to increased maternal depression and anxiety; however, it decreases morbidity and mortality for many congenital heart defects by allowing clinicians the opportunity to optimize prenatal care and plan delivery based on the specific lesion. Changes in prenatal care can include more frequent assessments through the remainder of the pregnancy, maternal medication administration, or, in selected cases, in utero cardiac catheter intervention or surgical procedures to optimize postnatal outcomes. Delivery planning may include changing the location, timing or mode of delivery to ensure that the neonate is delivered in the most appropriate hospital setting with the required level of hospital staff for immediate postnatal stabilization. Based on the specific congenital heart defect, prenatal echocardiogram assessment in late gestation can often aid in predicting the severity of postnatal instability and guide the medical or interventional level of care needed for immediate postnatal intervention to optimize the transition to postnatal circulation.

Latines have higher rates of eating disorders characterized by binge eating compared to their non-Latine white counterparts, yet culturally and socially relevant factors related to binge eating in Latines have been largely understudied. The purpose of the current study was to examine how discrimination and acculturative stress were associated with binge eating in a nationally representative sample of Latines. An additional aim was to test the extent to which family cohesion and social support could buffer against the effects of discrimination and acculturative stress on binge eating.Participants (56% female, N = 2550) were Latines enrolled in the National Latino and Asian American Study. Structural equation modeling using 1000 re-sampled data sets built from machine learning iterative sampling procedures was used to examine the effects of discrimination, acculturative stress, family cohesion, and social support on binge eating.Results indicated that only discrimination was significantly associated with binge eating. Neither the direct effect of acculturative stress, interaction of family cohesion and acculturative stress, interaction of social cohesion and acculturative stress, nor the interaction of social support and discrimination were significantly associated with binge eating.This study highlights the need for mental-health providers to understand and assess discrimination among Latines presenting with concerns of binge eating. Treatments that effectively provide coping strategies to manage discriminatory experiences and reduce binge eating could improve both effectiveness of treatment and retention rates for Latine individuals with binge eating.This study examined the association of discrimination, acculturative stress, family cohesion, and social support with binge eating in Latines. Only discrimination was significantly associated with binge eating, highlighting the importance for providers to assess discrimination among Latines with binge-eating concerns and to improve equity, inclusion, and belonging at a societal level. Modifying existing treatments to address coping with discrimination could improve the effectiveness for Latines with binge-eating concerns.

There is ongoing discussion about whether sports participation is a risk or protective factor for eating disorders (EDs). Research is mixed, with some studies suggesting that athletes have higher mean levels of ED psychopathology compared to nonathletes, while other studies suggest the opposite effect or no differences. The purpose of the current meta-analysis was to identify whether female athletes reported higher mean levels of ED psychopathology compared to nonathletes.Following PRISMA guidelines, we identified 56 studies that reported ED psychopathology for female athletes and nonathletes. A three-level random-effects model of between- and within-study variance was completed for the following outcome variables: overall ED psychopathology, body dissatisfaction, drive for thinness, restricting, and loss-of-control eating.Athletes reported lower levels of body dissatisfaction compared to nonathletes (g = -.21, p .0001). Athletes and nonathletes reported similar levels of overall ED psychopathology, drive for thinness, restricting, and loss-of-control eating on average. Sport type significantly moderated standardized mean difference effect sizes of ED psychopathology in athletes versus nonathletes. Effect sizes comparing levels of drive for thinness, restricting, and loss-of-control eating in athletes versus nonathletes were larger for studies with athletes participating in aesthetic/lean sports compared to nonaesthetic/nonlean sports.Findings from this meta-analysis could inform future ED prevention and treatment in female athletes by providing further evidence that athletes in aesthetic/lean sports may report higher levels of ED psychopathology. Participating in nonaesthetic/nonlean sports may be a protective factor for experiencing less body dissatisfaction.The current meta-analysis summarized findings from 56 studies that assessed levels of disordered eating, body dissatisfaction, dietary restricting, and loss-of-control eating in female athletes and nonathletes. Athletes reported lower levels of body dissatisfaction compared to nonathletes, highlighting that participation in sport could have some protective factors. Athletes participating in sports that require weight categories (e.g., judo) and sports that emphasize thinness/leanness (e.g., gymnastics and distance running) had higher levels of disordered eating relative to athletes participating in other types of sports that do not emphasize thinness/leanness (e.g., volleyball and basketball).Existe un debate abierto sobre si la participación en los deportes es un factor de riesgo o protector para los trastornos de la conducta alimentaria (TCA). La investigación es mixta, con algunos estudios que sugieren que los atletas tienen niveles medios más altos de psicopatología de TCA en comparación con los no atletas, mientras que otros estudios sugieren el efecto opuesto o ninguna diferencia. El propósito del presente metanálisis fue identificar si las atletas femeninas reportaron niveles medios más altos de psicopatología de TCA en comparación con las no atletas. MÉTODO: Siguiendo las guías PRISMA, se identificaron 56 estudios que informaron psicopatología de TCA para atletas femeninas y no atletas. Se completó un modelo de efectos aleatorios de tres niveles de varianza entre y dentro del estudio para las siguientes variables de resultado: psicopatología general de TCA, insatisfacción corporal, impulso por la delgadez, restricción y pérdida de control de la alimentación.Las atletas reportaron niveles más bajos de insatisfacción corporal en comparación con las no atletas (g = -.21, p.0001). Las atletas y las no atletas reportaron niveles similares de psicopatología general de TCA, impulso por la delgadez, restricción y pérdida de control de la alimentación en promedio. El tipo de deporte moderó significativamente los tamaños del efecto de la diferencia de medias estandarizada de la psicopatología de TCA en atletas versus no atletas. Los tamaños del efecto que compararon los niveles de impulso por la delgadez, la restricción y la pérdida de control de la alimentación en atletas versus no atletas fueron mayores para los estudios con atletas que participaron en deportes que valoran lo estético/cuerpo magro, esbelto, en comparación con deportes que no valoran lo estético/cuerpo magro, esbelto. DISCUSIÓN: Los hallazgos de este metanálisis podrían informar la prevención y el tratamiento futuros de los TCA en atletas femeninas al proporcionar más evidencia de que las atletas en deportes que dan un gran valor a lo estético o al cuerpo magro, esbelto, pueden reportar niveles más altos de psicopatología de TCA. Participar en deportes que no dan valor a lo estético o al cuerpo magro, puede ser un factor protector para experimentar menos insatisfacción corporal.

The Society for Cardiovascular Magnetic Resonance (SCMR) is an international society focused on the research, education, and clinical application of cardiovascular magnetic resonance (CMR). The SCMR web site (https://www.scmr.org) hosts a case series designed to present case reports demonstrating the unique attributes of CMR in the diagnosis or management of cardiovascular disease. Each clinical presentation is followed by a brief discussion of the disease and unique role of CMR in disease diagnosis or management guidance. By nature, some of these are somewhat esoteric, but all are instructive. In this publication, we provide a digital archive of the 2019 Case of the Week series as a means of further enhancing the education of those interested in CMR and as a means of more readily identifying these cases using a PubMed or similar search engine.

Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.

To assess the longitudinal incidence of Kawasaki disease (KD) within the well-defined predominantly White population of Olmsted County, MN. This retrospective cohort study used a population-based medical record linkage system and manual chart reviews to identify children with KD in Olmsted County, MN between January 1, 1979-December 31, 2016. Age- and gender-adjusted incidence rates were calculated using the 2010 U.S. White population. 124 children with KD were confirmed during the study period (median age 3.5, 61% male, 85% White, 9% Asian). The overall age- and gender-adjusted incidence rates for all ages and

BACKGROUND AND PURPOSE: EmboTrap II is a novel stent retriever with a dual-layer design and distal mesh designed for acute ischemic stroke emergent large-vessel occlusions. We present the first postmarket prospective multicenter experience with the EmboTrap II stent retriever. MATERIALS AND METHODS: A prospective registry of patients treated with EmboTrap II at 7 centers following FDA approval was maintained with baseline patient characteristics, treatment details, and clinical/radiographic follow-up. RESULTS: Seventy patients were treated with EmboTrap II (mean age, 69.9 years; 48.6% women). Intravenous thrombolysis was given in 34.3%, and emergent large-vessel occlusions were located in the ICA (n = 18), M1 (n = 38), M2 or M3 (n = 13), and basilar artery (n = 1). The 5 × 33 mm device was used in 88% of cases. TICI ≥ 2b recanalization was achieved in 95.7% (82.3% in EmboTrap II–only cases), and first-pass efficacy was achieved in 35.7%. The NIHSS score improved from a preoperative average of 16.3 to 12.1 postprocedure and to 10.5 at discharge. An average of 2.5 [SD, 1.8] passes was recorded per treatment, including non-EmboTrap attempts. Definitive treatment was performed with an alternative device (aspiration or stent retriever) in 9 cases (12.9%). Some hemorrhagic conversion was noted in 22.9% of cases, of which 4.3% were symptomatic. There were no device-related complications. CONCLUSIONS: Initial postmarket results with the EmboTrap II stent retriever are favorable and comparable with those of other commercially available stent retrievers. Compared with EmboTrap II, the first-generation EmboTrap may have a higher first-pass efficacy; however, data are limited by retrospective case analysis, incomplete clinical follow-up, and small sample size, necessitating future trials.

Variability in teicoplanin pharmacokinetics has been explained by multiple factors such as body weight, renal function, and serum albumin level. To improve mechanistic understanding of the causes of variability, a physiologically based pharmacokinetic (PBPK) model can be used as a systematic platform. In this study, a PBPK model of teicoplanin was developed to quantitatively assess the effects of physiological changes due to disease status using virtual populations. Predictive performance of the models was evaluated by comparing simulated and observed concentration-time profiles of teicoplanin. Subsequently, sensitivity analyses were conducted to identify potential factors contributing to individual differences in teicoplanin PK. The developed PBPK model generated concentration-time profiles that were comparable to clinical observations in healthy adults, including Caucasians and Japanese, and after single-dose and multiple-dose administration. The predicted PK parameters (i.e., Cmax, AUC, clearance) were within a two-fold range of the observed data in patients with renal impairments as well as healthy adults. Changes in total and unbound teicoplanin concentrations at 72 h, after various dosing regimens (tested 4-14 mg/kg q12h for three doses as a loading dose and then 4-14 mg/kg daily as a maintenance dose), were sensitive to renal function and serum albumin concentrations. The PBPK model of teicoplanin provides mechanistic insight into the factors altering its disposition and allows assessments of the theoretical and quantitative impact of individual changes in physiological parameters on its PK even when an actual assessment with adequate sample sizes of patients is challenging.

Fetal circulation is unique and the parameters describing hemodynamic status during development are critical for constructing a fetal physiologically based pharmacokinetic model. To date, a comprehensive review of circulatory changes during fetal development, with a specific focus on developing these models, has not been reported. The objective of this work was to collate, analyze, and mathematically describe physiological information on fetal cardiac output and tissue blood flows during development. A comprehensive literature search was carried out to collate and evaluate the changes to fetal cardiac output and fetal tissue blood flows during growth. The collated data were assessed, integrated, and analyzed to establish continuous mathematical functions describing the average parameter changes and variability during development. Data were available for fetal cardiac output (14 Doppler studies), blood flow through the fetal umbilical vein (15 studies), ductus venosus (6 studies), liver veins (5 studies), brain (4 studies), lungs (5 studies), and kidneys (2 studies). Fetal cardiac output is described as either an age- or weight-dependent function. The latter is preferred as it generates an individualized cardiac output that is correlated to the fetal body weight. Blood flow as a proportion of fetal cardiac output to the liver, placenta, brain, kidneys, and lungs was age varying, whilst for the adipose, bone, heart, muscle, and skin the blood flow proportions were fixed. The pattern of change (with respect to direction and pace) for each of these parameters was different. Despite limitations in the availability of some values, the collected data provide a useful resource for fetal physiologically based pharmacokinetic modeling. Potential applications of these data include predicting xenobiotic exposure and risk assessment in the fetus following the administration of maternally dosed drugs or unintended exposure to environmental toxicants.

Marriage and family therapy scholars have argued that therapists play a crucial role in successful couple therapy, yet little research has empirically documented that the therapist in couple therapy has a significant impact on outcomes. Known as the study of therapist effects, this study sought to assess the amount of variance attributed to the therapist in couple therapy outcomes. Using dropout as the outcome variable, this study analyzed data from 1,192 couples treated by 90 masters and doctoral student therapists at a university-based training clinic. Results from multilevel analysis indicated that therapists in the sample accounted for 9.4% of the variance in couple dropout while controlling for initial couple impairment. Therapist gender and therapist experience did not significantly predict variability in therapist effects. These findings give promise to future research on therapist effects in couple therapy and encourage exploration into which therapist characteristics and behaviors contribute to successful clinical outcome.

Background First-pass efficacy (FPE) is an established marker of technical and clinical efficacy among mechanical thrombectomy (MT) techniques. It is unclear what the optimal approach is in achieving FPE. We present a single-center experience comparing rates of FPE among 2 MT techniques and evaluate the potential predictors of FPE among other outcomes. Methods A single-center retrospective analysis was carried out of patients with consecutive large-vessel occlusion strokes (LVOS) of anterior circulation from September 2015 to April 2019 who underwent MT and for whom data were available on the status of FPE. Four MT techniques were identified: ADAPT (a direct first-pass aspiration), SrADAPT (stent retriever with aspiration), SRBG (stent retriever with balloon guide catheter), and STRAP (stent retriever-aspiration and proximal flow arrest). The primary outcome was FPE and secondary outcomes included the rate of successful reperfusion. Results Among 226 patients with LVOS of the anterior circulation who underwent MT, data were available for 164 on FPE for the 4 MT techniques. SRBG was the most prevalent technique. No significant difference was found in rates of FPE among the 4 MT techniques (P = 0.332). No independent predictors of FPE were identified on multivariable analysis. STRAP had the highest rate of successful reperfusion compared with the other techniques (P = 0.049) and was the only independent predictor of that outcome (P = 0.027). Conclusions Among patients with LVOS of the anterior circulation, the rate of FPE did not differ among the 4 MT techniques. There were no predictors of FPE among the studied variables. STRAP was the only predictor of successful reperfusion.

The evolution of medical techniques as well as legislative changes currently allow to propose fertility preservation strategies in the context of transidentity. During "female to male" transition, androgen therapy has an impact on gonadal function since it usually induces a blockage of ovulation with amenorrhea. Although this effect is reversible when treatment is stopped, the possible long-term effects of testosterone treatment on future fertility or health of future children are poorly known. In addition, transitional surgeries definitely compromise fecundity when they include bilateral ovariectomy and/or hysterectomy. Yet, although long ignored or poorly expressed, the desire for parenthood is a reality in transgender men. Fertility preservation options in FtM transition rely on oocyte or ovarian tissue cryopreservation. The purpose of this review is to provide an overview of the literature regarding fertility preservation in transgender men. Although series remain limited, the increase in the number of recently published articles reflects the interest in improving the management of fertility issues in transgender men.

Recent positron emission tomography (PET) studies of kappa opioid receptors (KOR) in humans reported significant relationships between KOR availability and social status, as well as cocaine choice. In monkey models, social status influences physiology, receptor pharmacology and behavior; these variables have been associated vulnerability to cocaine abuse. The present study utilized PET imaging to examine KOR availability in socially housed, cocaine-naïve female and male monkeys, and peripheral measures of KORs with neuron-derived extracellular vesicles (NDE). KOR availability was assessed in dominant and subordinate female and male cynomolgus macaques (N = 4/rank/sex), using PET imaging with the KOR selective agonist [

Bayesian modeling is becoming increasing popular as a method for data analyses in the social sciences and can move couple, marriage, and family therapy (C/MFT) research forward. Bayesian modeling helps researchers better understand the uncertainty of findings and incorporate previous research into analyses. Other benefits of Bayesian modeling are the straightforward interpretation of findings, high-quality inferences even with small samples (in combination with an informative prior), and the ability to work with complex data structures (observations nested in relationships and time points) which are common in C/MFT research. This article introduces the benefits of Bayesian modeling and provides an example of an Actor-Partner Interdependence Model using R. Information on how to conduct the same analyses using Stata and MPlus is provided in the Supplemental Information.

Highlights • U.S. neurosurgery residents report moderate burnout during the COVID-19 pandemic. • Neurosurgery residents report uncertainty about future healthcare reform & earnings. • The COVID-19 pandemic may impair residents’ achievement of surgical milestones. • Burnout is associated with altered rotation or vacation schedules and lower PGY. • Career satisfaction is associated with delivery of neurosurgical patient care., The coronavirus disease 2019 (COVID-19) pandemic has posed significant changes to resident education and workflow. However, the impact of the pandemic on U.S. neurosurgery residents has not been well characterized. We investigated the impact of the COVID-19 pandemic on U.S. neurosurgery resident workflow, burnout, and career satisfaction. In 2020, a survey evaluating factors related to career satisfaction and burnout was emailed to 1,374 American Association of Neurological Surgeons (AANS) residents. Bivariate and multivariate (logistic) analyses were performed to characterize predictors of burnout and career satisfaction. 167 survey responses were received, with a response rate (12.2%) comparable to that of similar studies. Exclusion of incomplete responses yielded 111 complete responses. Most respondents were male (65.8%) and White (75.7%). Residents reported fewer work hours (67.6%) and concern that COVID-19 would impair their achievement of surgical milestones (65.8%). Burnout was identified in 29 (26.1%) respondents and career satisfaction in 82 (73.9%) respondents. In multivariate analysis, burnout was significantly associated with alterations in elective rotation/vacation schedules (p = .013) and the decision to not pursue neurosurgery again if given the choice (p

Many autoimmune therapies focus on immune suppression to reduce symptom severity and halt disease progression; however, currently approved treatments lack specificity for the autoantigen and rely on more global immune suppression. Multivalent antigen arrays can disarm pathogenic autoimmune B cell populations that specifically recognize the antigen of interest via their B cell receptor (BCR). Disarmament may be achieved by BCR engagement, crosslinking, and sustained receptor occupancy as a result of multivalent, high avidity BCR binding. To engage and explore this mechanism, a tetramer display of the encephalogenic proteolipid peptide (PLP(139–151)), referred to as 4-arm PLP(139–151), was synthesized by copper-catalyzed azide-alkyne cycloaddition chemistry. Subcutaneous administration of 4-arm PLP(139–151) completely ameliorated symptoms of paralysis in a mouse model of multiple sclerosis known as experimental autoimmune encephalomyelitis. Competitive binding of 4-arm PLP(139–151) to PLP(139–151)-specific IgG in mouse serum demonstrated the enhanced avidity associated with the multivalent array compared to free peptide. Furthermore, key PLP(139–151)-reactive B cells were depleted following 4-arm PLP(139–151) treatment, resulting in significant reduction of pro-inflammatory cytokines. Together, these data demonstrate the potential of 4-arm PLP(139–151) to silence autoreactive B cell populations and limit downstream activation of effector cells.

Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor–positive (HR+) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of estrogen receptor expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations—in AKT1, RAS, and AURKA—have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients.Significance:We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ metastatic breast cancer.This article is highlighted in the In This Issue feature, p. 1079

Introduction We previously showed that the addition of valproic acid (VPA), a histone deacetylase inhibitor, to fresh frozen plasma (FFP) resuscitation attenuates brain lesion size and swelling following traumatic brain injury (TBI) and hemorrhagic shock (HS). The goal of this study was to use computational biology tools to investigate the effects of FFP+VPA on the brain transcriptome following TBI+HS. Methods Swine underwent TBI+HS, kept in shock for 2 h, and resuscitated with FFP or FFP + VPA (n = 5/group). After 6 h of observation, brain RNA was isolated and gene expression was analyzed using a microarray. iPathwayGuide, Gene Ontology (GO), Gene-Set Enrichment Analysis, and Enrichment Mapping were used to identify significantly impacted genes and transcriptomic networks. Results Eight hundred differentially expressed (DE) genes were identified out of a total of 9,118 genes. Upregulated genes were involved in promotion of cell division, proliferation, and survival, while downregulated genes were involved in autophagy, cell motility, neurodegenerative diseases, tumor suppression, and cell cycle arrest. Seven hundred ninety-one GO terms were significantly enriched. A few major transcription factors, such as TP53, NFKB3, and NEUROD1, were responsible for modulating hundreds of other DE genes. Network analysis revealed attenuation of interconnected genes involved in inflammation and tumor suppression, and an upregulation of those involved in cell proliferation and differentiation. Conclusion Overall, these results suggest that VPA treatment creates an environment that favors production of new neurons, removal of damaged cells, and attenuation of inflammation, which could explain its previously observed neuroprotective effects.

BACKGROUND AND PURPOSE: The Neuroform Atlas is a new microstent to assist coil embolization of intracranial aneurysms that recently gained FDA approval. We present a postmarket multicenter analysis of the Neuroform Atlas stent. MATERIALS AND METHODS: On the basis of retrospective chart review from 11 academic centers, we analyzed patients treated with the Neuroform Atlas after FDA exemption from January 2018 to June 2019. Clinical and radiologic parameters included patient demographics, aneurysm characteristics, stent parameters, complications, and outcomes at discharge and last follow-up. RESULTS: Overall, 128 aneurysms in 128 patients (median age, 62 years) were treated with 138 stents. Risk factors included smoking (59.4%), multiple aneurysms (27.3%), and family history of aneurysms (16.4%). Most patients were treated electively (93.7%), and 8 (6.3%) underwent treatment within 2 weeks of subarachnoid hemorrhage. Previous aneurysm treatment failure was present in 21% of cases. Wide-neck aneurysms (80.5%), small aneurysm size (

Background Environmental organic dust exposures enriched in Toll-like receptor (TLR) agonists can reduce allergic asthma development but are associated with occupational asthma and chronic bronchitis. The TLR adaptor protein myeloid differentiation factor88 (MyD88) is fundamental in regulating acute inflammatory responses to organic dust extract (ODE), yet its role in repetitive exposures is unknown and could inform future strategies. Methods Wild-type (WT) and MyD88 knockout (KO) mice were exposed intranasally to ODE or saline daily for 3 weeks (repetitive exposure). Repetitively exposed animals were also subsequently rested with no treatments for 4 weeks followed by single rechallenge with saline/ODE. Results Repetitive ODE exposure induced neutrophil influx and release of pro-inflammatory cytokines and chemokines were profoundly reduced in MyD88 KO mice. In comparison, ODE-induced cellular aggregates, B cells, mast cell infiltrates and serum IgE levels remained elevated in KO mice and mucous cell metaplasia was increased. Expression of ODE-induced tight junction protein(s) was also MyD88-dependent. Following recovery and then rechallenge with ODE, inflammatory mediators, but not neutrophil influx, was reduced in WT mice pretreated with ODE coincident with increased expression of IL-33 and IL-10, suggesting an adaptation response. Repetitively exposed MyD88 KO mice lacked inflammatory responsiveness upon ODE rechallenge. Conclusions MyD88 is essential in mediating the classic airway inflammatory response to repetitive ODE, but targeting MyD88 does not reduce mucous cell metaplasia, lymphocyte influx, or IgE responsiveness. TLR-enriched dust exposures induce a prolonged adaptation response that is largely MyD88-independent. These findings demonstrate the complex role of MyD88-dependent signaling during acute vs. chronic organic dust exposures.

In this study we examine the role that pressure to attend therapy, dyadic adjustment, and adverse childhood experiences (ACEs) play in developing the therapeutic alliance. A total of 351 couples received treatment as usual at three family therapy training clinics. Participants rated predictor variables at intake and alliance at the fourth session. Results of a path analysis indicate that each partner's dyadic adjustment is directly associated with the quality of her or his own alliance. In addition, when male partners report more ACEs and pressure to attend treatment, their own alliance scores decrease. Additionally, when one partner reports feeling pressure to attend therapy, the other partner's alliance decreases. Finally, for males, there is an indirect effect of dyadic adjustment on alliance through pressure to attend therapy. These results suggest that clinicians should routinely assess relationship adjustment, how pressured each partner is feeling to attend treatment, and ACEs; as these may impact alliance quality.

Background Cone beam computed tomography (CBCT) imaging is used commonly in neurointerventional surgery for rapid intraprocedural assessment and planning of intracranial interventions. Our goal was to evaluate the ability of immediate postprocedural CBCT scan in assessing potential complications in pediatric patients. Methods A retrospective review was completed to include all pediatric patients at our hospital with an immediate postprocedural CBCT scan with the Artis Q system. Demographic, clinical, and imaging data were examined. CBCT images were reviewed by 3 independent neurointerventionalists to assess ventricular system/subarachnoid spaces, gray-white differentiation, and ischemia or hemorrhage if present. Each assessment was rated qualitatively on a 4-point scale and was compared with conventional computed tomography (cCT) scan when available. Interrater reliability was assessed and radiation dose data were reviewed. Results Thirty-five patients were included with an average age of 11.0 ± 5.1 years (median, 10.9; range, 1.1–18 years). Of the patients, 54.3% were boys; 34.3% were Hispanic and 34.3% were non-Hispanic white. Diagnoses included a variety of vascular pathologies. CBCT scan had a mean score of 2.69 ± 0.54 out of 3 for ventricular and subarachnoid space assessment with a combined interrater reliability of 0.82, 1.71 ± 1.38 for hemorrhage with a combined interrater reliability of 1.00, and 0.52 ± 0.60 for gray-white differentiation with a combined interrater reliability of 0.79. Conclusions Immediate postprocedural CBCT images were adequate to detect ventricular size/subarachnoid spaces changes and large volume hemorrhage compared with cCT scan in pediatric patients. However, there are limitations using immediate CBCT images to detect small volume hemorrhage and ischemic changes.

OBJECTIVEWith the increasing use of flow diversion as treatment for intracranial aneurysms, there is a concomitant increased vigilance in monitoring complications. The low porosity of flow diverters is concerning when the origins of vessels are covered, whether large circle of Willis branches or critical perforators. In this study, the authors report their experience with flow diverter coverage of the lenticulostriate vessels and evaluate their safety and outcomes.METHODSThe authors retrospectively reviewed 5 institutional databases of all flow diversion cases from August 2012 to June 2018. Information regarding patient presentation, aneurysm location, treatment, and outcomes were recorded. Patients who were treated with flow diverters placed in the proximal middle cerebral artery (MCA), proximal anterior cerebral artery, or distal internal carotid artery leading to coverage of the medial and lateral lenticulostriate vessels were included. Clinical outcomes according to the modified Rankin Scale were reviewed. Univariate and multivariate analyses were performed to establish risk factors for lenticulostriate infarct.RESULTSFifty-two patients were included in the analysis. Postprocedure cross-sectional images were available in 30 patients. Two patients experienced transient occlusion of the MCA during the procedure; one was asymptomatic, and the other had a clinical and radiographic ipsilateral internal capsule stroke. Five patients had transient symptoms without radiographic infarct in the lenticulostriate territory. Two patients experienced in-stent thrombosis, leading to clinical MCA infarcts (one in the ipsilateral caudate) after discontinuing antiplatelet therapy. Discontinuation of dual antiplatelet therapy prior to 6 months was the only variable that was significantly correlated with stroke outcome (p < 0.01, OR 0.3, 95% CI 0–0.43), and this significance persisted when controlled for other risk factors, including age, smoking status, and aneurysm location.CONCLUSIONSThe use and versatility of flow diversion is increasing, and safety data are continuing to accumulate. Here, the authors provide early data on the safety of covering lenticulostriate vessels with flow diverters. The authors concluded that the coverage of these perforators does not routinely lead to clinically significant ischemia when dual antiplatelet therapy is continued for 6 months. Further evaluation is needed in larger cohorts and with imaging follow-up as experience develops in using these devices in more distal circulation.

The degree of approval for a relationship from one's social network has been shown to predict relationship outcomes. Additional research has shown that attachment can buffer the negative effects of various factors (e.g., depression) on relationships. Using an actor-partner interdependence model in an SEM framework, we research the effects of disapproval from parents and friends for one's relationship on marital relationship quality for self and partner in a sample of 858 married couples. We also examine whether each spouse's attachment behaviors can moderate these effects. Results indicated that one's own attachment behaviors moderate the effects of their own parents' and friends' disapproval on their self-reported relationship quality for both men and women. Partner's attachment behaviors moderate own friend's disapproval on self-reported relationship quality for men and women; additionally, the main effect of partner's friends' and parents' disapproval became nonsignificant with that test. The findings provide evidence that attachment behaviors of both partners play a role in buffering the negative effects of the social network disapproval on relationship outcomes. Clinical implications are discussed.Se ha demostrado que el grado de aprobación de una relación desde la red social de una persona predice los resultados de las relaciones. Otras investigaciones han demostrado que el apego puede moderar los efectos negativos de varios factores (p. ej.: la depresión) en las relaciones. Utilizando un modelo de interdependencia actor-pareja en un marco de modelos de ecuaciones estructurales, investigamos los efectos de la desaprobación por parte de los padres y los amigos de la relación de una persona en la calidad de la relación conyugal para la persona y su pareja en una muestra de 858 parejas casadas. También analizamos si las conductas de apego de cada cónyuge pueden moderar estos efectos. Los resultados indicaron que las conductas de apego propias de la persona moderan los efectos de la desaprobación por parte de sus propios padres y amigos en la calidad de la relación autoinformada tanto en el caso de los hombres como en el de las mujeres. Las conductas de apego del cónyuge moderan la desaprobación de sus propios amigos en la calidad de la relación autoinformada tanto en el caso de los hombres como en el de las mujeres. Además, el efecto principal de la desaprobación por parte de los padres y los amigos del cónyuge se volvió no significativo con esa prueba. Los resultados ofrecen pruebas de que las conductas de apego de ambos integrantes de la pareja desempeñan un papel en la moderación de los efectos negativos de la desaprobación por parte de la red social en los resultados de las relaciones. Se debaten las implicancias clínicas.从一个人的社会网络对某关系的认可程度已可以预测这种关系的结局。还有一些研究表明，依恋行为可以缓冲各种因素（例如抑郁）对人际关系的负面影响。本研究样本包括858对已婚夫妇，我们在SEM框架内使用行为者-伴侣相互依存模型来探究来自父母和朋友方面的不同意对自己和伴侣的婚姻关系质量的影响。我们还研究每个配偶的依恋行为是否能够减缓这些影响。结果表明，不管男性和女性，某一方本人的依恋行为减轻了父母和朋友的不同意对他们自我报告的关系质量的影响。伴侣的依恋行为减轻了自己朋友对男女自我报告的关系质量的不同意的影响；此外，伴侣的父母和朋友的不同意造成的主要影响在该测试中作用不大。该发现支持的结论是伴侣双方的依恋行为有缓冲作用，即对来自社会网络成员的不同意对伴侣关系结果的负面影响方面能发挥作用。临床意义进行了讨论。.

There are a paucity of data regarding the safety of laparoscopic inguinal hernia repair in patients on antiplatelet and anticoagulant therapy (APT/ACT). We aim to compare the postoperative outcomes of laparoscopic (LIHR) vs. open repair of inguinal hernias (OIHR) in patients on APT/ACT.We conducted a retrospective cohort study using the Vizient Clinical DataBase. We included adults receiving APT/ACT who underwent outpatient, elective, and primary inguinal hernia repair between 2017 and 2019. Subgroup analysis was performed on patients receiving aspirin, non-aspirin antiplatelet, and anticoagulant therapy. Mixed-effects logistic regression was used to assess both the effect of APT/ACT on the probability of receiving LIHR vs OIHR and their respective outcomes.A total of 142,052 repairs were included, of which 21,441 (15%) were performed on patients receiving APT/ACT. Mean age was 69 years (± 10.5) and 93% were male. 19% of hernias were bilateral. 40% of operations were performed at teaching hospitals. On multivariable analysis, patients on non-aspirin antiplatelet or anticoagulant therapy were more likely to receive an open procedure (Odds Ratio (OR) = 1.2; 95% Confidence Intervals (CI) [1.1, 1.4] and OR = 1.4; CI [1.3, 1.5], respectively). LIHR was associated with a lower rate of length of stay 1 day (OR = 0.65; CI [0.5, 0.9]). Rates of 30-day postoperative hematoma, transfusions, stroke, myocardial infarction, deep venous thrombosis, pulmonary embolism, readmission, and emergency department visits were similar between the two operative approaches.Patients on APT/ACT represent a substantial proportion of those undergoing inguinal hernia repair. Non-aspirin antiplatelet or anticoagulant therapy are independent predictors of choosing an open repair. Laparoscopic repair appears to be safe in patients receiving APT/ACT under current perioperative management patterns.

Fontan circulation leads to chronic elevation of central venous pressure. We sought to identify the incidence, risk factors, and survival among patients who developed acute kidney injury (AKI) after the Fontan operation. We retrospectively reviewed 1,166 patients who had Fontan operation/revision at Mayo Clinic Rochester from 1973 to 2017 and identified patients who had AKI (defined by AKI Network criteria) within 7 days of surgery. A total of 132 patients (11%) developed AKI after the Fontan operation with no significant era effect. Of those who developed AKI, severe (grade 3) kidney injury was present in 101 patients (76.5%). Multivariable risk factors for AKI were asplenia (odds ratio [OR] 4.2, p0.0001), elevated preoperative pulmonary artery pressure (per 1 mm Hg increase, OR 1.04, p = 0.0002), intraoperative arrhythmias (OR 1.9, p = 0.02), and elevated post-bypass Fontan pressure (per 1 mm Hg increase, OR 1.12, p = 0.0007). Renal replacement therapy (RRT) was used in 72 patients (54%), predominantly through peritoneal dialysis (n = 56, 78%). Multivariable risk factors for RRT were age ≤3 years (OR 9.7, p = 0.0004), female gender (OR 2.6, p = 0.02), and aortic cross-clamp time60 minutes (OR 3.1, p = 0.01). Patients with AKI had more postoperative complications, including bleeding, stroke, pericardial tamponade, low cardiac output state and cardiac arrest, than those without AKI. This resulted in longer intensive care unit stay (39 vs 17 days, p = 0.0001). In-hospital mortality was exceedingly higher among patients with AKI versus no AKI (58%, 76 of 132 vs 10%, 99 of 1,034, p0.0001); however, there was no significant difference based on the need for RRT. Recovery from AKI was observed in 56 patients (42%). Over 20-year follow-up, patients with AKI had a distinctly higher all-cause-mortality (82%) than those without AKI (35%). It is prudent to identity patients at a higher risk of developing postoperative AKI after Fontan operation to ensure renal protective strategies in the perioperative period. Postoperative AKI leads to substantial short and long-term morbidity and mortality, but the need for RRT does not affect the outcomes.

Fetal blood and plasma volume and binding components are critical parameters in a fetal physiologically based pharmacokinetic model. To date, a comprehensive review of their changes during fetal development has not been reported. The objective of this work was to collate and analyze physiological information on fetal blood and plasma volume and binding component data during development and to provide a mathematical description of these parameters that can be integrated within a fetal physiologically based pharmacokinetic model. A comprehensive literature search was conducted on fetal blood and plasma volume and binding component parameters and their changes during growth from apparently healthy fetuses from uncomplicated pregnancies. Collated data were assessed, integrated, and analyzed to establish continuous mathematical functions describing their growth trends with fetal age and weight. Data were available from 14 studies for blood, ten studies for hematocrit, 12 studies for albumin, and four studies for alpha-1-acid glycoprotein, while plasma and red blood cell volumes were described based on blood and hematocrit data. Fetal physiologically based pharmacokinetic parameters, including blood, plasma and red blood cell volumes, hematocrit, serum albumin, and acid glycoprotein were quantified as a function of fetal age and weight. Variability around the mean parameters at different fetal ages was also investigated. The growth of each of these parameters was different (with respect to direction and monotonicity). Despite the limitations identified in the availability of some values, the collected data presented in this article provide a useful resource for fetal physiologically based pharmacokinetic modeling. Potential applications include predicting xenobiotic exposure and risk assessment in the fetus following maternally administered drugs or unintended exposure to environmental toxicants.

To add to the dialogue regarding the long-term recovery and wellbeing of war and tsunami-affected women in Sri Lanka, we utilised the Conservation of Resources Theory (COR, Hobfoll, 2009) to inform an investigation of direct and indirect effects. The study was specifically designed to assess how traumatic exposure may represent a form of loss which may associate with related losses in the form of external and internal stigma which may then associate with poor mental health outcomes. The data for this study were collected in 2016 from a sample of 379 widowed women in Eastern Sri Lanka; participant spouses died in the civil war, in the tsunami, or from health or other problems. Our analyses yielded a model suggesting associations between remembered trauma event exposure from war and disaster, external stigma, internalised stigma and mental health symptom distress. Results further yielded direct and indirect effects suggesting that trauma may represent a form of loss, and potentially lead to distress through the weight and challenges of stigma.

Background Advances in acute and long-term poststroke care have resulted in improved survival and functional outcomes for patients who have suffered large vessel ischemic strokes. For years, tissue plasminogen activator was the mainstay of treatment for acute stroke. Its use was previously limited to patients without known comorbid intracranial vascular pathology because of concern for bleeding risk. More recently, however, the use of tissue plasminogen activator in select patients with vascular anomalies has increased and is now largely thought to be safe. With the safety and efficacy of mechanical thrombectomy now proven for large vessel occlusions (LVOs), similar investigation is needed to assess procedural safety in patients with concomitant arteriovenous (AV) malformations or fistulae. Methods We reviewed patients treated for LVOs at our institution and those of our collaborators and identified 6 patients who were treated for LVO with either known or incidentally identified concomitant AV malformations or dural AV fistulae. Results We present a case series of 6 patients with nonaneurysmal intracranial vascular lesions who underwent mechanical thrombectomy for LVO without complications related to these lesions. Conclusions Although limited by small size, our series adds to the literature evidence that mechanical thrombectomy for LVO can safely be performed with concomitant dural AV fistulae and AV malformations.

Objective:To evaluate the health status and quality of life of young patients who had cone reconstruction for Ebstein anomaly.Methods:We reviewed all patients who had cone reconstruction from 2007 to 2016 at our institution. Prospective surveys were mailed to all eligible patients. Quality of life was assessed using the PedsQL 4.0 Generic Core Scales, including four domains: physical, emotional, social, and school functioning.Results:Of 116 eligible patients, 72 (62%) responded. About 96% reported their health as excellent or good, and 52% were symptom-free. Only 37% of patients were taking any medications, the most common of which was aspirin (30%). Only 19% had been hospitalised for cardiac reasons following cone reconstruction. The average self-reported quality of life was 85.3/100, whereas the average parent proxy-reported quality of life was 81.8/100. There was no difference by self or parent proxy-report in quality of life between cone reconstruction patients and healthy children; however, quality of life was significantly better compared with children with other chronic health conditions. By self-report and parent proxy-report, 15.1 and 16.7% of patients were deemed “at risk” for reduced quality of life, respectively. Socially, 63/64 (98%) patients over 5 years old were either full-time students or working full-time.Conclusion:Children with Ebstein anomaly following cone reconstruction have excellent quality of life comparable with healthy peers and significantly better than other children with chronic health conditions. Families of children with Ebstein anomaly can expect excellent quality of life, long-term health status, and social functioning following cone reconstruction.

Background Vein of Galen malformations (VOGM) comprise nearly a third of pediatric cerebrovascular anomalies, with potentially devastating neurological and systemic complications. Advances in endovascular therapies have dramatically improved outcomes compared to historical surgical treatments, and neurosurgeons are an essential component of the multidisciplinary critical care team. Objective To retrospectively review pediatric patients with VOGM treated at Texas Children's Hospital (TCH), a quaternary referral center, over 15 yr, and present lessons learned in treating children with modern endovascular techniques. Methods Charts from TCH were retrospectively reviewed for the past 15 yr. Patients with diagnosis including "Vein of Galen," "Vein of Galen malformation," "Vein of Galen aneurysmal malformation," or any abbreviations (ie, VOG, VOGM, VOGAM) were reviewed. Presentation, imaging, treatment specifics, and clinical outcomes were reported. Results There were 18 patients with VOGM managed at TCH from 2002 to 2018 with a total of 29 embolizations. Seventeen were performed with a single embolisate (NBCA or Onyx), and 12 with a combination. A dual lumen balloon catheter was used as an adjunct in 3 embolizations. Complications occurred in 5 embolizations (24%), including hemorrhage, embolisate migration, and femoral vessel occlusion. Surviving patients were followed for a mean of 38 mo, with 12 having normal or near-normal neurological development. Conclusion VOGM can present with a myriad of neurological and systemic symptoms, potentially in extremis. Neurosurgical involvement in these cases is critical, as urgent treatment can be lifesaving. Patients may require multiple treatment sessions using a variety of endovascular tools and techniques.

OBJECTIVE: Evidence supports high rates of co-occurrence of posttraumatic stress disorder (PTSD) and chronic pain disorders involving central sensitization (CS). The nature of this relationship, however, remains relatively unexplored. In this study, we aimed to (1) assess how both trauma exposure and current PTSD symptoms are related to clinical manifestations of CS, and (2) test whether PTSD symptoms explain the relationship between trauma exposure and CS. Because experiential avoidance has been shown to impact the relationship between trauma and health outcomes, we (3) explored experiential avoidance as a possible mediator or moderator of the trauma-CS relationship. METHODS: A sample of 202 adult patients (79% female) with chronic pain completed validated self-report measures of trauma exposure, current PTSD symptoms, experiential avoidance, and three manifestations of CS: widespread pain, greater pain severity, and polysomatic symptom reporting. We used path analysis and multivariate regression to assess our study aims. RESULTS: Both trauma exposure and PTSD symptoms were significantly associated with all three clinical indicators of CS. PTSD symptoms partially explained the relationship between trauma exposure and widespread pain, pain intensity, and polysomatic symptoms. Experiential avoidance did not mediate or moderate the trauma-CS relationship. CONCLUSION: Our findings suggest that trauma exposure is linked to elevated clinical markers of CS, but a critical factor in this relationship is the mediating effect of current PTSD symptoms.

STUDY QUESTION: Is there an increased prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, as evidence of fetal exposure to blood and anti-Müllerian hormone (AMH) from a (vanished) male co-twin resulting in regression of the Müllerian duct derivatives?SUMMARY ANSWER: Predominant absence of male microchimerism in adult women with MRKH syndrome does not support our hypothesis that intrauterine blood exchange with a (vanished) male co-twin is the pathophysiological mechanism.WHAT IS KNOWN ALREADY: The etiology of MRKH is unclear. Research on the phenotype analogous condition in cattle (freemartinism) has yielded the hypothesis that Müllerian duct development is inhibited by exposure to AMH in utero. In cattle, the male co-twin has been identified as the source for AMH, which is transferred via placental blood exchange. In human twins, a similar exchange of cellular material has been documented by detection of chimerism, but it is unknown whether this has clinical consequences.STUDY DESIGN, SIZE, DURATION: An observational case-control study was performed to compare the presence of male microchimerism in women with MRKH syndrome and control women. Through recruitment via the Dutch patients' association of women with MRKH (comprising 300 members who were informed by email or regular mail), we enrolled 96 patients between January 2017 and July 2017. The control group consisted of 100 women who reported never having been pregnant.PARTICIPANTS/MATERIALS, SETTING, METHODS: After written informed consent, peripheral blood samples were obtained by venipuncture, and genomic DNA was extracted. Male microchimerism was detected by Y-chromosome-specific real-time quantitative PCR, with use of DYS14 marker. Possible other sources for microchimerism, for example older brothers, were evaluated using questionnaire data.MAIN RESULTS AND THE ROLE OF CHANCE: The final analysis included 194 women: 95 women with MRKH syndrome with a mean age of 40.9 years and 99 control women with a mean age of 30.2 years. In total, 54 women (56.8%) were identified as having typical MRKH syndrome, and 41 women (43.2%) were identified as having atypical MRKH syndrome (when extra-genital malformations were present). The prevalence of male microchimerism was significantly higher in the control group than in the MRKH group (17.2% versus 5.3%, P = 0.009). After correcting for age, women in the control group were 5.8 times more likely to have male microchimerism (odds ratio 5.84 (CI 1.59-21.47), P = 0.008). The mean concentration of male microchimerism in the positive samples was 56.0 male genome equivalent per 1 000 000 cells. The prevalence of male microchimerism was similar in women with typical MRKH syndrome and atypical MRKH syndrome (5.6% versus 4.9%, P = 0.884). There were no differences between women with or without microchimerism in occurrence of alternative sources of XY cells, such as older brothers, previous blood transfusion, or history of sexual intercourse.LIMITATIONS, REASON FOR CAUTION: We are not able to draw definitive conclusions regarding the occurrence of AMH exchange during embryologic development in women with MRKH syndrome. Our subject population includes all adult women and therefore is reliant on long-term prevalence of microchimerism. Moreover, we have only tested blood, and, theoretically, the cells may have grafted anywhere in the body during development. It must also be considered that the exchange of AMH may occur without the transfusion of XY cells and therefore cannot be discovered by chimerism detection.WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to test the theory that freemartinism causes the MRKH syndrome in humans. The study aimed to test the presence of male microchimerism in women with MRKH syndrome as a reflection of early fetal exposure to blood and AMH from a male (vanished) co-twin. We found that male microchimerism was only present in 5.3% of the women with MRKH syndrome, a significantly lower percentage than in the control group (17.2%). Our results do not provide evidence for an increased male microchimerism in adult women with MRKH as a product of intrauterine blood exchange. However, the significant difference in favor of the control group is of interest to the ongoing discussion on microchimeric cell transfer and the possible sources of XY cells.STUDY FUNDING/COMPETING INTEREST(S): None.TRIAL REGISTRATION NUMBER: Dutch trial register, NTR5961.

Background The local treatment of extremity sarcomas usually is predicated on a decision between limb salvage and amputation. The manner in which surgical options are presented in the context of shared decision-making may influence this decision. In a population of "simulated" patients-survey respondents presented with a mock clinical vignette and then asked to choose between treatments-we assessed cognitive bias by deliberate alteration of the subjective presentation of the same objective information. Questions/purposes (1) Will the manner in which information is presented to a simulated patient, in the setting of treatment for a bone sarcoma, bias their decision regarding pursuing amputation versus limb salvage? (2) At the time of decision-making, will a simulated patient's personal background, demographics, or mood affect their ultimate decision? Methods Survey respondents (Amazon MTurk platform) were presented with mock clinical vignettes simulating a sarcoma diagnosis and were asked to choose between amputation and limb salvage. Specific iterations were designed to assess several described types of cognitive bias. These scenarios were distributed, using anonymous online surveys, to potential participants aged 18 years or older. Recruitment was geographically restricted to individuals in the United States. Overall, 404 respondents completed the survey. The average age of respondents was 33 years (SD 1.2 years), 60% were male and 40% were female. In all, 12% of respondents worked in healthcare. Each respondent also completed questions regarding his or her demographics and his or her current mood. Associations between the type of bias presented and the respondent's choice of limb salvage versus amputation were examined. Independent sample t-tests were used to compare means. Statistical significance was defined as p Results When amputation was presented as an option to mitigate functional loss (framing bias), more patients chose it than when limb salvage was presented as means for increased functional gains (23% [23 of 100] versus 10% [12 of 118], odds ratio [OR], 2.26; p = 0.010). Older simulated patients were more likely to choose limb salvage when exposed to framing bias versus younger patients (mean age 33 years versus 30 years, p = 0.02). Respondents who were employed in healthcare more commonly chose amputation versus limb salvage when exposed to framing bias (24% [eight of 35] versus 9% [17 of 183]; OR, 2.46; p = 0.02). Those who chose amputation were more likely to score higher on scales that measured depression or negative affect. Conclusions Shared decision-making in orthopaedic oncology represents a unique circumstance in which several variables may influence a patient's decision between limb salvage and amputation. Invoking cognitive bias in simulated patients appeared to affect treatment decisions. We cannot be sure that these findings translate to the experience of actual sarcoma patients; however, we can conclude that important treatment decisions may be affected by cognitive bias and that patient characteristics (in this study, age, healthcare profession, and mood) may be associated with an individual's susceptibility to cognitive bias. We hope these observations will assist providers in the thoughtful delivery of highly charged information to patients facing difficult decisions, and promote further study of this important concept. Level of evidence Level III, economic and decision analyses.

Objective Advancements in transcatheter technology have now made it possible to safely close patent ductus arteriosus (PDA) in extremely low birth weight (ELBW) infants. The objective of this article is to describe our technique for transcatheter PDA closure (TCPC) in ELBW infants. Design The techniques employed are very specific to this population and are drastically different when compared to the procedure performed in patients weighing >5 kg. Setting A multidisciplinary team approach should be taken to evaluate and manage ELBW infants in order to achieve success. It is important that specific techniques with venous-only approach outlined in this article be followed to achieve optimal results with low risk of complications. Patients To date, in Memphis, 55 ELBW infants have had successful TCPC at a weight of ≤1000 g with minimal procedure-related complications. Interventions It is important that specific techniques with venous-only approach outlined in this article be followed to achieve optimal results with low risk of complications. Outcome measures This procedure entails a steep learning curve and should be limited to specialized centers with expertise in these thanscatheter procedures. Results There has been 100% procedural success of performing TCPC in children ≤1000 g. There have been only two procedure-related complications which happened to the first two patients, ≤1000 g, that we performed TCPC on. Conclusions It is feasible and probably safe to perform TCPC in children ≤1000 g. The techniques described in this article represent our institutional experience and have helped us improve clinical outcomes in ELBW infants.

The functional role of human derived stromal cells in the tumor microenviornment of CNS metastases (CM) remain understudied. The purpose of the current study was to isolate and characterize stromal cells of the tumor microenvironment in CM. Four different patient-derived cell lines (PDCs) of stromal and one PDC of tumorigenic origin were generated from breast or lung CM. PDCs were analyzed by DNA/RNA sequencing, DNA methylation profiling, and immunophenotypic assays. The stromal derived PDCs were termed CNS metastasis-associated stromal cells (cMASCs). Functional analysis of cMASCs was tested by co-implanting them with tumorigenic cells in mice. cMASCs displayed normal genotypes compared with tumorigenic cell lines. RNA-seq and DNA methylation analyses demonstrated that cMASCs highly resembled each other, suggesting a common cell of origin. Additionally, cMASCs revealed gene expression signatures associated with cancer associated fibroblasts (CAFs), epithelial to mesenchymal transition, mesenchymal stem cells and expressed high levels of collagen. Functionally, cMASCs restricted tumor growth, and induced desmoplasia in vivo, suggesting that cMASCs may promote a protective host response to impede tumor growth. In summary, we demonstrated the isolation, molecular characterization and functional role of human derived cMASCs, a subpopulation of cells in the microenvironment of CM that have tumor inhibitory functions.

BACKGROUND The influence of Fontan-associated protein-losing enteropathy's (PLE) severity, duration, and treatment on heart transplant (HTx) outcomes is unknown. We hypothesized that long-standing PLE and PLE requiring more intensive therapy are associated with increased post-HTx mortality. METHODS This 12-center, retrospective cohort study of post-Fontan patients with PLE referred for HTx from 2003 to 2015 involved collection of demographic, medical, surgical, and catheterization data, as well as PLE-specific data, including duration of disease, intensity/details of treatment, hospitalizations, and complications. Factors associated with waitlist and post-HTx outcomes and PLE resolution were sought. RESULTS Eighty patients (median of 5 per center) were referred for HTx evaluation. Of 68 patients listed for HTx, 8 were removed due to deterioration, 4 died waiting, and 4 remain listed. In 52 patients undergoing HTx, post-HTx 1-month survival was 92% and 1-year survival was 83%. PLE-specific factors, including duration of PLE pre-HTx, pre-HTx hospitalizations, need for/frequency of albumin replacement, PLE therapies, and growth parameters had no association with post-HTx mortality. Immunosuppressant regimen was associated with mortality; standard mycophenolate mofetil immunotherapy was used in 95% of survivors compared with only 44% of non-survivors (p = 0.03). Rejection (53%) and infection (42%) post-HTx were common, but not associated with PLE-specific factors. PLE resolved completely in all but 1 HTx survivor at a median of 1 month (interquartile range 1 to 3 months); resolution was not affected by PLE-specific factors. CONCLUSIONS PLE severity, duration, and treatment do not influence post-HTx outcome, but immunosuppressive regimen may have an impact on survival. PLE resolves in nearly all survivors.

Bariatric surgery effectively treats severe obesity and metabolic diseases. However, individual outcomes vary depending on sustainable lifestyle change. Little is known about lifestyle patterns after bariatric surgery among the US population.To compare the level of physical activity and eating behavior among postbariatric surgery patients, individuals eligible for surgery, and those with normal weight.A cross-sectional study using nationally representative survey data from National Health and Nutrition Examination Survey 2015-2018. Respondents included for analysis were age 18 years or older, and categorized by individuals with normal weight, individuals who received bariatric surgery, and individuals clinically eligible for bariatric surgery. Analyses were performed from February to October 2021.Self-reported measures were used to assess physical activity (moderate-to-vigorous physical activity [MVPA], sedentary activity, and whether PA guidelines were met) and eating behaviors (total energy intake and Healthy Eating Index [HEI]-2015 diet quality scores).Of 4659 study participants (mean [SD] age, 46.1 [18.6] years; 2638 [weighted percentage, 58.8%] women; 1114 [weighted percentage, 12.7%] Black, 1570 [weighted percentage, 68.6%] White), 132 (3.7%) reported that they had undergone any bariatric surgery. Median (IQR) time since surgery was 7 (3-10) years. After propensity-score weighting, individuals who underwent bariatric surgery reported more time spent in MVPA than those eligible for surgery (147.9 min/wk vs 97.4 min/wk). Among respondents with normal weight, 45.6% (95% CI, 40.8% to 52.4%) reported meeting PA guidelines, almost 2 times higher than those in the bariatric surgery (23.1%; 95% CI, 13.8% to 32.4%) or in the surgery-eligible group (20.3%; 95% CI, 15.6% to 25.1%). Propensity-score weighted overall HEI was higher for individuals with normal weight (54.4; 95% CI, 53.0 to 55.9) than those who underwent bariatric surgery (50.0; 95% CI, 47.2 to 52.9) or were eligible for the surgery (48.0; 95% CI, 46.0 to 50.0). Across all HEI components, mean scores were similar between the bariatric surgery and surgery-eligible groups. Total energy intake was the lowest among those who underwent bariatric surgery (1746 kcal/d; 95% CI, 1554 to 1937 kcal/d), followed by those with normal weight (1943 kcal/d; 95% CI, 1873 to 2013 kcal/d) and those eligible for bariatric surgery (2040 kcal/d; 1953 to 2128 kcal/d).In this cross-sectional study, individuals who underwent bariatric surgery had beneficial lifestyle patterns compared with those eligible for surgery; however, these improvements seemed suboptimal based on the current guidelines. Efforts are needed to incorporate benefits of physical activity and a healthy, balanced diet in postbariatric care.

Neonatal opioid withdrawal syndrome (NOWS) is a major public health concern whose incidence has paralleled the opioid epidemic in the United States. Sublingual buprenorphine is an emerging treatment for NOWS, but given concerns about long-term adverse effects of perinatal opioid exposure, precision dosing of buprenorphine is needed. Buprenorphine pharmacokinetics (PK) in newborns, however, is highly variable. To evaluate underlying sources of PK variability, a neonatal physiologically-based pharmacokinetic (PBPK) model of sublingual buprenorphine was developed using Simcyp (version 19.1). The PBPK model included metabolism by cytochrome P450 (CYP) 3A4, CYP2C8, UDP-glucuronosyltransferase (UGT) 1A1, UGT1A3, UGT2B7, and UGT2B17, with additional biliary excretion. Maturation of metabolizing enzymes was incorporated, and default CYP2C8 and UGT2B7 ontogeny profiles were updated according to recent literature. A biliary clearance developmental profile was outlined using clinical data from neonates receiving sublingual buprenorphine as NOWS treatment. Extensive PBPK model validation in adults demonstrated good predictability, with geometric mean (95% confidence interval (CI)) predicted/observed ratios (P/O ratios) of area under the curve from zero to infinity (AUC0-∞ ), peak concentration (Cmax ), and time to reach peak concentration (Tmax ) equaling 1.00 (0.74-1.33), 1.04 (0.84-1.29), and 0.95 (0.72-1.26), respectively. In neonates, the geometric mean (95% CI) P/O ratio of whole blood concentrations was 0.75 (95% CI 0.64-0.87). PBPK modeling and simulation demonstrated that variability in biliary clearance, sublingual absorption, and CYP3A4 abundance are likely important drivers of buprenorphine PK variability in neonates. The PBPK model could be used to guide development of improved buprenorphine starting dose regimens for the treatment of NOWS.

Insects can become lethally infected by the oral intake of a number of insect-specific viruses. Virus infection commonly occurs in larvae, given their active feeding behaviour, however, older larvae often become resistant to oral viral infections. To investigate mechanisms that contribute to resistance throughout the larval development, we orally challenged Drosophila larvae at different stages of their development with Drosophila C virus (DCV, Dicistroviridae). Here, we showed that DCV-induced mortality is highest when infection initiates early in larval development and decreases the later in development the infection occurs. We then evaluated the peritrophic matrix as an antiviral barrier within the gut using a Crystallin-deficient fly line (Crys−/−), whose PM is weakened and becomes more permeable to DCV-sized particles as the larva ages. This phenotype correlated with increasing mortality the later in development oral challenge occurred. Lastly, we tested in vitro the infectivity of DCV after incubation at pH conditions that may occur in the midgut. DCV virions were stable in a pH range between 3.0 and 10.5, but their infectivity decreased at least 100-fold below (1.0) and above (12.0) this range. We did not observe such acidic conditions in recently hatched larvae. We hypothesise that, in Drosophila larvae, the PM is essential for containing ingested virions separated from the gut epithelium, while highly acidic conditions inactivate the majority of the virions as they transit.

Durable control of invasive solid tumors necessitates identifying therapeutic resistance mechanisms and effective drug combinations. In this work, we used a network-based mathematical model to identify sensitivity regulators and drug combinations for the PI3Kα inhibitor alpelisib in ER+ PIK3CA mutant breast cancer. The model-predicted efficacious combination of alpelisib and BH3 mimetics, e.g., MCL1 inhibitors, was experimentally validated in ER+ breast cancer cell lines. Consistent with the model, FOXO3 downregulation reduced sensitivity to alpelisib, revealing a novel potential resistance mechanism. Cell line-specific sensitivity to combinations of alpelisib and BH3 mimetics depended on which BCL-2 family members were highly expressed. Based on these results, newly developed cell line-specific network models were able to recapitulate the observed differential response to alpelisib and BH3 mimetics. This approach illustrates how network-based mathematical models can contribute to overcoming the challenge of cancer drug resistance.

Background and ObjectivesWe aimed to determine the genetic and clinical phenotypes of patients with desmin-related myopathy and long-term outcomes after cardiac transplantation.MethodsWe performed a retrospective review of cardiac and neurologic manifestations of patients with genetically confirmed desmin-related myopathy (January 1, 1999–January 1, 2020).ResultsTwenty-five patients in 20 different families were recognized. Median age at onset of symptoms was 20 (range 4–50) years; median follow-up time was 36 (range 1–156) months. Twelve patients initially presented with skeletal muscle involvement, and 13 presented with cardiac disease. Sixteen patients had both cardiac and skeletal muscle involvement. Clinically muscle weakness distribution was distal (n = 11), proximal (n = 4), or both (n = 7) in 22 patients. Skeletal muscle biopsy from patients with missense and splice site variants (n = 12) showed abnormal fibers containing amorphous material in Gomori trichrome–stained sections. Patients with cardiac involvement had atrioventricular conduction abnormalities or cardiomyopathy. The most common ECG abnormality was complete atrioventricular block in 11 patients, all of whom required a permanent pacemaker at a median age of 25 (range 16–48) years. Sudden cardiac death resulting in implantable cardioverter-defibrillator (ICD) shocks or resuscitation was reported in 3 patients; a total of 5 patients had ICDs. Orthotopic cardiac transplantation was performed in 3 patients at 20, 35, and 39 years of age.DiscussionPathogenic variants in desmin can lead to varied neurologic and cardiac phenotypes beginning at a young age. Two-thirds of the patients have both neurologic and cardiac symptoms, usually starting in the third decade. Heart transplantation was tolerated with improved cardiac function and quality of life.

Breast cancer and cardiovascular-specific mortality are higher among blacks compared with whites, but disparities in cancer therapy-related adverse cardiovascular outcomes have not been well studied. We assessed for the contribution of race and socioeconomic status on cardiotoxicity among women with HER2-positive breast cancer. This retrospective cohort analysis studied women diagnosed with stage I-III HER2-positive breast cancer from 2004-2013. All underwent left ventricular ejection fraction assessment at baseline and at least one follow-up after beginning trastuzumab. Multivariable logistic regression was used to assess the association between race and socioeconomic status (SES) on cardiotoxicity, defined by clinical heart failure (New York Heart Association class III or IV) or asymptomatic left ventricular ejection fraction decline (absolute decrease ≥ 10% to < 53%, or ≥ 16%). Blacks had the highest prevalence of hypertension, diabetes, and increased BMI. Neighborhood-level SES measures including household income and educational attainment were lower for blacks compared with whites and others. The unadjusted cardiotoxicity risk was significantly higher in black compared with white women (OR, 2.10; 95% CI, 1.42 to 3.10). In a multivariable analysis, this disparity persisted after controlling for relevant cardiovascular risk factors (adjusted OR, 1.88; 95% CI, 1.25 to 2.84). Additional models adjusting for SES factors of income, educational attainment, and insurance status did not significantly alter the association between race and cardiotoxicity. In conclusion, black women are at increased risk of cardiotoxicity during HER2-targeted breast cancer therapy. Future etiologic analyses, particularly studies exploring biologic or genetic mechanisms, are needed to further elucidate and reduce racial disparities in cardiotoxicity.

The 20-question Revised Study Process Questionnaire (R-SPQ-2F), which is frequently used to categorize student learning approaches as either deep or surface, was administered to three sections of Anatomy & Physiology (A&P) courses at a highest research university in the southeastern United States as part of a larger research project. Two hundred thirty-one (231) respondents completed the full survey and 11 participants were recruited to a comparative case study. Initial review of interview transcripts raised concerns about the validity of the R-SPQ-2F results with the population of interest. Interview transcripts were coded using a priori codes corresponding to the R-SPQ-2F items, and qualitative and quantitative results were then triangulated. Additional survey responses were collected in a subsequent semester and a confirmatory factor analysis (CFA) was performed using the complete responses from 381 students. The CFA yielded similar or better measures of reliability and fit to the two-factor structure as those in previously reported work by other authors. Nonetheless, findings from triangulation suggest that the R-SPQ-2F was not able to group students by deep and surface approaches to learning in the context of an undergraduate A&P course. In addition, six interviews (3 deep, 3 surface) demonstrated a new theme of surface leading to deep with participants indicating that memorization was necessary for the purpose of gaining a full understanding of the course material. This mixed method analysis calls into question whether the results are valid for separating student approaches into the previously published descriptions of deep and surface approaches. The finding of the surface leading to deep orientation, which may align with previous descriptions of an achieving approach, has significant implications for both research and instruction, as memorizing and other “surface” strategies are often minimized and discouraged, yet are an important step in student learning.