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Colorectal cancer (CRC) is a leading cause of cancer death in the United States. Standard treatment for advanced stage CRC for decades has included 5-fluorouracil based chemotherapy. More recently, targeted therapies for metastatic CRC are being used based on the individual cancer's molecular profile. In the past few years, several different molecular subtype schemes for human CRC have been developed. The molecular subtypes can be distinguished by gene expression signatures and have the potential to be used to guide treatment decisions. However, many subtyping classification methods were developed using mRNA expression levels of hundreds to thousands of genes, making them impractical for clinical use. In this study, we assessed whether an immunohistochemical approach could be used for molecular subtyping of colorectal cancers. We validated two previously published, independent sets of immunohistochemistry classifiers and modified the published methods to improve the accuracy of the scoring methods. In addition, we evaluated whether protein and genetic signatures identified originally in the mouse were linked to clinical outcomes of patients with CRC. We found that low DDAH1 or low GAL3ST2 protein levels in human CRCs correlate with poor patient outcome. The results of this study have the potential to impact methods for determining the prognosis and therapy selection for CRC patients.

To determine whether a history of abortion is associated with the experience of infertility among women, 2,199 women who ever met medical criteria for infertility were studied. Data for the study c...

Objective The fetal risks and benefits of antihypertensives to treat gestational hypertension in pregnancy are understudied, particularly in low- and middle-income countries. Methods We performed a nested case-control study within a retrospective cohort of obstetrical patients in Botswana from 2014 to 2019. We included women carrying singletons who developed new onset non-severe hypertension (140-159 mm Hg systolic or 90-109 mm Hg diastolic blood pressure) after 20 weeks of pregnancy. Cases were defined as women with either small-for-gestational-age (SGA) infants or stillbirth, analyzed separately; controls were otherwise similar women without the adverse outcome in each analysis. Results We identified 1932 cases of SGA (7925 controls) and 316 cases of stillbirth (9619 controls). Cases with SGA were more likely to have used an anti-hypertensive than controls (33% vs 29%, adjusted odds ratio [aOR] 1.28, 95% confidence interval [CI] 1.15-1.43). Cases with stillbirth were more likely to have used an anti-hypertensive than controls (42% versus 29%, aOR 1.45, 95% CI 1.14-1.83). Conclusion Anti-hypertensive use for new-onset gestational hypertension was associated with an increased risk of having an SGA infant or a stillbirth among women who never developed severe hypertension. These data support conduct of a randomized clinical trial to determine the appropriate use of anti-hypertensives in non-severe gestational hypertension.

Objective: To examine the associations between the number and type of memory complaints with memory and sustained attention performance in healthy middle-aged adults. Method: Sixty-six healthy individuals aged 35–64 years ( Mage = 47.73 years) were administered the seven Questions, Rey Auditory Verbal Learning Test, Sustained Attention to Response Task, and Depression Anxiety Stress Scales 21. Results: The number of memory complaints was not associated with memory or sustained attention performance but was associated with anxiety symptoms. The type of memory complaint was likewise not associated with memory or sustained attention performance. The complaints “recent change in ability to remember things” and “trouble remembering things from one second to the next” were associated with anxiety symptoms. Conclusion: Complaints about memory in otherwise healthy middle-aged adults do not reliably indicate memory or sustained attention performance. Rather, these complaints are more likely to be associated with heightened, but nevertheless subclinical, anxiety.

Hepatocytes metabolize energy-rich cytoplasmic lipid droplets (LDs) in the lysosome-directed process of autophagy. An organelle-selective form of this process (macrolipophagy) results in the engulfment of LDs within double-membrane delimited structures (autophagosomes) before lysosomal fusion. Whether this is an exclusive autophagic mechanism used by hepatocytes to catabolize LDs is unclear. It is also unknown whether lysosomes alone might be sufficient to mediate LD turnover in the absence of an autophagosomal intermediate. We performed live-cell microscopy of hepatocytes to monitor the dynamic interactions between lysosomes and LDs in real-time. We additionally used a fluorescent variant of the LD-specific protein (PLIN2) that exhibits altered fluorescence in response to LD interactions with the lysosome. We find that mammalian lysosomes and LDs undergo interactions during which proteins and lipids can be transferred from LDs directly into lysosomes. Electron microscopy (EM) of primary hepatocytes or hepatocyte-derived cell lines supports the existence of these interactions. It reveals a dramatic process whereby the lipid contents of the LD can be “extruded” directly into the lysosomal lumen under nutrient-limited conditions. Significantly, these interactions are not affected by perturbations to crucial components of the canonical macroautophagy machinery and can occur in the absence of double-membrane lipoautophagosomes. These findings implicate the existence of an autophagic mechanism used by mammalian cells for the direct transfer of LD components into the lysosome for breakdown. This process further emphasizes the critical role of lysosomes in hepatic LD catabolism and provides insights into the mechanisms underlying lipid homeostasis in the liver.

Summary SMRTER (SMRT-related and ecdysone receptor interacting factor) is the Drosophila homologue of the vertebrate proteins SMRT and N-CoR, and forms with them a well-conserved family of transcriptional corepressors. Molecular characterization of SMRT-family proteins in cultured cells has implicated them in a wide range of transcriptional regulatory pathways. However, little is currently known about how this conserved class of transcriptional corepressors regulates the development of particular tissues via specific pathways. In this study, through our characterization of multiple Smrter (Smr) mutant lines, mosaic analysis of a loss-of-function Smr allele, and studies of two independent Smr RNAi fly lines, we report that SMRTER is required for the development of both ovarian follicle cells and the wing. In these two tissues, SMRTER inhibits not only the ecdysone pathway, but also the Notch pathway. We differentiate SMRTER9s influence on these two signaling pathways by showing that SMRTER inhibits the Notch pathway, but not the ecdysone pathway, in a spatiotemporally restricted manner. We further confirm the likely involvement of SMRTER in the Notch pathway by demonstrating a direct interaction between SMRTER and Suppressor of Hairless [Su(H)], a DNA-binding transcription factor pivotal in the Notch pathway, and the colocalization of both proteins at many chromosomal regions in salivary glands. Based on our results, we propose that SMRTER regulates the Notch pathway through its association with Su(H), and that overcoming a SMRTER-mediated transcriptional repression barrier may represent a key mechanism used by the Notch pathway to control the precise timing of events and the formation of sharp boundaries between cells in multiple tissues during development.

Objectives Lead exposure has been associated with hypertensive disorders of pregnancy. Angiogenic factors, including soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF), are aberrant in preeclampsia, but have not been correlated with lead levels. We evaluated the association of lead exposure with angiogenic factors. Study design This cross sectional study utilized a convenience sample of singleton pregnancies ≥34 weeks’ gestation. Blood lead and angiogenic factors were measured before delivery; bone lead was measured postpartum. We dichotomized bone and blood lead into the top tertile versus the bottom tertiles and used log-binomial regression to assess the association between lead and a high angiogenic ratio. Main outcome measures The outcomes were high sFlt1 to PlGF ratio and development of a hypertensive disorder of pregnancy. Results We enrolled 102 participants, of whom 98 had at least one lead measurement and an angiogenic factor result. Median bone lead was 3.8 ug/g (2.0 – 6.6) and median blood lead was 0.2 ug/dL (0.2 – 0.4). Incidence of hypertensive disorders of pregnancy was 31%. When comparing the highest tertile of bone lead to the bottom two tertiles, there was no association with a high sFlt1/PlGF ratio or hypertensive disorders of pregnancy. Similar results were observed for the exposure of blood lead. Conclusions Lead exposure was not an important contributor to an elevated angiogenic factor ratio or hypertensive disorders of pregnancy in our U.S. population. However, lead exposure was modest in our population and we cannot exclude a relationship with hypertensive disorders of pregnancy.

The role of community colleges in training public health professionals is of growing importance to the continuum of public health education. Some 5 years have passed since the Framing the Future initiative outlined curricular models at community colleges, and colleges deploying these models are serving as learning sites for public health education at community colleges. While past research has focused on capturing insights from community college executives and program administrators, this study captures perspectives from teaching faculty. Drawing on a national sample of teaching faculty at community colleges and universities accepting transfer students throughout the United States, an online survey of teaching faculty affiliated with public health programs was coupled with follow-up interviews. This study characterizes the nature and scope of public health programming in community colleges and transfer settings, and highlights associated challenges and opportunities as public health becomes further integrated into health professions pathways in 2-year settings and beyond.

BACKGROUND: High obesity rates among young black and Hispanic children place them at a higher risk for adult obesity and its co-morbidities. Neighborhoods with predominately racial and ethnic minority residents have fewer healthful food options, which may contribute to obesity disparities. Yet few studies have assessed the relationship between neighborhood food environments and obesity in this population. METHODS: Electronic health records from two pediatric primary care clinics serving predominately low-income, black and Hispanic children were used to create a cohort of 3,724 2-5 year-olds, encompassing 7,256 visits from 2007 to 2012 (mean 1.9 visits per patient, range: 1-5 visits per child). Longitudinal regression was used to model the association of mean body mass index z-score (BMI-z) over time and 3 measures of the neighborhood food environment: healthful food availability, availability of stores accepting the Special Supplemental Nutrition Program for Women, Infants and Children (WIC) benefits, and fast food availability. RESULTS: Compared to peers in neighborhoods with no or few stores accepting WIC, children in neighborhoods with many WIC stores had higher BMI-z at age 2 years (average difference of 0.272 95% CI 0.041 – 0.503; p=0.021). No relationship was found for healthful food or fast food availability. Although children in neighborhoods with low fast food availability did not have statistically significantly different BMI-z at age 2 as compared to children in areas with high fast food availability, they did have a statistically significantly higher change in average BMI-z over time (0.006 per month, 0.000 – 0.012, p=0.024). CONCLUSIONS: Access to WIC stores was associated with lower obesity rates and more healthful average BMI-z over time and represents a potentially important neighborhood food environment characteristic influencing racial/ethnic disparities in childhood obesity among young black and Hispanic children. More studies are needed to assess what aspects of WIC stores may underlie the observed association. WHAT’S NEW: Access to WIC stores represents a potentially important neighborhood food environment characteristic influencing racial and ethnic disparities in childhood obesity among young black and Hispanic children.

Studies of medical help-seeking presume that self-identifying as having a health problem precedes medical contact, but this ordering of the identity-behavior relationship has not been systematically examined. We used longitudinal data from the National Survey of Fertility Barriers (2004 to 2010) on 412 women with infertility to document the temporal relationship between self-identifying as having a fertility problem and making medical contact. The symbolic interactionist perspective suggests that infertility will be perceived as identity disruption and that in response women will align self-identity and medical behavior over time. Cross-tabulation analysis indicated that more women do self-identify as having a fertility problem first (24 percent) as opposed to making medical contact first (5.5 percent). There was also a tendency toward aligning self-identification and behavior over time. Latent class analyses revealed six patterns: 1) consistently involved, 2) early consulters, 3) consistently uninvolved, 4) consistent perceivers, 5) medical dropouts, and 6) early perceivers. Strong fertility intent and primary infertility, two identity-relevant characteristics, had the strongest associations with latent class membership. The relationship between self-identification and medical help-seeking is thus dynamic and complex.

Lanthanide ion (LnIII ) complexes, [Ln(3Tcbx)2 ]3+ (LnIII =YbIII , NdIII , ErIII ) are isolated with a new pyridine-bis(carboxamide)-based ligand with a 2,2':5',2''-terthiophene pendant (3TCbx), and their resulting photophysical properties are explored. Upon excitation of the complexes at 490 nm, only LnIII emission is observed with efficiencies of 0.29 % at 976 nm for LnIII =YbIII and 0.16 % at 1053 nm for LnIII =NdIII . ErIII emission is observed but weak. Upon excitation at 400 nm, concurrent 1 O2 formation is seen, with efficiencies of 11 % for the YbIII and NdIII complexes and 13 % for the ErIII complex. Owing to the concurrent generation of 1 O2 , as expected, the efficiency of metal-centered emission decreases to 0.02 % for YbIII and 0.05 % for NdIII . The ability to control 1 O2 generation through the excitation wavelength indicates that the incorporation of 2,2':5',2''-terthiophene results in access to multiple sensitization pathways. These energy pathways are unraveled through transient absorption spectroscopy.

Tumor heterogeneity is predicted to confer inferior clinical outcomes, however modeling heterogeneity in a manner that still represents the tumor of origin remains a formidable challenge. Sequencing technologies are limited in their ability to identify rare subclonal populations and predict response to the multitude of available treatments for patients. Patient-derived organotypic cultures have significantly improved the modeling of cancer biology by faithfully representing the molecular features of primary malignant tissues. Patient-derived cancer organoid (PCO) cultures contain numerous individual organoids with the potential to recapitulate heterogeneity, though PCOs are most commonly studied in bulk ignoring any diversity in the molecular profile or treatment response. Here we demonstrate the advantage of evaluating individual PCOs in conjunction with cellular level optical metabolic imaging to characterize the largely ignored heterogeneity within these cultures to predict clinical therapeutic response, identify subclonal populations, and determine patient specific mechanisms of resistance.

Representative models are needed to screen new therapies for patients with cancer. Cancer organoids are a leap forward as a culture model that faithfully represents the disease. Mouse-derived cancer organoids (MDCOs) are becoming increasingly popular, however there has yet to be a standardized method to assess therapeutic response and identify subpopulation heterogeneity. There are multiple factors unique to organoid culture that could affect how therapeutic response and MDCO heterogeneity are assessed. Here we describe an analysis of nearly 3,500 individual MDCOs where individual organoid morphologic tracking was performed. Change in MDCO diameter was assessed in the presence of control media or targeted therapies. Individual organoid tracking was identified to be more sensitive to treatment response than well-level assessment. The impact of different generations of mice of the same genotype, different regions of the colon, and organoid specific characteristics including baseline size, passage number, plating density, and location within the matrix were examined. Only the starting size of the MDCO altered the subsequent growth. Here we establish organoid culture parameters for individual organoid morphologic tracking to determine therapeutic response and growth/response heterogeneity for translational studies using murine colorectal cancer organoids.

A new pyridine-bis(carboxamide)-based ligand with a bithiophene pendant, 2Tcbx, was synthesized. Its lanthanide ion (LnIII) complexes, [Ln(2Tcbx)2]3+, were isolated and their photophysical properties were explored. Upon excitation at 360 nm, these complexes display emission in the near-infrared (NIR) with efficiencies of 0.69% for LnIII = YbIII, 0.20% for LnIII = NdIII, and 0.01% for LnIII = ErIII, respectively. Concurrent 1O2 formation was seen for all complexes, with efficiencies of 19% for the YbIII complex, 25% for the NdIII complex, and 9% for the ErIII complex. When exciting at a longer wavelength, 435 nm, only LnIII emission was observed and larger efficiencies of LnIII-centered emission were obtained. The lack of 1O2 generation indicates that energy pathways involving different ligand conformations, which were investigated by transient absorption spectroscopy, are involved in the sensitization process, and enable the wavelength-dependent generation of 1O2.

Nearly one-third to one-half of U.S. women meets the medical criteria for infertility at some point in their reproductive lives. Yet many do not view lack of conception as problematic. Why might some women self-identify as having a fertility problem but others do not? Using two waves of the National Survey of Fertility Barriers, we conducted binary and longitudinal multinomial logistic regression to answer this question. Results suggest that only a portion of women actually experience infertility as a “spoiled identity” or as disruptive to their lives. Rather, consistent with symbolic interactionist perspectives, there is evidence that infertility symptoms (i.e., not conceiving) depend upon interpretations and definitions of the situation. Multiple patterns of self-identification over time (identity non-adopters, maintainers, adopters, and relinquishers) suggest an indeterminate association between illness and impacts on the self, even for a condition that is highly medicalized in the United States.

We examine responses to infertility among a sample of 2,361 women with infertility from the National Survey of Fertility Barriers. Latent class analysis uncovered seven latent classes of behavioral response which can be arranged in a rough continuum from least medicalized to most medicalized response. We then aggregated these seven categories into three schemas representing various degrees of medicalization. Women in each class combine treatment-seeking, knowledge-seeking, socio-emotional support seeking, and non-medical solution-seeking strategies. Even women pursuing the greatest degree of medicalization in their health-seeking (e.g., fertility treatments, assisted reproduction) made use of a variety of medical and non-medical health-seeking resources.

OBJECTIVES: To evaluate the association of fresh and frozen embryo transfer with the development of ischemic placental disease (IPD), hypothesizing that differences in implantation environment affect placentation and thus pregnancy outcomes. DESIGN: We performed a secondary analysis of a retrospective cohort study of deliveries linked to in vitro fertilization (IVF) cycles. SETTING: Deliveries were performed over fifteen years at a single tertiary hospital. All IVF cycles were performed at a single infertility treatment center. PATIENTS: We included all women who underwent an autologous IVF cycle and had a live born infant or an intrauterine fetal demise (IUFD). We excluded women less than 18 years of age. INTERVENTION: We compared pregnancies resulting from frozen embryo transfer (frozen) cycles to those resulting from fresh embryo transfer (fresh) cycles. MAIN OUTCOME MEASURES: The primary outcome was a composite outcome of IPD or IUFD due to placental insufficiency. IPD included preeclampsia, placental abruption, and small for gestational age (SGA). We calculated risk ratios (RR) and 95% confidence intervals (CI). RESULTS: Compared to fresh cycles, frozen cycles had a lower risk of IPD or IUFD from placental insufficiency (RR 0.75, 95% CI: 0.59-0.97). Frozen cycles also conferred a lower risk of SGA than fresh cycles (RR 0.58, 95% CI: 0.41-0.81). Risks of preeclampsia (RR 1.3, 95% CI: 0.84-1.9) and abruption (RR 1.2, 95% CI: 0.56-2.4) were similar. CONCLUSION: There was a lower risk of IPD among frozen cycles compared to fresh cycles. This association was largely driven by lower risk of SGA among frozen cycles.

Alphaviruses and flaviviruses have class II fusion glycoproteins that are essential for virion assembly and infectivity. Importantly, the tip of domain II is structurally conserved between the alphavirus and flavivirus fusion proteins, yet whether these structural similarities between virus families translate to functional similarities is unclear. Using in vivo evolution of Zika virus (ZIKV), we identified several novel emerging variants including an envelope glycoprotein variant in β-strand c (V114M) of domain II. We have previously shown that the analogous β-strand c and the ij loop, located in the tip of domain II of the alphavirus E1 glycoprotein, are important for infectivity. This led us to hypothesize that flavivirus E β-strand c also contributes to flavivirus infection. We generated this ZIKV glycoprotein variant and found that while it had little impact on infection in mosquitoes, it reduced replication in human cells and mice, and increased virus sensitivity to ammonium chloride, as seen for alphaviruses. In light of these results and given our alphavirus ij loop studies, we mutated a conserved alanine at the tip of the flavivirus ij loop to valine to test its effect on ZIKV infectivity. Interestingly, this mutation inhibited infectious virion production of ZIKV and yellow fever virus, but not West Nile virus. Together, these studies show that structurally analogous residues in the alphavirus and flavivirus class II fusion proteins contribute to virus infection in vivo and highlight these shared domains as targets for broad-spectrum arbovirus therapies.Author SummaryArboviruses are a significant global public health threat, yet there are no antivirals targeting these viruses. This problem is in part due to our lack of knowledge on the molecular mechanisms involved in the arbovirus life cycle. In particular, virus entry and assembly are essential processes in the virus life cycle and steps that can be targeted for the development of antiviral therapies. Therefore, understanding common, fundamental mechanisms used by different arboviruses for entry and assembly is essential. In this study, we show that flavivirus and alphavirus residues located in structurally conserved and analogous regions of the class II fusion proteins contribute to common mechanisms of entry, dissemination, and infectious virion production. These studies highlight how class II fusion proteins function and provide novel targets for development of antivirals.

One of the earliest identifiable features of Autism Spectrum Disorder (ASD) is altered attention. Mice expressing the ASD-associated R451C mutation in synaptic adhesion protein neuroligin-3 (NL3) exhibit impaired reciprocal social interactions and repetitive and restrictive behaviors. The role of this mutation in attentional abnormalities has not been established. We assessed attention in male NL3R451C mice using two well-established tasks in touchscreen chambers. In the 5-choice serial reaction task (5CSRT), rodents were trained to attend to light stimuli that appear in any one of 5 locations. While no differences between NL3R451C and WT mice were seen in accuracy or omissions, slower response times and quicker reward collection latencies were seen across all training and probe trials. In the rodent continuous-performance test (rCPT), animals were required to discriminate, and identify a visual target pattern over multiple distractor stimuli. NL3R451C mice displayed enhanced ability to attend to stimuli when task-load was low during training and baseline but lost this advantage when difficulty was increased by altering task parameters in probe trials. NL3R451C mice made less responses to the distractor stimuli, exhibiting lower false alarm rates during all training stages and in probe trials. Slower response times and quicker reward latencies were consistently seen in NL3R451C mice in the rCPT. Slower response times are a major cognitive phenotype reported in ASD patients and are indicative of slower processing speed. Enhanced attention has been shown in a subset of ASD patients and we have demonstrated this phenotype also exists in the NL3R451C mouse model.

Placenta accreta spectrum includes the full range of abnormal placental attachment to the uterus or other structures, encompassing placenta accreta, placenta increta, placenta percreta, morbidly adherent placenta, and invasive placentation. The incidence of placenta accreta spectrum has increased in recent years, largely driven by increasing rates of cesarean delivery. Prenatal detection of placenta accreta spectrum is primarily made by ultrasound and is important to reduce maternal morbidity associated with the condition. Despite a large body of research on various placenta accreta spectrum ultrasound markers and their screening performance, inconsistencies in the literature persist. In response to the need for standardizing the definitions of placenta accreta spectrum markers and the approach to the ultrasound examination, the Society for Maternal-Fetal Medicine convened a task force with representatives from the American Institute of Ultrasound in Medicine, the American College of Obstetricians and Gynecologists, the American College of Radiology, the International Society of Ultrasound in Obstetrics and Gynecology, the Society for Radiologists in Ultrasound, the American Registry for Diagnostic Medical Sonography, and the Gottesfeld-Hohler Memorial Ultrasound Foundation. The goals of the task force were to assess placenta accreta spectrum sonographic markers on the basis of available data and expert consensus, provide a standardized approach to the prenatal ultrasound evaluation of the uterus and placenta in pregnancies at risk of placenta accreta spectrum, and identify research gaps in the field. This manuscript provides information on the Placenta Accreta Spectrum Task Force process and findings.

Management of gastrointestinal stromal tumors (GISTs) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of RTK inhibitors in advanced disease. Stratification of GISTs into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GISTs, resistance remains a significant clinical problem. Development of effective treatment strategies for refractory GISTs requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases essential in GISTs. Using multiplexed inhibitor beads and mass spectrometry, we explored the majority of the kinome in GIST specimens from the 3 most common molecular subtypes (KIT mutant, PDGFRA mutant, and succinate dehydrogenase deficient) to identify kinase targets. Kinome profiling with loss-of-function assays identified an important role for G2/M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT mutant and PDGFRA mutant GIST cell lines as well as notable efficacy of MK-1775 as a monotherapy in the engineered PDGFRA mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

This article provides a summary of a landmark study in obstetrics. The article provides insight on a pivotal question; Is delivery before 39 weeks among patients undergoing elective repeat cesarean delivery associated with increased risk of adverse neonatal outcomes? The authors describe the basics of the study, including study location, study population, number of patients, study design, endpoints, results, and limitations. The article briefly reviews other relevant studies and information, discusses implications, and concludes with a relevant clinical case. The article places these finding in contemporary context and highlights its impact on obstetric care. In addition, the author reference updated national guidelines developed as a result of this study.

ObjectivesThe present study explores the effect of visual art training on people with dementia, utilizing a randomized control trial design, in order to investigate the effects of an 8-week visual art training program on cognition. In particular, the study examines overall cognition, delayed recall, and working memory, which show deficits in people with dementia.MethodFifty-three individuals with dementia were randomly assigned into either an art training (n = 27) or usual-activity waitlist control group (n = 26). Overall cognition and delayed recall were assessed with the Montreal Cognitive Assessment (MoCA), and working memory was assessed with the Backward Digit Span task.ResultsThere were no group differences in overall cognition, or working memory, while a difference in delayed recall was undetermined, based on post-test—pre-test difference scores. Groups were comparable at baseline on all measures.ConclusionThe measures of cognition, delayed recall, and working memory used in this study were not affected by an 8-week visual art training program.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT03175822.

The present study characterizes changes in sustained attention ability over ages 9-14, and whether longitudinal trajectories of attention development differ between persistent ADHD, remitted ADHD and control groups. The Sustained Attention to Response Task (SART) was administered to 120 children with ADHD and 123 controls on three occasions between ages 9 and 14. Trajectories of sustained attention development, indicated by changes in SART performance (standard deviation of response time [SDRT], omission errors, and ex-Gaussian parameters sigma and tau), were examined using generalized additive mixed models. For all measures there was a significant main effect of age; response time variability and number of omission errors improved linearly as children aged. However, children with ADHD had significantly greater SDRT, tau and omission errors than controls across waves. There were no significant group differences in sigma, indicating that the greater overall response time variability (SDRT) observed in ADHD was likely driven by more intermittent long responses (larger tau). Trajectories of sustained attention performance did not differ between children with persistent ADHD or ADHD in remission. Longitudinal trajectories of sustained attention development are comparable between ADHD and controls, however children with ADHD (regardless of remission status) display a performance deficit equivalent to typical controls 1-3 years younger. Findings highlight the need for continued clinical support for children in remission from ADHD and provide support for tau as an endophenotype of ADHD.

Objectives Ischemic placental disease (IPD), including preeclampsia, abruption, and fetal growth restriction, often recurs in subsequent pregnancies. Angiogenic factors of placental origin have been implicated in the pathogenesis of preeclampsia, but have not been studied as predictors of IPD in subsequent pregnancies. We hypothesized that elevated angiogenic factors in an index pregnancy would be associated with recurrence of IPD. Study design We conducted a retrospective cohort study of patients undergoing evaluation for preeclampsia who had angiogenic factors measured in an index pregnancy and experienced a subsequent pregnancy at the same institution. Patients with IPD in the index pregnancy were included. A high ratio of soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF) was defined as greater than or equal to 85. Main outcome measures The primary outcome was IPD in a subsequent pregnancy. Results We included 109 patients in the analysis. The sFlt1/PlGF ratio was elevated in 30% of participants. Those with an elevated ratio were more likely to be nulliparous in the index pregnancy, and less likely to have chronic hypertension. The recurrence of IPD in the study was 27%, with a non-significant difference in risk based on a high sFlt-1/P1GF ratio RR 0.58 (95% CI 0.21 – 1.6) compared to a low ratio. Conclusions A high sFlt1/P1GF ratio in an index pregnancy is not associated with a higher risk of IPD in a subsequent pregnancy. These data suggest placental angiogenic biomarkers are specific to the pregnancy and not a reflection of maternal predisposition to IPD.

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by degeneration of motor neurons and muscles, and death is usually a result of impaired respiratory function due to loss of motor neurons that control upper airway muscles and/or the diaphragm. Currently, no cure for ALS exists and treatments to date do not significantly improve respiratory or swallowing function. One cause of ALS is a mutation in the superoxide dismutase-1 (SOD1) gene; thus, reducing expression of the mutated gene may slow the progression of the disease. Our group has been studying the SOD1(G93A) transgenic mouse model of ALS that develops progressive respiratory deficits and dysphagia. We hypothesize that solely treating the tongue in SOD1 mice will preserve respiratory and swallowing function, and it will prolong survival. At 6 weeks of age, 11 SOD1(G93A) mice (both sexes) received a single intralingual injection of gene therapy (AAVrh10-miR(SOD1)). Another 29 mice (both sexes) were divided into two control groups: (1) 12 SOD1(G93A) mice that received a single intralingual vehicle injection (saline); and (2) 17 non-transgenic littermates. Starting at 13 weeks of age, plethysmography (respiratory parameters) at baseline and in response to hypoxia (11% O(2)) + hypercapnia (7% CO(2)) were recorded and videofluoroscopic swallow study testing were performed twice monthly until end-stage disease. Minute ventilation during hypoxia + hypercapnia and mean inspiratory flow at baseline were significantly reduced (p 0.05). AAVrh10-miR(SOD1) injections also significantly extended survival in females by ∼1 week. In conclusion, this study indicates that intralingual AAVrh10-miR(SOD1) treatment preserved respiratory (but not swallowing) function potentially via increasing upper airway patency, and it is worthy of further exploration as a possible therapy to preserve respiratory capacity in ALS patients.

Objective To evaluate the association between in vitro fertilization (IVF) and ischemic placental disease (IPD), stratified by gestational age. Design We performed a secondary analysis of a retrospective cohort study of deliveries. Setting Deliveries were performed over 15 years at a single tertiary hospital. Patient(s) We included all parturients who had a live born infant or an intrauterine fetal demise (IUFD). Intervention(s) We compared pregnancies resulting from IVF cycles to non-IVF pregnancies. Main Outcome Measure(s) The primary outcomes were preterm and term IPD (preeclampsia, placental abruption, small-for-gestational age infant [SGA], or an intrauterine fetal demise [IUFD] due to placental insufficiency). Result(s) Of the 69,084 deliveries during the study period, 3,763 (5.4%) were conceived with IVF. The incidence of preterm delivery was 32.6% in IVF pregnancies and 10.8% in non-IVF pregnancies. Multiple gestations were more common in IVF pregnancies. Compared to non-IVF pregnancies, IVF pregnancies were more likely to develop both preterm and term IPD, even after adjustment for maternal age and parity. The risk of preterm IPD was 4 times higher (95% confidence interval, 3.7–4.4) in patients who underwent IVF compared with those who did not undergo IVF. Among parturients who delivered at ≥37 weeks of gestation, IVF pregnancies had 1.7 times the risk of term IPD (95% confidence interval, 1.6–1.9) compared with non-IVF pregnancies. Conclusion(s) IVF was strongly associated with preterm IPD. We found a similar, but attenuated, association between IVF and term IPD. The stronger association with preterm IPD suggests an association between IVF and placental insufficiency.

Objective The incidence of placenta accreta spectrum (PAS) has been increasing in the United States. In addition, there has also been an increase in the utilization of in vitro fertilization (IVF). The IVF pregnancies confer an increased risk of adverse obstetric and neonatal outcomes, but there is limited data on whether IVF is associated with PAS. The aim of this study is to assess the association between IVF and the risk of PAS. Study Design This was a retrospective cohort study of deliveries from January 1, 2013 to August 1, 2018 at a tertiary hospital in the Massachusetts. IVF pregnancies were compared with non-IVF pregnancies, and PAS diagnosis was confirmed by histopathology reports. Hospital administrative data and medical record review were used, and supplemented with data from birth certificates from the Massachusetts Department of Public Health. Results We identified 28,344 pregnancies that met inclusion criteria, of which 1,418 (5.0%) were IVF pregnancies. The overall incidence of PAS was 0.4% (2.2% in the IVF group and 0.3% in the non-IVF group). Women who underwent IVF had 5.5 times the risk of PAS (95% confidence interval [CI]: 3.4–8.7) compared with women in the non-IVF group, adjusted for maternal age, nulliparity, and year of delivery (Table 5). Compared with women in the non-IVF group, the IVF group had fewer prior cesarean deliveries (22.6 vs. 64.2%) and a lower prevalence of placenta previa (19.4 vs. 44.4%). Conclusion Women with an IVF pregnancy carry an increased risk of PAS compared with non-IVF. Among women who underwent IVF, there was a lower prevalence of prior cesarean deliveries and placenta previa. Future work is needed to identify the mechanism of association for this increased risk as well as a reliable tool for antenatal detection in this cohort of women. Key Points

In the wake of the coronavirus (COVID-19) pandemic, U.S. organizations that provide applied behavior analysis (ABA) programs to individuals with autism spectrum disorder have implemented a variety of safety precautions to minimize the spread of the virus, often shifting center-based services to the home or telehealth. Considered essential workers, ABA providers are exempt from government directives to close, so they have both the freedom and the great responsibility to make their own decisions about how best to keep their clients safe while continuing to provide medically necessary services. In the coming weeks and months, ABA providers will be faced with the decision about whether to reopen centers. This article does not address that decision, except to acknowledge the urgency to reopen, both to help clients and to remain solvent. Political rhetoric and contradictory public information further complicate this daunting decision. Because ABA providers do not have legal guidance to shift the burden of such decisions to local and state regulators, the burden is theirs alone. The unprecedented nature of the COVID-19 pandemic means that no decision is clearly wrong or right, and every decision has consequences. Although ABA providers do not have their own state guidance, many states have issued guidelines for childcare providers whose operations have continued throughout the pandemic. This article analyzes that guidance, identifies common variables potentially relevant to ABA organizations, highlights clinical considerations and procedural compliance, and provides ABA organizations with the tools to make the best decision for their clients, in their community, and on their timeline. Electronic supplementary material The online version of this article (10.1007/s40617-020-00462-7) contains supplementary material, which is available to authorized users.

Management of gastrointestinal stromal tumor (GIST) has been revolutionized by the identification of activating mutations in KIT and PDGFRA, and the clinical application of receptor tyrosine kinase (RTK) inhibitors in the advanced disease setting. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in the majority of GIST, resistance to these agents remains a significant clinical problem. Development of effective treatment strategies for refractory GIST subtypes requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Using Multiplexed Inhibitor Beads and Mass Spectrometry, we explored the majority of the kinome in GIST specimens from the three most common molecular subtypes to identify novel kinase targets. Kinome profiling revealed distinct signatures in GIST subtypes and identified kinases that are universally activated in all GIST, as well as kinases that are unique to each subtype. Kinome profiling in combination with loss-of-function assays identified a significant role for the G2-M tyrosine kinase, Wee1, in GIST cell survival.In vitroandin vivostudies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib inKITandPDGFRA-mutant GIST cell lines, and notable efficacy of MK-1775 as a single agent in thePDGFRA-mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

Over the past 15 years, significant advances have been made in public health education in the United States, creating new opportunities for community colleges, especially in terms of clarif...

The capacity for tumor cells to metastasize efficiently is directly linked to their ability to colonize secondary sites. Here we identify Six2, a developmental transcription factor, as a critical regulator of a breast cancer stem cell program that enables metastatic colonization. In several triple-negative breast cancer (TNBC) models, Six2 enhanced the expression of genes associated with embryonic stem cell programs. Six2 directly bound the Sox2 Srr2 enhancer, promoting Sox2 expression and downstream expression of Nanog, which are both key pluripotency factors. Regulation of Sox2 by Six2 enhanced cancer stem cell properties and increased metastatic colonization. Six2 and Sox2 expression correlated highly in breast cancers including TNBC, where a Six2 expression signature was predictive of metastatic burden and poor clinical outcome. Our findings demonstrate that a SIX2/SOX2 axis is required for efficient metastatic colonization, underscoring a key role for stemness factors in outgrowth at secondary sites. Significance: These findings provide novel mechanistic insight into stemness and the metastatic outgrowth of triple-negative breast cancer cells.

Though many advancements in personalized medicine have been made, better methods are still needed to predict treatment benefit for patients with colorectal cancer. Patient-derived cancer organoids (PDCOs) are a major advance towards true personalization of treatment strategies. A growing body of literature is demonstrating the feasibility of PDCOs as an accurate and high-throughput preclinical tool for patient treatment selection. Many studies demonstrate that these cultures are readily generated and represent the tumors they were derived from phenotypically and based on their mutation profile. This includes maintenance of the driver muatations giving the cancer cells a selective growth advantage, and also heterogeneity, including molecular and metabolic heterogeneity. Additionally, PDCOs are now being utilized to develop patient biospecimen repositories, perform high to moderate-throughput drug screening, and to potentially predict treatment response for individual patients that are undergoing anti-cancer treatments. In order to develop PDCOs as a true clinical tool, further studies are required to determine the reproducibility and accuracy of these models to predict patient response.

Objective: To characterize head movements in children with ADHD using an ex-Gaussian distribution and examine associations with out-of-scanner sustained attention. Method: Fifty-six children with ADHD and 61 controls aged 9 to 11 years completed the Sustained Attention to Response Task (SART) and resting-state functional magnetic resonance imaging (fMRI). In-scanner head motion was calculated using ex-Gaussian estimates for mu, sigma, and tau in delta variation signal and framewise displacement. Sustained attention was evaluated through omission errors and tau in response time on the SART. Results: Mediation analysis revealed that out-of-scanner attention lapses (omissions during the SART) mediated the relationship between ADHD diagnosis and in-scanner head motion (tau in delta variation signal), indirect effect: B = 1.29, 95% confidence interval (CI) = [0.07, 3.15], accounting for 29% of the association. Conclusion: Findings suggest a critical link between trait-level sustained attention and infrequent large head movements during scanning (tau in head motion) and highlight fundamental challenges in measuring the neural basis of sustained attention.

Hormone analysis is a valuable tool for understanding how physiology and behavior interact. Cortisol in hair has recently been examined as a measure of longer-term hormone output. The aim of this study was to investigate the relationships between other androgens in hair and anthropometric measures. In a child sample (n = 114, mean age: 8.5 years, 66 females) levels of cortisol, dehydroepiandrosterone (DHEA) and testosterone were assayed in the 0-3 cm section proximal to scalp. The 3-6 cm segment within a subsample of female participants (n = 35) was examined and compared. Results showed that testosterone strongly correlated with DHEA, and moderately correlated with cortisol (0-3 cm only). Higher hormone concentrations were present in the 3-6 cm segment. Finally, there was a weak positive association between DHEA and height. The replication of previously identified associations between androgens, particularly testosterone-DHEA, and with developmental measures suggests hair may offer a valid method of hormone measurement for DHEA and testosterone.

In this article, we show that social science research on fertility and infertility consists of largely separate research traditions, despite shared interest in pregnancies and births (or lack thereof). We describe four ways these two traditions differ: (1) publication trajectories and outlets, (2) fields of study and major theoretical frameworks, (3) degree of attention to the other topic, and (4) language and definitions used. We then discuss why future integration of these bodies of research would be beneficial, outline potential steps toward rapprochement, and provide common areas of dialogue that could facilitate and enrich these bodies of research. We offer a more holistic framework using the reproductive career as an extension of existing lifecourse approaches in both fertility and infertility research. We conclude with a brief empirical example and discussion of methodological issues for measuring and modeling reproductive careers.

The new reproductive technologies have significantly impacted definitions of motherhood. Historically, mothers were defined through the act of giving birth, but egg donation, embryo donation, and surrogacy disrupt this. Now multiple women can potentially claim maternity through gestational, genetic, legal, and social ties. Although there is some legal precedent for designating parentage, there is no simple solution to identify the 'true' mother. I address maternal claims-making in third party reproduction via a content analysis of US patient literature for infertile women. Major tensions arise over which link to privilege, especially regarding genetic versus gestational ties in egg donation versus surrogacy; however, adding embryo donation to the analysis illuminates another crucial dimension previously overlooked - that heterosexual women's maternal claims are supported by their partner's paternity claims. Ultimately, I argue that although reproductive organisational discourse carefully constructs credible options for maternal claims-making, contemporary reproductive medicine does not define maternity through assisted reproduction as a truly autonomous connection. Rather, maternity is highly contingent and thus potentially discreditable.

Inhibitory control and sustained attention are important cognitive abilities; however, their developmental trajectories remain unclear. In total, 35 6-year-olds, 32 8-year-olds, and 37 10-year-olds performed a Go/No-Go task; this required frequent responding to stimuli with infrequent inhibition to a target that appeared unpredictably. Children performed this task three times over 12months. Response time variability and accuracy measures, linked to inhibition and sustained attention, were assessed. Specifically, fast Fourier transform and ex-Gaussian analyses of response time data provided several measures of response time variability; these measures are thought to represent different components of sustained attention. The 6-year-olds performed less well than the older groups on most measures. The 8-year-olds exhibited greater momentary fluctuations in response time and made more long responses than the 10-year-olds; otherwise, there were few differences between the two older groups. Response inhibition and sustained attention developed significantly between 6 and 8years of age, with subtle changes in attentional control between 8 and 11years of age.

Endometrial carcinoma (EC) is the most common gynecologic malignancy in the United States, with limited effective targeted therapies. Endometrial tumors exhibit frequent alterations in protein kinases, yet only a small fraction of the kinome has been therapeutically explored. To identify kinase therapeutic avenues for EC, we profiled the kinome of endometrial tumors and normal endometrial tissues using Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). Our proteomics analysis identified a network of kinases overexpressed in tumors, including Serine/Arginine-Rich Splicing Factor Kinase 1 (SRPK1). Immunohistochemical (IHC) analysis of endometrial tumors confirmed MIB-MS findings and showed SRPK1 protein levels were highly expressed in endometrioid and uterine serous cancer (USC) histological subtypes. Moreover, querying large-scale genomics studies of EC tumors revealed high expression of SRPK1 correlated with poor survival. Loss-of-function studies targeting SRPK1 in an established USC cell line demonstrated SRPK1 was integral for RNA splicing, as well as cell cycle progression and survival under nutrient deficient conditions. Profiling of USC cells identified a compensatory response to SRPK1 inhibition that involved EGFR and the up-regulation of IGF1R and downstream AKT signaling. Co-targeting SRPK1 and EGFR or IGF1R synergistically enhanced growth inhibition in serous and endometrioid cell lines, representing a promising combination therapy for EC.

Background: There is limited research on mental health literacy and stigmatization attitudes towards mental illness in Tunisia, despite the increasing need for such research to better understand its complexity in a specific country context. Using an exploratory mixed-method approach this study attempted to assess the needs and perceptions about mental health within a population of Tunis-based young adults. Methods: A sample of 80 participants completed an online survey on different aspects of mental health attitudes, mental illness literacy and stigma, with a subset of survey participants participating in one-on-one interviews. Results: Survey results show that 77% of respondents completely agreed or somewhat agreed that they would like to learn more about mental health. This study also found that 68% of the sample reported a lack of accessibility to mental healthcare services resulting in 49% reporting their preference to search their symptoms on the internet instead of informing someone. Throughout the interviews phase, the main factors identified to have a crucial impact on young adults' choice to openly communicate feelings and thoughts with each other and to seek professional help are: culture, gender roles, sexual orientation, and family approval. Conclusion: This study suggests a great desire among young adults to learn more about mental health, and highlights the cultural complexities regarding mental health stigmatization in Tunisia. It also highlights the need for culturally relevant approaches raising awareness about mental health.

There has been substantial interest in US cesarean rates, which increased from 5% of deliveries in the 1970s to nearly one-third of births by the mid-2000s. Explanations typically emphasize individual risk factors (e.g., advanced maternal age, increased BMI, and greater desire for control over delivery) of women giving birth, or address institutional factors, such as the medicalization of childbirth and the culture of liability leading physicians to practice defensive medicine. We focus here on another non-medical explanation – childbirth education (CBE). CBE is an important, underexplored mechanism that can shape women’s expectations about labor and birth and potentially lead them to expect, or desire, a cesarean delivery as a normalized outcome. We analyze data from three waves (2002, 2006, 2013) of the Listening to Mothers national survey on US women’s childbearing experiences (n = 3,985). Using logistic regression analysis, we examined both mode of delivery (vaginal versus cesarean), and attitudes about future request for elective cesarean among both primiparous and multiparous women. Despite previous research suggesting that CBE increased the likelihood of vaginal delivery, we find that CBE attendance was not associated with likelihood of vaginal delivery among either primiparous or multiparous women. However, both primiparous and multiparous women who attended CBE classes were significantly more likely to say they would request a future, elective cesarean. Furthermore, these effects were in the opposite direction of effects for natural birth attitudes. Our findings suggest that contemporary CBE classes may be a form of “anticipatory socialization”, potentially priming women’s acceptance of medicalized childbirth.

The fundamental basis of how arboviruses evolve in nature and what regulates the adaptive process remain unclear. To address this problem, we established a Zika virus (ZIKV) vector-borne transmission system in immunocompromised mice to study the evolutionary characteristics of ZIKV infection. Using this system, we defined factors that influence the evolutionary landscape of ZIKV infection and show that transmission route and specific organ microenvironments impact viral diversity and defective viral genome production. In addition, we identified in mice the emergence of ZIKV mutants previously seen in natural infections, including variants present in currently circulating Asian and American strains, as well as mutations unique to the mouse infections. With these studies, we have established an insect-to-mouse transmission model to study ZIKV evolution in vivo. We also defined how organ microenvironments and infection route impact the ZIKV evolutionary landscape, providing a deeper understanding of the factors that regulate arbovirus evolution and emergence.

ObjectiveHIV-infected women on antiretroviral therapy have a higher risk of preterm birth than HIV-uninfected women in Botswana. To better understand the mechanism for preterm birth among HIV-infected women, we evaluated whether mid-trimester cervical length differed by HIV status as cervical shortening is associated with an increased risk for preterm birth.MethodsWe conducted a prospective cohort study among pregnant women receiving care at the Scottish Livingstone Hospital in Molepolole, Botswana. Consecutive women referred for routine obstetrical ultrasound were consented and enrolled if between 22w0d and 24w6d by ultrasound biometry. Blinded to maternal HIV status, an obstetrician measured transvaginal cervical length using standardized criteria. Cervical length, as well as the proportion of women with a short cervix (ResultsBetween April 2016 and April 2017, 853 women presenting for obstetric ultrasound were screened, 187 (22%) met eligibility criteria, and 179 (96%) were enrolled. Of those enrolled, 50 (28%) were HIV-infected (86% on antiretroviral therapy), 127 (71%) were HIV-uninfected, and 2 (1%) had unknown HIV status. There was no significant difference in mean cervical length between HIV-infected and HIV-uninfected women (32mm vs 31mm, p = 0.21), or in the proportion with a short cervix (10% vs 14%, p = 0.44). Acceptability data was available for 115 women who underwent a transvaginal ultrasound exam. Of these, 112 of 115 (97%) women deemed the transvaginal scan acceptable.ConclusionsThe increased risk of preterm birth observed among HIV-infected women receiving antiretroviral therapy in Botswana is unlikely associated with mid-trimester cervical shortening. Further research is needed to understand the underlying mechanism for preterm birth among HIV-infected women.

Individuals with Attention Deficit Hyperactivity Disorder (ADHD) tend to perform cognitive tasks with greater Response Time Variability (RTV). Greater RTV in ADHD may be due to inefficient functional connectivity of the brain during information processing. This study aimed to investigate the relationship between brain connectivity, RTV, and levels of ADHD symptoms. Twenty-eight children aged 9–12 years and 49 adolescents aged 15–18 years performed the Sustained Attention to Response Task (SART) while EEG was recorded. The participants’ levels of ADHD symptoms were measured using self- and parent-rated questionnaires. The ex-Gaussian analysis and The Fast Fourier Transform were used to measure multiple aspects of RTV. Functional connectivity between 64 electrodes was computed during task performance, and global efficiency and modularity were calculated, reflecting integration and segregation of the brain, respectively. There was a positive association between multiple RTV measures and the level of ADHD symptoms, where participants with higher levels of ADHD symptoms showed greater RTV, except for sigma from the ex-Gaussian analysis. More efficient brain network activity, measured by global efficiency, was associated with reduced RTV. Children showed greater RTV and less efficient brain network activity compared with the adolescents. These findings support the view that stable responses are achieved with more integrated (and efficient) brain connectivity.