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Abstract: Epilepsy affects more than 40 million people worldwide, constituting one of the most debilitating disorders of the Central Nervous System (CNS). It results from an imbalance in the electrical activity of neurons, which is primarily mediated by calcium ions. In many cases, treatment with Antiepileptic Drugs (AEDs) that regulate calcium channel activity results in successful seizure control. However, AEDs frequently cause adverse effects that range in severity from minimal impairment of the CNS to death from aplastic anemia or hepatic failure. Moreover, 30% of epileptic patients show drug-resistant epilepsy and do not respond to any form of medical treatment. In this context, nanotechnology has emerged as an excellent tool to overcome AEDs limitations. Numerous nano-strategies have been proposed as therapeutics and diagnostics for epilepsy through inhibition of different calcium channel types in the brain. In addition, limited brain access of classical AEDs in patients showing refractory epilepsy could be improved through the design of targeted drug delivery nanosystems. This report presents a review of the nanocarriers developed so far that could facilitate the interaction with calcium channels in the brain and the transport of AEDs through the blood-brain-barrier, mapping out a potential future direction in the research of epilepsy treatment.

Objective To estimate the prevalence of perinatal cannabis use (ie, before and/or during pregnancy); document the frequency, modes, and motivations for use; and identify predictors of perinatal cannabis use. Methods Six states in the Pregnancy Risk Assessment Monitoring System, a state-specific, population-based surveillance system, administered a supplemental questionnaire on perinatal cannabis use in 2016-2018. Women with live births were surveyed 2-6 months postpartum about behaviors ≤3 months preconception and during pregnancy. Demographic, psychosocial, and behavioral characteristics were examined in relation to perinatal cannabis use using multinomial regression models. Those who: (1) never used cannabis, (2) only used in preconception period, and (3) used in both preconception and prenatal periods were compared. Results Among 6428 respondents, 379 (5.8%) used cannabis preconceptionally only and 466 (4.4%) used in both the preconception and prenatal periods. Among those using prenatally, most reported smoking as their single mode (87.1%), with the two most common reasons being stress (83.8%) and nausea/vomiting (79.2%). Marital status, race/ethnicity, socioeconomic status, parity, and cigarette and alcohol use were significantly associated with perinatal cannabis use. Single (vs partnered) women were more likely to use cannabis prenatally (odds ratio = 2.4, 95% confidence interval: 1.5, 3.9) and non-Hispanic Black (vs White) women were less likely to use prenatally (odds ratio = 0.4, 95% confidence interval: 0.2, 0.8). Conclusions Using a population-based sample of US births in six states, several demographic, psychosocial, and behavioral characteristics were identified in relation to perinatal cannabis use. These data are valuable for counseling in prenatal care and investigations of health effects.

Psoriatic arthritis is a chronic systemic inflammatory disease that affects the skin, musculoskeletal structures and other organs and systems compromising functionality, quality of life and reducing the life expectancy of patients. It is a complex disease that requires specialist and timely care and management. The alternatives for treating the manifestations of psoriatic arthritis have increased and the effect of the different agents on specific manifestations has been clarified in recent studies. Therefore, we should incorporate the available evidence to build a strategy for the treatment of these patients. The Mexican College of Rheumatology selected a committee to evaluate these different alternatives and make recommendations. Methods The study group included 16 rheumatologists and 3 certified dermatologists, selected from different health institutions and regions of the country. An executive committee was formed to coordinate the meetings and a committee of experts selected the literature search criteria, prepared the research questions, rated the quality of the evidence, and produced the recommendations in the different disease domains based on the GRADE methodology. Results 24 updated recommendations were generated for the treatment of patients with psoriatic arthritis. The recommendations establish the role of the drugs currently available in our country. The importance of adequate disease control is emphasized, individualizing the level of involvement of each patient in each of the six domains potentially affected by the disease. In addition, the sequence in the choice of treatments available for each domain is established, based on their efficacy, safety profile and accessibility. Conclusions With this consensus document, it will be possible to improve the care of patients with psoriatic arthritis. The recommendations were generated based on the best available information and in consideration of the Mexican health system.

Background A question frequently raised in the field is whether evidence-based interventions have adequate translational capacity for delivery in real-world settings where patients are presumed to be more complex, clinicians less specialized, and multidisciplinary teams less coordinated. The dual purpose of this article is to (a) outline a model for implementing evidence-driven, outpatient treatments for eating disorders in a non-academic clinical setting, and (b) report indicators of feasibility and quality of care. Main Body Since our inception (2015), we have completed nearly 1000 phone intakes, with first-quarter 2021 data suggesting an increase in the context of COVID-19. Our caseload for the practice currently consists of approximately 200 active patients ranging from 6 to 66 years of age. While the center serves a transdiagnostic and trans-developmental eating disorder population, modal concerns for which we receive inquiries are Anorexia Nervosa and Avoidant Restrictive Food Intake Disorder, with the most common age range for prospective patients spanning childhood through late adolescence/emerging adulthood; correspondingly, the modal intervention employed is Family-based treatment. Our team for each case consists, at a minimum, of a primary internal therapist and a physician external to the center. Short Conclusion We will describe our processes of recruiting, training and coordinating team members, of ensuring ongoing fidelity to evidence-based interventions, and of training the next generation of clinicians. Future research will focus on a formal assessment of patient outcomes, with comparison to benchmark outcomes from randomized controlled trials., Plain English summary A question frequently raised in the eating disorders field is whether treatments that were developed and tested in research environments can achieve the same results in real-world clinical settings, where patients’ diagnoses are presumed to be more complex, clinicians less specialized, and multi-professional care teams less coordinated. The purpose of this article is to outline a model for implementing evidence-driven, outpatient treatments for eating disorders in non-academic clinical settings, specifically private practices and specialty programs. We describe the philosophy, infrastructure, training processes, personnel, and procedures utilized to optimize care delivery and to create accountability for both scientifically-adherent practice and positive patient outcomes. We also outline ways to be producers—not just consumers—of research in the private sector, and to train the next generation of scientifically-informed eating disorder specialists, all with the goal to bridge the research-practice divide.

Objective To explore the use of electronic health record (EHR) data to estimate surgery resident duty hours and monitor real time workload. Design Retrospective analysis of resident duty hours logged using a voluntary global positioning system (GPS)-based smartphone application compared to duty hour estimates by an EHR-based algorithm. The algorithm estimated duty hours using EHR activity data and operating room logs. A dashboard was developed through Plan-Do-Study-Act cycles for real-time monitoring of workload. Setting Single tertiary/quaternary medical center general surgery residency program with approximately 90 categorical, preliminary, and integrated residents at eight clinical sites. Participants Categorical, preliminary, and integrated surgery residents of all clinical years who volunteered to pilot a GPS application to track duty hours. Results Of 2,623 work periods by 59 residents were logged with both methods. EHR-estimated work periods started later than GPS logs (median 0.3 hours, interquartile range [IQR] -0.1 - 0.3); EHR-estimated work periods ended earlier than GPS logs (median 0.1 hours, IQR -0.7 - 0.3); and EHR-estimated duty hour totals were less than totals logged by GPS (median -0.3 hours, IQR -0.8 - +0.1). Overall correlation between weekly duty hours logged by EHR and GPS was 0.79. Correlations between the 2 systems stratified from PGY-1 through PGY-5 were 0.76, 0.64, 0.82, 0.87, and 0.83, respectively. The algorithm identified six 80-hour workweek violations (averaged over 4 weeks), while GPS logs identified 8. EHR-based duty hours and operational data were integrated into a dashboard to enable real time monitoring of resident workloads. Conclusions EHR-based estimation of surgical resident duty hours has good correlation with GPS-based assessment of duty hours and identifies most workweek duty hour violations. This approach allows for dynamic workload monitoring and may be combined with operational data to anticipate and prevent duty hour violations, thereby optimizing learning.

Pleuropulmonary blastoma (PPB) is a rare intrathoracic malignancy, which arises from the lung parenchyma and/or pleura. PPB has strong genetic association with mutations in DICER1 gene. Despite being rare, PPB is the most common lung tumor in children below 6 years of age. International registry of the disease has a total of 350 cases worldwide. We report the first case of PPB in the state of Qatar, which presented as a large cystic lung lesion. The patient was first thought to have benign congenital pulmonary airway malformation (CPAM) based on chest X-ray findings. The diagnosis of PPB was suspected based on chest CT scan findings and was confirmed after surgical resection of the cystic mass. The case highlights the need to consider PPB in the differential diagnosis of cystic lung lesions in children and the need for further radiological imaging (i.e., CT scan), genetic testing, and/or excisional biopsy to confirm the diagnosis.

Background/Objective SARS-CoV-2 continues to spread widely in the US and worldwide. Pregnant women are more likely to develop severe or critical illness than their non-pregnant counterparts. Known risk factors for severe and critical disease outside of pregnancy, such as asthma, diabetes, and obesity have not been well-studied in pregnancy. We aimed to determine which clinical and pregnancy-related factors were associated with severe and critical COVID illness in pregnancy. Study design This was a retrospective cohort study of women with confirmed intrauterine pregnancy and positive nasopharyngeal swab for SARS-CoV-2 who presented to an academic medical center in New York City from 1 March 2020 to 1 July 2020. Severe and critical COVID-19 disease was defined by World Health Organization criteria. Women with severe/critical disease were compared to women with asymptomatic/mild disease. Continuous variables were compared with Mann–Whitney or t-test and categorical variables were compared using chi-square and Fisher’s exact. Statistical significance was set at p

Background: Spontaneous muscle hematomas (SMH) are rare but potentially life-threatening. We report three patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who developed hemorrhagic shock, due to large SMHs, during their intensive care unit stay. Case Presentation: All the patients were receiving mechanical ventilation and anticoagulation therapy with enoxaparin. The bleeding was located in the gluteal muscles in two of the patients and in the iliopsoas muscle with retroperitoneal extension in the other. Anemia and hemodynamic instability were the main signs; however, because of their gradual onset, they were initially confused with the anemia of the critically ill patient and sepsis related to secondary infections. All received conservative medical treatment, but unfortunately one patient died within hours of diagnosis. Conclusion: This report highlights that clinicians should also be alert to major spontaneous hemorrhage in patients with SARSCoV- 2 infection. Since it is a novel disease, a possible association with bleeding events cannot be disregarded and, on the contrary, should be considered, particularly to determine the appropriate use of anticoagulation in this type of patients.

Background & Aims Liver fibrosis is a multifactorial trait that develops in response to chronic liver injury. Our aim was to characterize the genetic architecture of carbon tetrachloride (CCl4)-induced liver fibrosis using the Hybrid Mouse Diversity Panel, a panel of more than 100 genetically distinct mouse strains optimized for genome-wide association studies and systems genetics. Methods Chronic liver injury was induced by CCl4 injections twice weekly for 6 weeks. Four hundred thirty-seven mice received CCl4 and 256 received vehicle, after which animals were euthanized for liver histology and gene expression. Using automated digital image analysis, we quantified fibrosis as the collagen proportionate area of the whole section, excluding normal collagen. Results We discovered broad variation in fibrosis among the Hybrid Mouse Diversity Panel strains, demonstrating a significant genetic influence. Genome-wide association analyses revealed significant and suggestive loci underlying susceptibility to fibrosis, some of which overlapped with loci identified in mouse crosses and human population studies. Liver global gene expression was assessed by RNA sequencing across the strains, and candidate genes were identified using differential expression and expression quantitative trait locus analyses. Gene set enrichment analyses identified the underlying pathways, of which stellate cell involvement was prominent, and coexpression network modeling identified modules associated with fibrosis. Conclusions Our results provide a rich resource for the design of experiments to understand mechanisms underlying fibrosis and for rational strain selection when testing antifibrotic drugs., Graphical abstract

Fragile X mental retardation 1 (FMR1) encodes the RNA binding protein FMRP. Loss of FMRP drives Fragile X syndrome (FXS), the leading inherited cause of intellectual disability and a leading monogenic cause of autism. While cortical hyperexcitability is a hallmark of FXS, the reported phenotypes and underlying mechanisms, including alterations in synaptic transmission and ion channel properties, are heterogeneous and at times contradictory. Here, we report the generation of new isogenic FMR1y/+ and FMR1y/- human pluripotent stem cell (hPSC) lines using CRISPR-Cas9 to facilitate the study of how complete FMRP loss, independent of genetic background, drives molecular and cellular alterations relevant for FXS. After differentiating these stem cell tools into excitatory neurons, we systematically assessed the impact of FMRP loss on intrinsic membrane and synaptic properties over time. Using whole-cell patch clamp analyses, we found that FMR1y/- neurons overall showed an increased intrinsic membrane excitability compared to age-matched FMR1y/+ controls, with no discernable alternations in synaptic transmission. Surprisingly, longitudinal analyses of cell intrinsic defects revealed that a majority of significant changes emerged early following in vitro differentiation and some were not stable over time. Collectively, this study provides a new isogenic hPSC model which can be further leveraged by the scientific community to investigate basic mechanisms of FMR1 gene function relevant for FXS. Moreover, our results suggest that precocious changes in the intrinsic membrane properties during early developmental could be a critical cellular pathology ultimately contributing to cortical hyperexcitability in FXS.

The aim of this study was to determine the prevalence of Motoric Cognitive Risk (MCR) syndrome, describe associated risk factors and to determine the risk of progression to cognitive impairment after three years of follow-up, in a sample of Mexican older adults. A prospective panel study of health and aging in Mexico. Baseline and follow-up information was obtained from the Mexican Health and Aging Study’s 2012 and 2015 waves. A total of 726 subjects aged 60 years or older with normal cognition at baseline were classified into 4 groups: 1) with MCR, 2) with memory complaint only, 3) with slow gait speed only and, 4) without MCR. Cox regression analysis controlling for confounder factors was performed to determine the risk of progression to cognitive impairment in the MCR group. Data such as gait speed, functional status and cognitive performance (standardized by age and sex in Mexican population) was collected. MCR prevalence was 14.3%. When compared with non-MCR subjects, the presence of MCR was associated with older age (p

Background Recent studies have shown that fluoroquinolones, specifically, enrofloxacin and its active metabolite (ciprofloxacin), cross the equine placenta without causing gross or histological lesions in the first and third trimester fetuses or resulting foal. However, it is possible that in utero exposure to fluoroquinolones may cause subtle lesions not detectable by standard means; thus, a more in-depth assessment of potential toxicity is warranted. Objectives To use quantitative magnetic resonance imaging (qMRI), biomechanical testing, and chondrocyte gene expression to evaluate the limbs of foals exposed to enrofloxacin during the third trimester of pregnancy. Study design In vivo and control terminal experiment. Methods Healthy mares at 280 days gestation were assigned into three groups: untreated (n = 5), recommended therapeutic (7.5 mg/kg enrofloxacin, PO, SID, n = 6) or supratherapeutic (15 mg/kg, PO, SID, n = 6) doses for 14 days. Mares carried and delivered to term and nursed their foals for ~30 days. Two additional healthy foals born from untreated mares were treated post-natally with enrofloxacin (10 mg/kg PO, SID, for 5 days). By 30 days, foal stifles, hocks, elbows, and shoulders were radiographed, foals were subjected to euthanasia, and foal limbs were analysed by quantitative MRI, structural MRI, biomechanical testing and chondrocyte gene expression. Results Osteochondral lesions were detected with both radiography and structural MRI in foals from both enrofloxacin-treated and untreated mares. Severe cartilage erosions, synovitis and joint capsular thickening were identified in foals treated with enrofloxacin post-natally. Median cartilage T2 relaxation times differed between joints but did not differ between treatment groups. Main limitations A small sample size was assessed and there was no long-term follow-up. Conclusion While further research is needed to address long-term foal outcomes, no differences were seen in advanced imaging, biomechanical testing or gene expression by 30 days of age, suggesting that enrofloxacin may be a safe and useful antibiotic for select bacterial infections in pregnant mares.

Appendicitis in pregnancy is the most common nonobstetric surgical emergency. Pregnancy causes changes in anatomy, which could lead to uncertainty regarding the diagnosis of appendicitis. This case report describes a case of appendicitis presenting with peritoneovaginal fistula in a pregnant woman in the second trimester, with interesting finding of isolated appendiceal endometriosis on pathology. The importance of complete physical examination, including speculum examination, is emphasized in the pregnant patient presenting with acute-onset abdominal pain. Imaging criteria for diagnosis of appendicitis should be adjusted to account for the gravid uterus, which may cause appendiceal abscess to appear in a variety of locations, such as posterior to the cervix, as in this case.

Background. Preeclampsia is a major cause of pregnancy-related maternal, fetal, and neonatal morbidities and mortalities. We aimed to review the effect of maternal preeclampsia on the hematological profile of newborns in the Qatari population. Methods. In this case-control study, we reviewed data and complete blood count results of neonates born to Qatari women diagnosed of preeclampsia in 2017 in comparison with data of a control group. Statistical analysis was done using unpaired t-test, chi-square test, and logistic regression analysis. Results. A total of 108 neonates of women with preeclampsia and 103 neonates of healthy normotensive women were recruited. The mean weight, length, head circumference, placental weight, and gestational age were significantly lower (P<0.05) in neonates born to women with preeclampsia. Only 13% of babies born to women with preeclampsia developed neonatal thrombocytopenia which is significantly higher compared to only 2% in the control group (chi-square χ2=9.14; P=0.003). No significant difference (P>0.05) was noted between the two groups regarding the white blood cells (WBC) or the absolute neutrophilic count (ANC). Multivariate logistic regression showed that the gestational age, birth weight, length, and ANC had significant association with preeclampsia (P<0.05). Conclusions. We found that there was a positive association between preeclampsia and neonatal thrombocytopenia in the Qatari population. Prematurity, placenta insufficiency, fetal growth restriction, and need for neonatal resuscitation were significantly higher in babies born to women with preeclampsia. We recommend that hematological parameters of neonates of those women should be properly monitored to reduce the chances of developing complications.

Introduction Vascular dementia is the second most common cause of dementia. Physical disability and cognitive impairment due to stroke are conditions that considerably affect quality of life. We estimated the prevalence and incidence of possible vascular dementia (PVD) in older adults using data from the Mexican Health and Aging Study (MHAS 2012 and 2015 waves). Methods The MHAS is a representative longitudinal cohort study of Mexican adults aged ≥50 years. Data from 14, 893 participants from the 2012 cohort and 14,154 from the 2015 cohort were analyzed to estimate the prevalence and incidence of PVD. Self-respondents with history of stroke were classified as PVD if scores in two or more cognitive domains in the Cross-Cultural Cognitive Examination were ≥ 1.5 standard deviations below the mean on reference norms and if limitations in ≥ 1 instrumental activities of daily living were present. For proxy respondents with history of stroke, we used a score ≥3.4 on the Informant Questionnaire on Cognitive Decline in the Elderly. Crude and standardized rates of prevalent and incident PVD were estimated. Results Prevalence of PVD was 0.6% (95% CI, 0.5–0.8) (0.5 with age and sex- standardization). Rates increased with age reaching 2.0% among those aged 80 and older and decreased with educational attainment. After 3.0 years of follow-up, 87 new cases of PVD represented an overall incident rate of 2.2 (95% CI, 1.7–2.6) per 1,000 person-years (2.0 with age and sex- standardization). Incidence also increased with advancing age reaching an overall rate of 9.4 (95% CI, 6.3–13.6) per 1,000 person-years for participants aged >80 years. Hypertension and depressive symptoms were strong predictors of incident PVD. Conclusion These data provide new estimates of PVD prevalence and incidence in the Mexican population. We found that PVD incidence increased with age. Males aged 80 years or older showed a greater incidence rate when compared to females, which is comparable to previous estimates from other studies.

Background Malignant gliomas are the most frequent primary brain tumors and remain among the most incurable cancers. Although the role of the gap junction protein, connexin43 (Cx43), has been deeply investigated in malignant gliomas, no compounds have been reported with the ability to recapitulate the tumor suppressor properties of this protein in in vivo glioma models. Methods TAT-Cx43266–283 a cell-penetrating peptide which mimics the effect of Cx43 on c-Src inhibition, was studied in orthotopic immunocompetent and immunosuppressed models of glioma. The effects of this peptide in brain cells were also analyzed. Results While glioma stem cell malignant features were strongly affected by TAT-Cx43266–283, these properties were not significantly modified in neurons and astrocytes. Intraperitoneally administered TAT-Cx43266–283 decreased the invasion of intracranial tumors generated by GL261 mouse glioma cells in immunocompetent mice. When human glioma stem cells were intracranially injected with TAT-Cx43266–283 into immunodeficient mice, there was reduced expression of the stemness markers nestin and Sox2 in human glioma cells at 7 days post-implantation. Consistent with the role of Sox2 as a transcription factor required for tumorigenicity, TAT-Cx43266–283 reduced the number and stemness of human glioma cells at 30 days post-implantation. Furthermore, TAT-Cx43266–283 enhanced the survival of immunocompetent mice bearing gliomas derived from murine glioma stem cells. Conclusion TAT-Cx43266–283 reduces the growth, invasion, and progression of malignant gliomas and enhances the survival of glioma-bearing mice without exerting toxicity in endogenous brain cells, which suggests that this peptide could be considered as a new clinical therapy for high-grade gliomas.

Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive but provide the most effective improvements in obesity and Type 2 diabetes. We hypothesized a potential role for the gut hormone Fibroblast-Growth Factor 15/19 which is increased after VSG and pharmacologically can improve energy homeostasis and glucose handling. We generated intestinal-specific FGF15 knockout (FGF15INT-KO) mice which were maintained on high-fat diet. FGF15INT-KO mice lost more weight after VSG as a result of increased lean tissue loss. FGF15INT-KO mice also lost more bone density and bone marrow adipose tissue after VSG. The effect of VSG to improve glucose tolerance was also absent in FGF15INT-KO. VSG resulted in increased plasma bile acid levels but were considerably higher in VSG-FGF15INT-KO mice. These data point to an important role after VSG for intestinal FGF15 to protect the organism from deleterious effects of VSG potentially by limiting the increase in circulating bile acids., The mechanisms that mediate the effects of weight loss surgeries such as vertical sleeve gastrectomy (VSG) are incompletely understood. Here the authors show that intestinal FGF15 is necessary to improve glucose tolerance and to prevent the loss of muscle and bone mass after VSG, potentially via protection against bile acid toxicity.

Autophagy is a physiological process by which various damaged or non-essential cytosolic components are recycled, contributing to cell survival under stress conditions. In cancer, autophagy can have antitumor or protumor effects depending on the developmental stage. Here, we use Western blotting, immunochemistry, and transmission electron microscopy to demonstrate that the antitumor peptide TAT-Cx43266-283, a c-Src inhibitor, blocks autophagic flux in glioblastoma stem cells (GSCs) under basal and nutrient-deprived conditions. Upon nutrient deprivation, GSCs acquired a dormant-like phenotype that was disrupted by inhibition of autophagy with TAT-Cx43266-283 or chloroquine (a classic autophagy inhibitor), leading to GSC death. Remarkably, dasatinib, a clinically available c-Src inhibitor, could not replicate TAT-Cx43266-283 effect on dormant GSCs, revealing for the first time the possible involvement of pathways other than c-Src in TAT-Cx43266-283 effect. TAT-Cx43266-283 exerts an antitumor effect both in nutrient-complete and nutrient-deprived environments, which constitutes an advantage over chloroquine and dasatinib, whose effects depend on nutrient environment. Finally, our analysis of the levels of autophagy-related proteins in healthy and glioma donors suggests that autophagy is upregulated in glioblastoma, further supporting the interest in inhibiting this process in the most aggressive brain tumor and the potential use of TAT-Cx43266-283 as a therapy for this type of cancer.

Millions of patients suffer yearly from bone fractures and disorders such as osteoporosis or cancer, which constitute the most common causes of severe long-term pain and physical disabilities. The intrinsic capacity of bone to repair the damaged bone allows normal healing of most small bone injuries. However, larger bone defects or more complex diseases require additional stimulation to fully heal. In this context, the traditional routes to address bone disorders present several associated drawbacks concerning their efficacy and cost-effectiveness. Thus, alternative therapies become necessary to overcome these limitations. In recent decades, bone tissue engineering has emerged as a promising interdisciplinary strategy to mimic environments specifically designed to facilitate bone tissue regeneration. Approaches developed to date aim at three essential factors: osteoconductive scaffolds, osteoinduction through growth factors, and cells with osteogenic capability. This review addresses the biological basis of bone and its remodeling process, providing an overview of the bone tissue engineering strategies developed to date and describing the mechanisms that underlie cell–biomaterial interactions.

INTRODUCTION AND OBJECTIVES: The prevalence of mixed dementia (MixD), defined as the coexistence of Alzheimer's disease (AD) and vascular dementia (VaD), is likely to increase as the population ages. The five-word test (5WT) is a neuropsychological test that differentiates between major and mild neurocognitive disorder (NCD). The objective of the study is to validate 5WT for the detection of MixD. METHODS: 230 participants were evaluated: cognitively healthy (CH) (n=70), mild NCD (n=70), and major NCD (n=90): AD (n=30), VaD (n=30), and MixD (n=30). The Spearman's coefficient, d Sommer and ROC curves were used to determine the construct validity of the 5WT. The linear regression model was performed to determine the association between age and education with 5WT performance. RESULTS: The mean age was 79 ±7.7 years (P≤.001), 58% were female (P=.252), and the mean education was 9 ±5.3 years (P≤.001). Construct validity when comparing 5WT and MMSE was: Spearman's correlation ρ=.830 (P

Background Cognitive impairment is twice more frequent in elderly with type 2 diabetes mellitus (DM). This study was conducted to determine the association between glycemic control and cognitive performance among community-dwelling elderly persons in Mexico. Methods Cross-sectional study conducted in individuals aged 60 years or elderly participating in the 2012 Mexican Health and Aging Study. Type 2 DM participants were classified in 3 groups according to their glycated hemoglobin levels (HbA1c): Results Two hundred sixteen community-dwelling adults aged 60 and older with type 2 diabetes were selected. Subjects in the low cognitive performance group were older (69.7 ± 6.6 vs 65.86 ± 5.18 years, p p A1c ≥ 8% was associated with having low (Odds Ratio (OR) 3.17, 95% CI 1.17–8.60, p = .024), and intermediate (OR 3.23, 95% CI 1.27–8.20, p = .014) cognitive performance; this trend was not found for HbA1c 7.0–7.9% group. The multinomial regression analysis showed that the presence of HbA1c ≥ 8% (poor glycemic control) was associated with low (OR 3.17, 95% CI = 1.17–8.60, p = .024), and intermediate (OR 3.23, 95% CI = 1.27–8.20, p = .014) cognitive performance. After adjusting for confounding variables. Conclusions Glycemic control with a HbA1c ≥ 8% was associated with worse cognitive performance.

JAK2–STAT3 and TrkA signaling pathways have been separately implicated in aggressive breast cancers, however, whether they are co-activated or undergo functional interaction has not been thoroughly investigated. Herein we report, for the first time that STAT3 and TrkA are significantly co-overexpressed and co-activated in triple-negative breast cancer (TNBC) and HER2-enriched breast cancer, as shown by immunohistochemical staining and data mining. Through immunofluorescence staining–confocal microscopy and immunoprecipitation–Western blotting, we found that TrkA and STAT3 co-localize and physically interact in the cytoplasm, and the interaction is dependent on STAT3-Y705 phosphorylation. TrkA–STAT3 interaction leads to STAT3 phosphorylation at Y705 by TrkA in breast cancer cells and cell-free kinase assays, indicating that STAT3 is a novel substrate of TrkA. β-NGF-mediated TrkA activation induces TrkA–STAT3 interaction, STAT3 nuclear transport and transcriptional activity, and the expression of STAT3 target genes, SOX2 and MYC. The co-activation of both pathways promotes breast cancer stem cells. Finally, we found that TNBC and HER2-enriched breast cancer with JAK2–STAT3 and TrkA co-activation are positively associated with poor overall metastasis-free and organ-specific metastasis-free survival. Collectively, our study uncovered that TrkA is a novel activating kinase of STAT3, and their co-activation enhances gene transcription and promotes breast cancer stem cells in TNBC and HER2-enriched breast cancer.

Maternal diet, prior to and during pregnancy, plays an important role in the immediate and long-term health of the mother and her offspring. Our objectives were to assess diet quality among a large, diverse, urban cohort of pregnant women, and examine associations with sociodemographic and health behavior characteristics. Data were from 1,325 pregnant women enrolled in New York University Children's Health and Environment Study (NYU CHES). Diet quality was assessed using the Healthy Eating Index (HEI)-2015. Mean total HEI-2015 score was 74.9 (SD = 8.5); 376 (28%), 612 (46%), 263 (20%), and 74 (6%) of women had scores that fell into the grade range of A/B, C, D, and F, respectively. Mean HEI-2015 component scores were high for fruit and whole grains and low for protein-related, sodium, and fat-related components. In multivariable linear regression models, Hispanic women scored 1.65 points higher on the total HEI-2015 (95% CI: 0.21, 3.10) compared to non-Hispanic White women, while younger age (

Heřmanský-Pudlak syndrome (HPS), a rare autosomal recessive disorder, manifests with oculocutaneous albinism and a bleeding diathesis. However, severity of disease can be variable and is typically related to the genetic subtype of HPS; HPS type 6 (HPS-6) is an uncommon subtype generally associated with mild disease. A Caucasian adult female presented with a history of severe bleeding; ophthalmologic examination indicated occult oculocutaneous albinism. The patient was diagnosed with a platelet storage pool disorder, and platelet whole mount electron microscopy demonstrated absent delta granules. Genome-wide SNP analysis showed regions of homozygosity that included the HPS1 and HPS6 genes. Full length HPS1 transcript was amplified by PCR of genomic DNA. Targeted next-generation sequencing identified a novel homozygous missense variant in HPS6 (c.383 T > C; p.V128A); this was associated with significantly reduced HPS6 mRNA and protein expression in the patient's fibroblasts compared to control cells. These findings highlight the variable severity of disease manifestations in patients with HPS, and illustrate that HPS can be diagnosed in patients with excessive bleeding and occult oculocutaneous albinism. Genetic analysis and platelet electron microscopy are useful diagnostic tests in evaluating patients with suspected HPS. Clinical Trial registration: Registrar: ClinicalTrials.gov Website: www.clinicaltrials.gov Registration Numbers: NCT00001456 and NCT00084305.

Zika has been associated with a variety of severe neurologic manifestations including meningitis and encephalitis. We hypothesized that it may also cause mild to subclinical neurocognitive alterations during acute infection or over the long term. In this observational cohort study, we explored whether Zika cause subclinical or mild neurocognitive alterations, estimate its frequency and duration, and compare it to other acute illnesses in a cohort of people with suspected Zika infection, in the region of Tapachula in Chiapas, Mexico during 2016–2018. We enrolled patients who were at least 12 years old with suspected Zika virus infection and followed them up for 6 months. During each visit participants underwent a complete clinical exam, including a screening test for neurocognitive dysfunction (Montreal Cognitive Assessment score). We enrolled 406 patients [37 with Zika, 73 with dengue and 296 with other acute illnesses of unidentified origin (AIUO)]. We observed a mild and transient impact over cognitive functions in patients with Zika, dengue and with other AIUO. The probability of having an abnormal MoCA score (p = 0.014: Zika vs. AIUO 0.264, 95% CI 0.059, 0.469; p = 0.012). The low memory performance in patients with Zika and AIUO accounts for most of the differences in the overall MoCA score when compared with patients with dengue. Our results show a decrease in cognitive function during acute illness and provides no evidence to support the hypothesis that Zika might cause neurocognitive alterations longer than the period of acute infection or different to other infectious diseases. While effects on memory or perhaps other cognitive functions over the long term are possible, larger studies using more refined tools for neurocognitive functioning assessment are needed to identify these.Trial Registration: NCT02831699.

Schistosomiasis is a parasitic disease that affects more than 250 million people. The treatment is limited to praziquantel and the control of the intermediate host with the highly toxic molluscicidal niclosamide. Marine algae are a poorly explored and promising alternative that can provide lead compounds, and the use of multivariate analysis could contribute to quicker discovery. As part of our search for new natural compounds with which to control schistosomiasis, we screened 45 crude extracts obtained from 37 Brazilian seaweed species for their molluscicidal activity against Biomphalaria glabrata embryos and schistosomicidal activities against Schistosoma mansoni. Two sets of extracts were taxonomically grouped for metabolomic analysis. The extracts were analyzed by GC–MS, and the data were subjected to Pattern Hunter and Pearson correlation tests. Overall, 22 species (60%) showed activity in at least one of the two models. Multivariate analysis pointed towards 3 hits against B. glabrata veliger embryos in the Laurencia/Laurenciella set, 5 hits against B. glabrata blastula embryos, and 31 against S. mansoni in the Ochrophyta set. Preliminary annotations suggested some compounds such as triquinane alcohols, prenylated guaianes, dichotomanes, and xenianes. Despite the putative identification, this work presents potential candidates and can guide future isolation and identification.

Mild cognitive impairment (MCI) (amnestic or non-amnestic) has different clinical and neuropsychological characteristics, and its evolution is heterogeneous. Cardiovascular risk factors (CVRF), such as hypertension, diabetes, or dyslipidemia, and the presence of the Apolipoprotein E &epsilon, 4 (ApoE &epsilon, 4) polymorphism have been associated with an increased risk of developing Alzheimer&rsquo, s disease (AD) and other dementias but the relationship is inconsistent worldwide. We aimed to establish the association between the ApoE &epsilon, 4 carrier status and CVRF on MCI subtypes (amnestic and non-amnestic) in Mexican older adults. Cross-sectional study including 137 older adults (n = 63 with normal cognition (NC), n = 24 with amnesic, and n = 50 with non-amnesic MCI). Multinomial logistic regression models were performed in order to determine the association between ApoE &epsilon, 4 polymorphism carrier and CVRF on amnestic and non-amnestic-MCI. ApoE &epsilon, 4 carrier status was present in 28.8% participants. The models showed that ApoE &epsilon, 4 carrier status was not associated neither aMCI nor naMCI condition. The interaction term ApoE &epsilon, 4 &times, CVRF was not statistically significant for both types of MCI. However, CVRF were associated with both types of MCI and the association remained statistically significant after adjustment by sex, age, and education level. The carrier status of the ApoE genotype does not contribute to this risk.

espanolAntecedentes: se ha propuesto que la vitamina D ayuda a reducir la acumulacion de β-amiloide-42 cerebral mediante la estimulacion inmune innata y la activacion de la fagocitosis. Se ha establecido una asociacion entre los niveles bajos de vitamina D y la demencia de Alzheimer (EA). Determinamos la asociacion entre vitamina D, deterioro cognitivo leve (DCL) y EA en adultos mayores mexicanos (> 65 anos) Metodos: estudio transversal realizado en la clinica de memoria de un hospital de nivel terciario de la Ciudad de Mexico. Evaluamos sujetos con DCL, EA y cognicion normal (NC) con niveles sericos de vitamina D [25 (OH) D] disponibles (ultimos 6 meses). Se asignaron tres categorias de acuerdo con los niveles de 25 (OH) D: suficiencia (> 30 ng / ml), insuficiencia (21-29 ng / ml) y deficiencia (≤ 20 ng / ml). Se utilizo estadistica descriptiva, medias y desviaciones estandar. Se realizaron analisis de regresion logistica ajustados por edad, sexo y nivel educativo Resultados: Evaluamos a 208 pacientes. La edad media fue 79 ± 1 ano, el 65% (n = 136) eran mujeres; y el nivel educativo medio fue de 6,7 ± 2,3 anos. Treinta y un sujetos (14%) tenian NC; 42% (n = 88) tenia DCL; y el 43% (n = 89) tenia EA. La prevalencia de la deficiencia de vitamina D fue del 54%, mas frecuente en el grupo de EA (64%) seguido por los grupos de DCL (59%) y NC (13%) (p EnglishBackground: It has been proposed that Vitamin D helps reduce the accumulation of cerebral β-amyloid-42 by innate immune stimulation and phagocytosis activation. An association between low Vitamin D levels and Alzheimer’s dementia (AD) has been established. We determined the association between Vitamin D, mild cognitive impairment (MCI), and AD in older Mexican adults (> 65 years). Methods: Cross-sectional study conducted at the memory clinic in a tertiary-level hospital in Mexico City. We evaluated subjects with MCI, AD, and normal cognition (NC) with available serum Vitamin D [25(OH)D] levels (past 6 months). Three categories were assigned according to 25(OH)D levels: sufficiency (> 30 ng/mL), insufficiency (21-29 ng/mL), and defi- ciency (≤ 20 ng/mL). Descriptive statistics, means and standard deviations were used. Logistic regression analyses adjusted by age, sex, and educational level were performed. Results: We evaluated 208 patients. Mean age was 79 ± 1 year, 65% (n = 136) were female; and mean educational level was 6.7 ± 2.3 years. Thirty-one subjects (14%) had NC; 42% (n = 88) had MCI; and 43% (n = 89) had AD. Prevalence of Vitamin D deficiency was 54%, more frequent in the AD group (64%) followed by the MCI (59%) and NC (13%) (p

Objectives We describe a standardized, scalable outpatient surveillance model for pregnant women with COVID-19 with several objectives: (1) to identify and track known, presumed, and suspected COVID-positive pregnant patients both during their acute illness and after recovery, (2) to regularly assess patient symptoms and escalate care for those with worsening disease while reducing unnecessary hospital exposure for others, (3) to educate affected patients on warning symptoms, hygiene, and quarantine recommendations, and (4) to cohort patient care, isolating stable infected patients at home and later within the same physical clinic area upon their return to prenatal care. Methods Pregnant women in an urban public hospital system with presumed or confirmed COVID-19 were added to a list in our electronic medical record as they came to the attention of providers. They received a series of phone calls based on their illness severity and were periodically assessed until deemed stable. Results A total of 83 patients were followed between March 19 and May 31, 2020. Seven (8%) were asymptomatic, 62 (75%) had mild disease, 11 (13%) had severe disease, and three (4%) had critical illness. Conclusions We encourage others to develop and utilize outpatient surveillance systems to facilitate appropriate care and to optimize maternal and fetal well-being.

Background In Italy, the incidence of human tick-borne disease has increased over the last decades. Since 2015 a multidisciplinary group has been established in Sacco Hospital for the management of the patients affected by Lyme disease (LD). A retrospective evaluation (2015-2017) was performed for LD in non-endemic areas. Methods Retrospective analysis of all 1000 samples for 800 patients screened for LD antibodies at the Sacco Hospital in 3 years (2015-2017). Clinical and epidemiological data were collected and compared with the serological results. Results Among the 800 patients screened, 134 of them were diagnosed with borreliosis during 2015 (37 cases), 2016 (31 cases) and 2017 (66 cases). Localized LD was diagnosed 100 out of 134 cases (69%): in most of them (N.=63) erythema migrans has been documented; in 37 out of 100 it was not possible to detect it. In only three cases, patients complained of different clinical symptoms such as headache, arm and facial pain respectively. 23 out of 134 cases (16%) showed a persistence of serological positivity and symptoms with osteomuscular involvement and fatigue, despite the therapy (late LD). In that same study 11 out of 134 patients (7%) received a diagnosis of neuroborreliosis. Conclusions Our data reported a high percentage of LD infection (19%) in a non-endemic area. The definition of a Multidisciplinary Working Group and a clinical care pathway allowed a better clinical management of LD cases treated in Sacco Hospital, Milan.

Introduction Racemic ketoconazole (RK) is a steroidogenesis inhibitor used for treatment of Cushing’s syndrome. Levoketoconazole (COR-003), the pure 2S,4R enantiomer, is potentially more potent and safe compared to RK. We compared in vitro effects of levoketoconazole and RK on adrenocortical and pituitary adenoma cells. Materials and methods HAC15 cells and 15 primary human neoplastic adrenocortical cultures (+/− ACTH), and murine (AtT20) and human corticotroph adenoma cultures were incubated with levoketoconazole or RK (0.01-10 µM). Cortisol and ACTH were measured using a chemiluminescence immunoassay system, and steroid profiles by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results In HAC15, levoketoconazole inhibited cortisol at lower concentrations (IC50: 0.300 µM) compared to RK (0.611 µM; P < 0.0001). IC50 values of levoketoconazole for basal cortisol production in primary adrenocortical cultures varied over a 24-fold range (0.00578-0.140 µM), with 2 patients having a higher sensitivity for levoketoconazole vs RK (2.1- and 3.7-fold). LC-MS/MS analysis in selected cases revealed more potent inhibition of cortisol and other steroid profile components by levoketoconazole vs RK. In AtT20, levoketoconazole inhibited cell growth and ACTH secretion (10 µM: −54% and −38%, respectively), and levoketoconazole inhibited cell number in 1 of 2 primary human corticotroph pituitary adenoma cultures (−44%, P < 0.001). Conclusion Levoketoconazole potently inhibits cortisol production in adrenocortical cells, with a variable degree of suppression between specimens. Levoketoconazole inhibits adrenal steroid production more potently compared to RK and might also inhibit ACTH secretion and growth of pituitary adenoma cells. Together with previously reported potential advantages, this indicates that levoketoconazole is a promising novel pharmacotherapy for Cushing’s syndrome.

There is a current paucity of information about the obstetric and perinatal outcomes of pregnant novel coronavirus disease 2019 (COVID-19) patients in North America. Data from China suggest that pregnant women with COVID-19 have favorable maternal and neonatal outcomes, with rare cases of critical illness or respiratory compromise. However, we report two cases of pregnant women diagnosed with COVID-19 in the late preterm period admitted to tertiary care hospitals in New York City for respiratory indications. After presenting with mild symptoms, both quickly developed worsening respiratory distress requiring intubation, and both delivered preterm via caesarean delivery. These cases highlight the potential for rapid respiratory decompensation in pregnant COVID-19 patients and the maternal-fetal considerations in managing these cases.

Introduction Since the first reports of the emergence of the novel coronavirus SARS-CoV-2 and its associated disease (COVID-19), concerns remain about whether the virus is transmissible in pregnant women from the mother to the fetus during either the antepartum period or the process of labor and delivery. One recent review reported that in a small number of cases, two PCR swabs of the placenta were sent in additional to neonatal and cord blood testing, and both placental PCR swabs were negative.1 Other studies have demonstrated the finding of SARS-CoV2 IgM in neonates born to mothers diagnosed with COVID-19 during pregnancy,2,3 findings that may indicate vertical transmission of the virus in utero. We report our experience with placental/membrane SARS-CoV2 RNA PCR swab results after delivery to a series of symptomatic mothers with confirmed COVID-19 infection in pregnancy. Methods IRB approval was obtained. All pregnant patients diagnosed with COVID-19 who gave birth between March 1, 2020 and April 20, 2020 at NYU Langone Health were identified by a search of the electronic medical record. Charts were reviewed for documentation of SARS-CoV-2 RNA RT-PCR testing sent from either the placenta or membranes within 30 minutes following delivery. PCR testing for SARS-COV-2 was performed using the cobas SARS-CoV-2 assay (Roche) or the Cepheid Xpert Xpress assay. Placental swabs were obtained from the amniotic surface after clearing the surface of maternal blood (placental PCR). Membrane swabs were obtained from between the amnion and chorion after manual separation of the membranes (membrane PCR). Maternal COVID-19 illness was categorized as mild, severe, or critical.4 The time interval from maternal diagnosis of COVID-19 to delivery was calculated in days. Infants were tested with nasopharyngeal swabs for SARS-CoV-2 PCR between days of life 1 and 5 while hospitalized. Hospitalized infants were also assessed for clinical signs and symptoms, including fever, cough, and nasal congestion. Results Of 32 COVID-19 positive pregnant patients who gave birth in this timeframe, placental or membrane swabs were sent from 11 patients (Table). Three of 11 swabs were positive. None of the infants tested positive for SARS-CoV2 on days of life 1 through 5, and none demonstrated symptoms of COVID-19 infection. Discussion Of 11 placental or membrane swabs sent following delivery, 3 swabs were positive for SARS-CoV-2, all in women with moderate to severe COVID-19 illness at time of delivery. This is the first study to demonstrate the presence of SARS-CoV-2 RNA in placental or membrane samples. While there were no clinical signs of vertical transmission, our findings raise the possibility of intrapartum viral exposure. Given the mixing of maternal and fetal fluid and tissue at time of delivery, the origin of the detected SARS-CoV-2 RNA in our series is unclear. It may represent contamination from maternal blood, amniotic fluid, or COVID-19 infection of the membranes and amniotic sac. For those infants who were delivered vaginally, contamination with vaginal secretions is also a possible source, although prior studies on vaginal secretions have failed to demonstrate the presence of COVID-19.5,6 Although all of our neonates tested negative in the first 5 days of life, many were born via cesarean deliveries with decreased length of exposure to these tissues, which may be associated with a decreased likelihood of vertical transmission. Additionally, nasopharyngeal testing immediately after delivery may not be the ideal approach to evaluate vertical transmission if exposure occurs at the time of delivery, as the virus may require a longer incubation period before these swabs convert to positive. In summary, the presence of viral RNA by RT-PCR in placenta/membranes at the time of delivery suggests the need for further research into the possibility of vertical transmission.

Background Glioblastoma is the most aggressive primary brain tumour and has a very poor prognosis. Inhibition of c-Src activity in glioblastoma stem cells (GSCs, responsible for glioblastoma lethality) and primary glioblastoma cells by the peptide TAT-Cx43266–283 reduces tumorigenicity, and boosts survival in preclinical models. Because c-Src can modulate cell metabolism and several reports revealed poor clinical efficacy of various antitumoral drugs due to metabolic rewiring in cancer cells, here we explored the inhibition of advantageous GSC metabolic plasticity by the c-Src inhibitor TAT-Cx43266-283. Methods Metabolic impairment induced by the c-Src inhibitor TAT-Cx43266-283 in vitro was assessed by fluorometry, western blotting, immunofluorescence, qPCR, enzyme activity assays, electron microscopy, Seahorse analysis, time-lapse imaging, siRNA, and MTT assays. Protein expression in tumours from a xenograft orthotopic glioblastoma mouse model was evaluated by immunofluorescence. Findings TAT-Cx43266–283 decreased glucose uptake in human GSCs and reduced oxidative phosphorylation without a compensatory increase in glycolysis, with no effect on brain cell metabolism, including rat neurons, human and rat astrocytes, and human neural stem cells. TAT-Cx43266-283 impaired metabolic plasticity, reducing GSC growth and survival under different nutrient environments. Finally, GSCs intracranially implanted with TAT-Cx43266–283 showed decreased levels of important metabolic targets for cancer therapy, such as hexokinase-2 and GLUT-3. Interpretation The reduced ability of TAT-Cx43266-283–treated GSCs to survive in metabolically challenging settings, such as those with restricted nutrient availability or the ever-changing in vivo environment, allows us to conclude that the advantageous metabolic plasticity of GSCs can be therapeutically exploited through the specific and cell-selective inhibition of c-Src by TAT-Cx43266-283. Funding Spanish Ministerio de Economia y Competitividad (FEDER BFU2015-70040-R and FEDER RTI2018-099873-B-I00), Fundacion Ramon Areces. Fellowships from the Junta de Castilla y Leon, European Social Fund, Ministerio de Ciencia and Asociacion Espanola Contra el Cancer (AECC).

Adrenocortical carcinoma (ACC) is diagnosed using the histopathological Weiss score (WS), but remains clinically elusive unless it has metastasized or grows locally invasive. Previously, we proposed the objective IGF2 methylation score as diagnostic tool for ACC. This multicenter European cohort study validates these findings. Patient and tumor characteristics were obtained from adrenocortical tumor patients. DNA was isolated from frozen specimens, where after DMR2, CTCF3, and H19 were pyrosequenced. The predictive value of the methylation score for malignancy, defined by the WS or metastasis development, was assessed using receiver operating characteristic curves and logistic and Cox regression analyses. Seventy-six ACC patients and 118 patients with adrenocortical adenomas were included from seven centers. The methylation score and tumor size were independently associated with the pathological ACC diagnosis (OR 3.756 95% CI 2.224–6.343; OR 1.467 95% CI 1.202–1.792, respectively; Hosmer–Lemeshow test P = 0.903), with an area under the curve (AUC) of 0.957 (95% CI 0.930–0.984). The methylation score alone resulted in an AUC of 0.910 (95% CI 0.866–0.952). Cox regression analysis revealed that the methylation score, WS and tumor size predicted development of metastases in univariate analysis. In multivariate analysis, only the WS predicted development of metastasis (OR 1.682 95% CI 1.285–2.202; P < 0.001). In conclusion, we validated the high diagnostic accuracy of the IGF2 methylation score for diagnosing ACC in a multicenter European cohort study. Considering the known limitations of the WS, the objective IGF2 methylation score could potentially provide extra guidance on decisions on postoperative strategies in adrenocortical tumor patients.

© 2020 by the authors., Choline is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which, upon absorption by the host is converted into trimethylamine-N-oxide (TMAO) in the liver. A high accumulation of both components is related to cardiovascular disease, inflammatory bowel disease, non-alcoholic fatty liver disease, and chronic kidney disease. However, the relationship between the microbiota production of these components and its impact on these diseases still remains unknown. In this review, we will address which microbes contribute to TMA production in the human gut, the extent to which host factors (e.g., the genotype) and diet affect TMA production, and the colonization of these microbes and the reversal of dysbiosis as a therapy for these diseases., This work was supported by the Ministry of Science, Innovation and Universities (PSI2017-83893-R to J.L.A.) and the Ministry of Economy and Business (PSI2015-73111-EXP to J.L.A., PSI2017-90806-REDT to J.L.A. and AGL2017-83653R to M.G.) (Spain). S.A. was the recipient of a postdoctoral Juan de la Cierva Contract (Ministry of Science, Innovation and Universities, Ref. IJCI-2017-32156).

Hispanic women have a higher prevalence of weight associated complications in pregnancy. This ethnic disparity is likely related to behavior patterns, social circumstances, environmental exposures, and access to healthcare, rather than biologic differences. The objective was to determine associations between sociodemographic characteristics, health behaviors, and psychosocial stressors and gestational weight gain (GWG) in low-income Hispanic women. During pregnancy, information on sociodemographic characteristics, health behaviors, and psychosocial stressors were collected. Linear regression estimated mean differences in GWG by selected predictors. Multinomial logistic regression estimated odds of inadequate and excessive GWG by selected predictors. Five-hundred and eight women were included, 38% had inadequate and 28% had excessive GWG, 57% with a normal pre-pregnancy BMI had inadequate GWG. Compared to women with normal BMI, women with overweight or obesity were more likely to have excessive GWG (aRRR = 1.88, 95% CI: 1.04, 3.40 and aRRR = 1.98, 95% CI: 1.08, 3.62, respectively). Mean total GWG was higher among women who were nulliparous (&szlig, = 1.34 kg, 95% CI: 0.38, 2.29) and those who engaged in &ge, 3 h of screen time daily (&szlig, = 0.98 kg, 95% CI: 0.02, 1.94), and lower among women who were physically active during pregnancy (&szlig, = &minus, 1.00 kg, 95% CI: &minus, 1.99, &minus, 0.03). Eating breakfast daily was associated with lower risk of inadequate GWG (aRRR = 0.47, 95% CI: 0.26, 0.83). Depressive symptoms and poor adherence to dietary recommendations were prevalent, but none of the psychosocial or dietary variables were associated with GWG. In this cohort of primarily immigrant, low-income, Hispanic women, there were high rates of poor adherence to diet and physical activity recommendations, and a majority of women did not meet GWG guidelines. Modifiable health behaviors were associated with GWG, and their promotion should be included in prenatal care.

The autosomal dominant neuronal ceroid lipofuscinoses (NCL) CLN4 is caused by mutations in the synaptic vesicle (SV) protein CSPα. We developed animal models of CLN4 by expressing CLN4 mutant human CSPα (hCSPα) in Drosophila neurons. Similar to patients, CLN4 mutations induced excessive oligomerization of hCSPα and premature lethality in a dose-dependent manner. Instead of being localized to SVs, most CLN4 mutant hCSPα accumulated abnormally, and co-localized with ubiquitinated proteins and the prelysosomal markers HRS and LAMP1. Ultrastructural examination revealed frequent abnormal membrane structures in axons and neuronal somata. The lethality, oligomerization and prelysosomal accumulation induced by CLN4 mutations was attenuated by reducing endogenous wild type (WT) dCSP levels and enhanced by increasing WT levels. Furthermore, reducing the gene dosage of Hsc70 also attenuated CLN4 phenotypes. Taken together, we suggest that CLN4 alleles resemble dominant hypermorphic gain of function mutations that drive excessive oligomerization and impair membrane trafficking.

Glioblastoma is the most aggressive primary brain cancer, with a median survival of 1 to 2 years1. These tumours contain glioma stem cells (GSCs), which are highly tumorigenic, resistant to conventional therapies2, 3, and exhibit metabolic plasticity to adapt to challenging environments4, 5. GSCs can be specifically targeted by a short cell-penetrating peptide based on connexin43 (Cx43) (TAT-Cx43266-283) that reduces tumour growth and increases survival in preclinical models6via c-Src inhibition7. Because several reports revealed poor clinical efficacy of various antitumoral drugs due to metabolic rewiring in cancer cells8–10, we investigated the effect of TAT-Cx43266-283on GSC metabolism and metabolic plasticity. Here we show that TAT-Cx43266-283decreases GSC glucose uptake and oxidative phosphorylation without a compensatory increase in glycolysis, with no effect on neuron or astrocyte metabolism. GSC changes were mediated by decreased hexokinase (HK) activity and aberrant mitochondrial localization, ultrastructure and function. Moreover, TAT-Cx43266-283reduced GSC growth and survival under different nutrient availability conditions by impairing the metabolic plasticity needed to exploit glucose as an energy source in the absence of other nutrients. Finally, GSCs intracranially implanted into mice together with TAT-Cx43266-283showed decreased levels of important targets for cancer therapy, such as HK-211, 12and glucose transporter 3 (GLUT-3)13, evidencing the reduced ability of treated GSCs to survive in challenging environments. Our results confirm the value of TAT-Cx43266-283for glioma therapy alone or in combination with therapies whose resistance relies on metabolic adaptation. More importantly, these results allow us to conclude that the advantageous metabolic plasticity of GSCs is a targetable vulnerability in malignant gliomas.

Objective The aim of this study was to assess the ability of drug-induced sleep endoscopy (DISE) to change therapeutic decisions through the identification of obstruction sites in patients with obstructive sleep apnea (OSA). Materials and methods A systematic review and meta-analysis were conducted concerning studies that reported the impact of DISE on therapeutic recommendations. The percentage of change was collected for each study and per site of the collapse. The pooled rate of change and the respective 95% confidence interval (CI) were computed. Subgroup analysis was performed based on patients’ age, sample size, the applied DISE protocol, and the originally used diagnostic modality before DISE. Results In a total of nine studies, 1247 patients were included (69.2% males, 59.7% children, 78.04% with a multilevel collapse). Therapeutic decisions changed in 43.69% of patients (CI, 33.84 to 53.54). The change rates were significantly higher in adults (54.0% versus 25.9% in children, P = 0.001), midazolam-based DISE protocols (78.4% versus 48.45% for midazolam plus propofol and 33.9% for propofol, P < 0.001), and after awake endoscopy (62.2% as compared to 44.6% after clinical basic examination [CBE], 40.1% after CBE, lateral cephalometry, and Muller maneuver, P = 0.02). Changes at uvular and palatal sites were more frequent in adults and at the tonsils in children. Conclusion The DISE approach can be promoted via implementing unified classification systems of obstruction sites; the widescale application of target-controlled infusion and its therapeutic benefits can be explored in well-designed randomized studies that compare its efficacy with other diagnostic modalities.

Poultry carry zoonotic bacteria that can cause gastroenteritis in humans. Environmental transmission of pathogens from poultry operations may increase gastrointestinal infection risk in surrounding communities. To evaluate associations between residential proximity to high-density poultry operations and individual-level diarrheal illnesses, we conducted a nested case-control study among 514,488 patients in Pennsylvania (2006–2015). Using electronic health records, we identified cases of five gastrointestinal outcomes: three pathogen-specific infections, including Escherichia coli (n = 1425), Campylobacter (n = 567), and Salmonella (n = 781); infectious diarrhea (n = 781); and non-specific diarrhea (2012–2015; n = 28,201). We estimated an inverse-distance squared activity metric for poultry operations based on farm and patient addresses. Patients in the second and fourth (versus first) quartiles of the poultry operation activity metric had increased odds of Campylobacter (AOR [CI], Q2: 1.36 [1.01, 1.82]; Q3: 1.38 [0.98, 1.96]; Q4: 1.75 [1.31, 2.33]). Patients in the second, third, and fourth quartiles had increased odds of infectious diarrhea (Q2: 1.76 [1.29, 2.39]; Q3: 1.76 [1.09, 2.85]; Q4: 1.60 [1.12, 2.30]). Stratification revealed stronger relations of fourth quartile and both Campylobacter and infectious diarrhea in townships, the most rural community type in the study geography. Increasing extreme rainfall in the week prior to diagnosis strengthened fourth quartile Campylobacter associations. The poultry operation activity metric was largely unassociated with E. coli, Salmonella, and non-specific diarrhea. Findings suggest high-density poultry operations may be associated with campylobacteriosis and infectious diarrhea in nearby communities, highlighting additional public health concerns of industrial agriculture.

Importance Early evidence shows a decrease in the number of US births during the COVID-19 pandemic, yet few studies have examined individual-level factors associated with pregnancy intention changes, especially among diverse study populations or in areas highly affected by COVID-19 in the US. Objective To study changes in pregnancy intention following the outbreak of the COVID-19 pandemic and identify factors possibly associated with these changes. Design, setting, and participants A cross-sectional, population-based study was conducted among women who were currently pregnant or had delivered a live infant and responded to a survey emailed to 2603 women (n = 1560). Women who were mothers of young children enrolled in the prospective New York University Children's Health and Environment Study birth cohort were included; women who were not currently pregnant or recently postpartum were excluded. Exposures Demographic, COVID-19-related, stress-related, and financial/occupational factors were assessed via a survey administered from April 20 to August 31, 2020. Main outcomes and measures Pregnancy intentions before the COVID-19 pandemic and change in pregnancy intentions following the outbreak. Results Of the 2603 women who were sent the survey, 1560 (59.9%) who were currently pregnant or had delivered a live infant responded, and 1179 women (75.6%) answered the pregnancy intention questions. Mean (SD) age was 32.2 (5.6) years. Following the outbreak, 30 of 61 (49.2%) women who had been actively trying to become pregnant had ceased trying, 71 of 191 (37.2%) women who had been planning to become pregnant were no longer planning, and 42 of 927 (4.5%) women who were neither planning nor trying were newly considering pregnancy. Among those who ceased trying, fewer than half (13 [43.3%]) thought they would resume after the pandemic. Of those pre-COVID-19 planners/triers who stopped considering or attempting pregnancy, a greater proportion had lower educational levels, although the difference was not statistically significant on multivariable analysis (odds ratio [OR], 2.14; 95% CI, 0.92-4.96). The same was true for those with higher stress levels (OR, 1.09; 95% CI, 0.99-1.20) and those with greater financial insecurity (OR, 1.37; 95% CI, 0.97-1.92. Those who stopped considering or attempting pregnancy were more likely to respond to the questionnaire during the peak of the outbreak (OR, 2.04; 95% CI, 1.01-4.11). Of those pre-COVID-19 nonplanners/nontriers who reported newly thinking about becoming pregnant, a smaller proportion responded during the peak, although the finding was not statistically significant on multivariable analysis (OR, 0.52; 95% CI, 0.26-1.03). Likewise, fewer respondents who were financially insecure reported newly considering pregnancy, although the finding was not statistically significant (OR, 0.69; 95% CI, 0.46-1.03). They were significantly less likely to be of Hispanic ethnicity (OR, 0.27; 955 CI, 0.10-0.71) and more likely to have fewer children in the home (OR, 0.62; 95% CI, 0.40-0.98) or self-report a COVID-19 diagnosis (OR, 2.70; 95% CI, 1.31-5.55). Conclusions and relevance In this cross-sectional study of 1179 women who were mothers of young children in New York City, increased stress and financial insecurity owing to the COVID-19 pandemic paralleled a reduction in pregnancy intention in the early months of the pandemic, potentially exacerbating long-term decreases in the fertility rate.

Simple Summary Adrenocortical carcinoma is a rare cancer with a poor prognosis. Adrenal tumors are, however, commonly identified in clinical practice. Discrimination between benign and malignant adrenal tumors is of great importance to determine the appropriate treatment and follow-up strategy. This review summarizes the current diagnostic strategies and challenges to distinguish benign from malignant adrenal lesions. We will focus both on radiological and biochemical assessments, enabling diagnosis of the adrenal lesion preoperatively, and on histopathological and a wide variety of molecular assessments that can be done after surgical removal of the adrenal lesion. Furthermore, new non-invasive strategies such as liquid biopsies, in which blood samples are used to study circulating tumor cells, tumor DNA and microRNA, will be addressed in this review. Abstract Adrenocortical carcinoma (ACC) is a rare cancer with a poor prognosis. Adrenal incidentalomas are, however, commonly identified in clinical practice. Discrimination between benign and malignant adrenal tumors is of great importance considering the large differences in clinical behavior requiring different strategies. Diagnosis of ACC starts with a thorough physical examination, biochemical evaluation, and imaging. Computed tomography is the first-level imaging modality in adrenal tumors, with tumor size and Hounsfield units being important features for determining malignancy. New developments include the use of urine metabolomics, also enabling discrimination of ACC from adenomas preoperatively. Postoperatively, the Weiss score is used for diagnosis of ACC, consisting of nine histopathological criteria. Due to known limitations as interobserver variability and lack of accuracy in borderline cases, much effort has been put into new tools to diagnose ACC. Novel developments vary from immunohistochemical markers and pathological scores, to markers at the level of DNA, methylome, chromosome, or microRNA. Molecular studies have provided insights into the most promising and most frequent alterations in ACC. The use of liquid biopsies for diagnosis of ACC is studied, although in a small number of patients, requiring further investigation. In this review, current diagnostic modalities and challenges in ACC will be addressed.

Pregnant women are widely exposed to organophosphate (OP) pesticides, which are potentially neurotoxicant for the developing fetus. We aimed to identify principal demographic and dietary predictors of OP pesticide exposure among 450 pregnant women participating in the New York University Children’s Health and Environment Study (enrolled 2016–19). Urinary concentrations of six dialkyl phosphate (DAP) metabolites (3 dimethyl (DM) metabolites and 3 diethyl (DE) metabolites) of OP pesticides were determined at three time points across pregnancy. At mid-gestation, the Diet History Questionnaire II was used to assess women’s dietary intake over the past year. Demographic characteristics were obtained using questionnaires and/or electronic health records. We used linear mixed models to evaluate the associations of demographic and food groups with DAP metabolite levels, and partial-linear single-index (PLSI) models to analyze the contribution proportions of food groups to DAP metabolite concentrations and the dose-response relationships between them. We observed that pregnant women in NYC had lower levels of OP pesticide metabolites than pregnant populations in Europe, Asia, and other regions in the U.S. Having lower pre-pregnancy body mass index and being Asian, employed, and single were associated with higher DAP metabolite concentrations. Fruit and grain intakes were associated with higher ∑DM, ∑DE, and ∑DAP levels. ∑DE concentrations increased 9.0% (95% confidence interval (CI) = 1.2%, 17.4%) per two-fold increase in dairy consumption, whereas ∑DE concentrations decreased 1.8% (95%CI = −3.1%, −0.4%) per two-fold increase in seafood consumption. The PLSI model indicated that among the food mixture, fruit and grains were the main food groups contributed to higher levels of ∑DAP, while meat contributed to lower levels of ∑DAP. The contribution proportions of fruit, grains, and meat were 18.7%, 17.9%, and 39.3%, respectively. Our results suggest that fruit, grains, and meat are major dietary components associated with OP pesticide exposure in urban pregnant women.

Breast cancer is the leading cause of cancer-related deaths in American women. Despite the current standard-of-care, which implements tumor resection, radiotherapy, and chemotherapy, triple-negative and HER2-positive breast cancer patients often relapse and present with recurrent disease, for which there is no cure. Thus, there is an urgent need to identify new molecular targets to improve patient response to anti-cancer therapies. The JAK2-STAT3 and TrkA receptor tyrosine kinase signaling pathways have been separately implicated in metastatic breast cancers, but information about their crosstalk remains limited. Activated Janus kinase 2 (JAK2) receptor tyrosine kinase phosphorylates signal transducer and activator of transcription 3 (STAT3) transcription factor, inducing STAT3 nuclear translocation and transcriptional activity. Abnormal activation of STAT3-mediated transcription has been identified as a pro-tumorigenic event in breast cancers and promotes progression through induction of breast cancer stem cells, invasion, and angiogenesis. Tropomyosin receptor kinase A (TrkA) frequently forms oncogenic fusion proteins and its overexpression has been shown to drive malignant transformation of breast cancer cells. JAK2 inhibitors, while approved for treatment of myeloproliferative neoplasms, are currently in clinical trials for triple-negative breast cancers. Currently, there are two FDA-approved TrkA inhibitors for treatment of NTRK1 fusion-positive solid tumors, one of which is considered a tumor-agnostic inhibitor. However, whether these two important pathways are co-activated in breast cancers and whether the co-activation is associated with overall progression of breast cancer have not been investigated. Herein, we report that STAT3 and TrkA are more co-activated in triple-negative and HER2-enriched breast cancers, compared to luminal subtypes, as determined by immunohistochemical staining of 33 invasive breast carcinomas and datamining data of over 1,500 breast cancer patients. We also observed that high co-activation of both JAK2-STAT3 and TrkA pathways significantly shortens overall metastasis-free survival of both triple-negative and HER2-enriched breast cancer patients when compared to patients with low co-activation. Similarly, we also find that JAK2-STAT3 and TrkA co-activation also significantly shortens brain, lung, and bone metastasis-free survival in both of these breast cancer subtypes, suggesting a critical role for JAK2-STAT3 and TrkA in distant metastasis of aggressive breast cancers. Taken together, our findings indicate a novel signaling crosstalk between JAK2-STAT3 and TrkA pathways in triple-negative and HER2-enriched breast cancers, and the use of their co-activation as a prognostic indicator for metastatic breast cancers of both subtypes. Citation Format: Angelina T. Regua, Noah R. Aguayo, Sara Abu Jalboush, Daniel L. Doheny, Sara G. Manore, Dongqin Zhu, Grace L. Wong, Austin Arrigo, Calvin J. Wagner, Yang Yu, Karen Baylon, Alexandra Thomas, Michael D. Chan, Jimmy Ruiz, Guangxu Jin, Roy E. Strowd, Peiqing Sun, Linda J. Metheny-Barlow, Jiayuh Lin, Hui-Wen Lo. JAK2/STAT3 and TrkA pathways are frequently co-activated in triple-negative and HER2-enriched breast cancers and the co-activation correlates with an increased potential of metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1979.

Breast cancer is the second leading cause of brain metastases in women; patients with breast cancer brain metastasis (BCBM) survive only 6-18 months following diagnosis. Current standard of care options for BCBM include stereotactic radiosurgery, whole-brain radiotherapy, and surgical resection. Novel agents that act on targetable driver mutations (EGFR, ALK, PI3K, etc) and penetrate the blood-brain barrier have recently shown increasing promise as systemic options for patients with distant lung and melanoma metastases. Nevertheless, brain metastases represent an area of unmet clinical need for which new pathways, novel mechanisms, and innovative therapies are needed. Cancer stem cells are thought to be one of the driving forces behind not only distant metastasis, but also late-stage recurrence. The hedgehog pathway has been identified as an important mediator of breast cancer stem cells (BCSC); however, FDA-approved therapies targeting this pathway have demonstrated limited efficacy in breast cancer clinical trials. Despite advances made in understanding BCSC, it is still challenging to effectively target BCSC underscoring the need to identify and inhibit novel mediators of BCSC for treating BCBM patients. Our laboratory recently reported that truncated glioma-associated oncogene homolog 1 (tGLI1) promotes preferential metastasis to the brain in breast cancer by activating BCSC and astrocytes in the tumor microenvironment (Oncogene 39:64-78, 2020). tGLI1 is an alternatively spliced GLI1 variant that functions as a tumor-specific gain-of-function transcription factor and terminal effector of the hedgehog pathway. We found that tGLI1 knockdown abrogated BCBM, providing the rationale to therapeutically target tGLI1. Cell-based chemical screens followed by validations demonstrated that ketoconazole, an FDA-approved azole antifungal, specifically inhibits tGLI1 leading to suppression of BCSC in vitro and BCBM in vivo. Modification of KCZ side chains produced derivative compounds that retained tGLI1-selectivity in both in vitro models of BCSC and in vivo models of BCBM with increased blood-brain barrier penetrance. Mechanistic studies suggest that KCZ-dependent cell kill is, in part, mediated through downregulation of tGLI1 target genes OCT4, Nanog, and VEGFA. Based on these data, we opened a window-of-opportunity study in patients with BCBM to determine if ketoconazole penetrates the blood-brain barrier and alters tGLI1 signaling in humans (NCT03796273). Preliminary sample analysis has confirmed tGLI1 expression in collected BCBM and glioma samples. To help identify more effective tGLI1 inhibitors, we screened 63 azole compounds for tGLI1-selectivity and identified four additional compounds as potential tGLI1 inhibitors. Collectively, these data establish tGLI1 as an actionable target for BCBM. Citation Format: Daniel L. Doheny, Sherona R. Sirkisoon, Tadas Rimkus, Dongqin Zhu, Noah R. Aguayo, Marlyn Anguelov, Sara Manore, Fei Xing, Linda Metheny-Barlow, Kounosuke Watabe, Alexandra Thomas, Adrianna Henson Masters, Roy E. Strowd, Hui-Wen Lo. Truncated glioma-associated oncogene homolog 1 (tGLI1) is an actionable therapeutic target in breast cancer brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2866.