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Background: Childbirth posttraumatic stress disorder (PTSD) poses significant challenges, impacting both mothers and infants. This work investigates whether childbirth PTSD is less recognized than PTSD caused by other index events., Methods: In two preregistered experimens we investigated the public and professional perception of PTSD resulting from childbirth compared to other traumatic events (i.e., sexual assault, car accident, terror attack, and an earthquake)., Findings: Study 1, conducted among the general population in the U.S. revealed that a woman depicted as experiencing PTSD symptoms due to childbirth, was less likely to be recognized as suffering from PTSD than a woman with the same symptoms resulting from other traumatic events. Study 2 demonstrated that mental health professionals worldwide are also less inclined to diagnose PTSD when childbirth is the index event in comparison to other index events., Discussion: Due to the importance of social recognition in the treatment of PTSD, the findings underscore the urgent need for heightened awareness and education regarding childbirth PTSD to bridge the recognition gap among the general population and mental health professionals., Competing Interests: Declaration of Competing Interest We hereby declare that we have no potential conflicts of interest with respect to the authorship or the publication of this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Psoriasis is an immune-mediated skin disease affecting approximately 3% of the global population. Proper management of this condition necessitates the assessment of the body surface area and the involvement of nails and joints. The integration of natural language processing with electronic medical records (EMRs) has recently shown promise in advancing disease classification and research. This study evaluates the performance of ChatGPT-4, a commercial artificial intelligence platform, in analyzing unstructured EMR data of psoriasis patients, particularly in identifying affected body areas. The study analyzed EMR data from 94 patients treated at the Dermatology Department and Psoriasis Outpatient Clinic of Sheba Medical Center between 2008 and 2022. The data were processed using the ChatGPT-4 interface to identify and report the body areas affected by psoriasis. These identified areas were then categorized, and the accuracy of ChatGPT-4's analysis was compared with that of a senior dermatologist. The results revealed that the dermatologist identified 477 psoriasis-affected body areas. ChatGPT-4 accurately recognized 443 (92.8%) of these areas, missed 34, and incorrectly identified 30 areas as affected. From 94 cases, nail involvement was detected in 32 cases (34.0%), with ChatGPT-4 correctly identifying 29 cases. Joint involvement was noted in 25 cases (26.6%), with 24 correctly identified using ChatGPT-4. Complete accuracy was achieved in 54 cases (57.4%), although inaccuracies were observed in 40 cases (42.6%). We found that cases with more characters, words, or identified body areas were more prone to errors, suggesting that increased data complexity heightens the likelihood of inaccuracies in artificial intelligence analysis. ChatGPT-4 demonstrated high performance in analyzing detailed and complex unstructured EMR data from patients with psoriasis, effectively identifying involved body areas, including nails and joints. This highlights the potential of NLP algorithms to enhance the analysis of unstructured EMR data for both clinical follow-up and research purposes., Competing Interests: Declaration of competing interest All authors declare that they have no commercial or other associations that might pose a conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Endothelial microvascular dysfunction affects multi-organ pathologic processes that contribute to increased vascular tone and is at the base of impaired metabolic and cardiovascular diseases. The vascular dilation impaired by nitric oxide (NO) deficiency in such dysfunctional endothelium is often balanced by endothelial-derived hyperpolarizing factors (EDHFs), which play a critical role in managing vascular tone. Our latest research has uncovered a new group of lactone oxylipins produced in the polyunsaturated fatty acids (PUFAs) CYP450 epoxygenase pathway, significantly affecting vascular dilation. The lactone oxylipin, derived from arachidonic acid (5,6-diHET lactone, AA-L), has been previously shown to facilitate vasodilation dependent on the endothelium in isolated human microvessels. The administration of the lactone oxylipin derived from eicosapentaenoic acid (5,6-diHETE lactone, EPA-L) to hypertensive rats demonstrated a significant decrease in blood pressure and improvement in the relaxation of microvessels. However, the molecular signaling processes that underlie these observations were not fully understood. The current study delineates the molecular pathways through which EPA-L promotes endothelium-dependent vascular dilation. In microvessels from hypertensive individuals, it was found that EPA-L mediates endothelium-dependent vasodilation while the signaling pathway was not dependent on NO. In vitro studies on human endothelial cells showed that the hyperpolarization mediated by EPA-L relies on G-protein-coupled receptor (GPR)-phospholipase C (PLC)-IP3 signaling that further activates calcium-dependent potassium flux. The pathway was confirmed using a range of inhibitors and cells overexpressing GPR40, where a specific antagonist reduced the calcium levels and outward currents induced by EPA-L. The downstream AKT and endothelial NO synthase (eNOS) phosphorylations were non-significant. These findings show that the GPR-PLC-IP3 pathway is a key mediator in the EPA-L-triggered vasodilation of arterioles. Therefore, EPA-L is identified as a significant lactone-based PUFA metabolite that contributes to endothelial and vascular health., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andrea Szuchman Sapir reports financial support, equipment, drugs, or supplies, and travel were provided by Migal Galilee Technology Center. Andrea Szuchman Sapir has patent #5,6-DIHETE LACTONE FOR TREATMENT OF MICROVASCULAR DYSFUNCTION pending to 17/615,670. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Andrea Szuchman Sapir reports financial support, equipment, drugs, or supplies, and travel were provided by Migal Galilee Technology Center. Andrea Szuchman Sapir has patent #5,6-DIHETE LACTONE FOR TREATMENT OF MICROVASCULAR DYSFUNCTION pending to 17/615,670. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Minimally invasive surgical techniques have become more common in pelvic floor reconstructive urogynaecological surgery, specifically, robotic-assisted pelvic floor surgery. Female pelvic floor anatomy is complex, and some repairs require highly experienced surgical skills that can be gained more easily using robotic-assisted surgery. A common application of the robotic platform in urogynaecological surgeries includes sacrocolpopexy, which has become the gold standard approach in the last decade for the correction of apical prolapse. Additional procedures include sacrohysteropexy, sacrocervicopexy, fistula repair, and complex procedures involving the bladder and other pelvic organs. Despite its increasing use and clear benefit in our field, data in the literature and, in particular, randomised controlled trials are sparse. This review provides an update, incorporating recently published literature and our personal experience in that field., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Respiratory sequela after acute COVID-19 is common and requires medical follow-up. Considering its vast economic impact, there is still no consensus regarding the mid-term follow-up plan after recovery., Objective: To evaluate the necessity of a close pulmonary follow-up schedule after acute COVID-19 and its related investigations., Methods: A prospective cohort study including adult patients after acute COVID-19 pneumonia. Patients were invited or referred to a 3- and 6-month follow-up visits at a large pulmonary institute in a tertiary center. Before each visit, patients completed demographic and clinical questionnaires, pulmonary function tests (PFTs), and chest CT scans., Results: 168 patients were included after completing both visits (medians of 80 and 177 days). Their mean age was 58 ± 15 and 52% recovered from severe or critical COVID-19. Between the two visits, there was no change in DLCOc (mean 73 ± 18 %predicted in both visits) and FVC (mean 90 ± 16 vs. 89 ± 16 %predicted). The COPD assessment tool and modified Medical Research Council scale had inverse correlations with the DLCOc, and similarly did not change between the visits. Occupational exposures were the only factor associated with a change in DLCOc during follow-up (3% decrease, p = 0.04). An improvement in chest CT findings at the second visit was not associated with a change in PFTs., Conclusions: Most clinical variables did not change during a close follow-up schedule in the first six months after acute COVID-19. Such a follow-up plan does not appear necessary and should be personalized to limit excessive costs and resources., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Premenstrual dysphoric disorder (PMDD) is characterized by affective, cognitive, and physical symptoms, suggesting alterations at the brain network level. Women with PMDD demonstrate aberrant discrimination of facial emotions during the luteal phase of the menstrual cycle and altered reactivity to emotional stimuli. However, previous studies assessing emotional task-related brain reactivity using region-of-interest or whole-brain analysis have reported conflicting findings. Therefore, we utilized both region-of-interest task-reactivity and seed-voxel functional connectivity (FC) approaches to test for differences in the default mode network, salience network, and central executive network between women with PMDD and control participants during an emotional-processing task that yields an optimal setup for investigating brain network changes in PMDD., Methods: Twenty-four women with PMDD and 27 control participants were classified according to the Daily Record of Severity of Problems. Participants underwent functional magnetic resonance imaging scans while completing the emotional face-matching task during the midfollicular and late-luteal phases of their menstrual cycle., Results: No significant between-group differences in brain reactivity were found using region-of-interest analysis. In the FC analysis, a main effect of diagnosis was found showing decreased default mode network connectivity, increased salience network connectivity, and decreased central executive network connectivity in women with PMDD compared with control participants. A significant interaction between menstrual cycle phase and diagnosis was found in the central executive network for right posterior parietal cortex and left inferior lateral occipital cortex connectivity. A post hoc analysis revealed stronger FC during the midfollicular than the late-luteal phase of PMDD., Conclusions: Aberrant FC in the 3 brain networks involved in PMDD may indicate vulnerability to experience affective and cognitive symptoms of the disorder., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Purpose: Cognitive behavioural therapy (CBT) has been found to be an effective treatment for OCD, but there remains a significant proportion of individuals who fail to show a treatment response. Aerobic exercise has previously been associated with decreases in anxiety and depression, as well as improvements in OCD symptoms in small-scale studies. The purpose of the present research was to use a randomized control trial design to examine the effects of exercise alone and in combination with CBT, on OCD symptoms and secondary symptoms., Method: 125 participants were randomly assigned to one of four treatment groups: waitlist control, exercise, CBT, and CBT with exercise. OCD symptom severity was measured at four points over the course of treatment, secondary outcome measures were gathered at three points over treatment., Results: CBT alone and combined with exercise was associated with significantly greater OCD symptom reduction than exercise alone or the control groups. Total exercise frequency predicted OCD symptom reduction in the groups in which exercise was measured. Group membership did not significantly predict reductions in secondary outcome measures., Conclusion: Exercise frequency, rather than the presence or absence of exercise, appears to predict OCD symptom reduction, as did participation in CBT., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Neil Rector reports financial support was provided by Canadian Institutes for Health Research., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Studies have suggested an association between particulate matter (PM) air pollution and certain congenital anomalies (CAs). However, most studies assumed a linear concentration-response relation and were based on anomalies that were ascertained at birth or up to 1 year of age. We investigated associations between exposures to PM during the first trimester of pregnancy and CAs in 9 organ systems using birth and childhood follow-up data from a leading health care provider in Israel. We conducted a retrospective population-based cohort study among 396,334 births, 2004-2015. Daily PM data at a 1 × 1 km spatial grid were obtained from a satellite-derived prediction models and were linked to the mothers' residential addresses at birth. Adjusted odds ratios (ORs) were estimated with logistic regression models using exposure levels as either continuous or categorical variables. We captured 57,638 isolated CAs with estimated prevalence of 96 and 136 anomalies per 1000 births in the first year of life and by age 6 years, respectively. Analysis of continuous PM with diameter < 2.5 μm (PM 2.5 ) indicated a supra-linear relation with anomalies in the circulatory, respiratory, digestive, genital and integument systems (79 % of CAs). The slope of the concentration-response function was positive and steepest for PM 2.5 lower than the median concentration (21.5 μg/m 3 ) and had a less steep or negative slope at higher levels. Similar trends were observed for PM 2.5 quartiles. For example, for cardiac anomalies, the ORs were 1.09 (95 % confidence interval: 1.02, 1.15), 1.04 (0.98, 1.10) and 1.00 (0.94, 1.07) for births in the second, third and fourth quartiles, respectively, when compared to the first quartile. In sum, this study adds new evidence for adverse effects of air pollution on neonatal health even with low-level air pollution. Information on late diagnosis of children with anomalies is important in evaluating the burden of disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to assess the association between neonatal SARS-CoV-2 antibody level at delivery and infant SARS-CoV-2 infection under the age of 6 months and to identify predictive factors for neonatal antibody level at delivery., Methods: In a prospective observational study, conducted between September 2021 and mid-February 2022, cord blood sera were tested for SARS-CoV-2 anti-spike receptor-binding domain antibodies after maternal BNT162b2 vaccination or infection. Infants were followed up for 6 months for SARS-CoV-2 infection., Results: Sixty-seven mother-infant dyads were enrolled; nine of those did not meet the eligibility criteria. Of the 58 mother-infant dyads included, 6-month follow-up data were available for 57 mother-infant dyads. The mean ± standard deviation log SARS-CoV-2 anti-spike antibody level at delivery was lower among infants who were COVID-19 positive versus negative during follow-up (3.41 ± 0.74 AU/mL, n = 12; vs. 3.87 ± 0.84 AU/mL, n = 46; p 0.036); a log titre of ≥4.07 AU/mL (11 750) at delivery was associated with a significantly lower likelihood of infant infection (1/26 vs. 11/32 in infants with antibody level of <4.07 log AU/mL, OR = 0.076 [95% CI, 0.076, 0.64], p 0.018). A spline curve model showed a linear decrease in antibody levels when the last dose was administered at ≤30 weeks of gestation (50 days before delivery), after which the antibody levels increased (R 2  = 0.50). In multivariate analysis, more vaccine doses, prior maternal infection, and last administered dose at ≥31 weeks of gestation were associated with higher antibody levels at delivery., Discussion: Higher anti-spike antibodies at delivery were associated with decreased risk of COVID-19 at the age of <6 months; the antibody level decreased linearly when the last dose was administered at ≤30 weeks of gestation. Future research should assess the effectiveness of a second booster during pregnancy against infant infection., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Study Objective: To establish a clinically relevant prediction score for the diagnosis of adnexal torsion (AT) in women who were operated on for suspected AT., Design: A retrospective cohort study conducted between 2014 and 2021., Setting: A large tertiary teaching medical center., Patients: Women who underwent urgent laparoscopy for suspected AT., Interventions: Analyses included univariate and multivariate models combined with the machine learning (ML) Random Forest model, which included all information available about the women and reported the accuracy of the model and the importance of each variable. Based on this model, we created a predictive score and evaluated its accuracy by receiver operating characteristic (ROC) curve., Measurements and Main Results: A total of 503 women were included in our study, 244 (49%) of whom were diagnosed with AT during the surgery, and 44 (8.8%) cases of necrotic ovary were found. Based on the Random Forrest and multivariate models, the most important preoperative clinical predictive variables for AT were vomiting, left-side complaints, and concurrent pregnancy; cervical tenderness and urinary symptoms decreased the likelihood of surgically confirmed AT. The most important sonographic findings that predicted increased risk of surgically confirmed AT were ovarian edema and decreased vascular flow; in contrast, hemorrhagic corpus luteum decreased the likelihood of surgically confirmed AT. The accuracy of the Random Forest model was 71% for the training set and 68% for the testing set, and the area under the curve for the multivariate model was 0.75 (95% confidence interval [CI] 0.69-0.80). Based on these models, we created a predictive score with a total score that ranges from 4 to 12. The area under the curve for this score was 0.72 (95% CI 0.67-0.76), and the best cutoff for the final score was >5, with a sensitivity, specificity, positive predictive value, and negative predictive value of 64%, 73%, 70%, and 67%, respectively., Conclusion: Clinical characteristics and ultrasound findings may be incorporated into the emergency room workup of women with suspected AT. ML in this setting has no diagnostic/predictive advantage over the performance of logistic regression methods. Additional prospective studies are needed to confirm the accuracy of this model., (Copyright © 2023 AAGL. Published by Elsevier Inc. All rights reserved.)

Figurative language is one of the most prevalent expressions of verbal creativity, and use of novel metaphors is the most significant source of verbal innovation. As environmental and personality trait factors can impact creativity, the current study aimed to examine whether exposure to an environment rich in visual stimuli (artwork) and verbal stimuli (novel metaphors) contributes to verbal creativity, taking into account the personality trait of "openness to experience." Study participants (132) were divided into three groups: (1) a group exposed to a creative verbal environment (reading novel metaphors), (2) a group exposed to a visually creative environment (observing abstract and figurative artwork), and (3) a group not exposed to any creative environment. Participants completed personality questionnaire and a metaphor generation questionnaire that asked participants to describe 10 emotions using novel metaphors. Results showed the type of creative environment exposure had a graded effect on creativity (i.e., generation of novel metaphors): the non-exposed control group generated fewer novel than conventional metaphors, the group exposed to novel verbal metaphors produced a similar number of novel and conventional metaphors, and the group exposed to artwork produced more novel than conventional metaphors. This may imply that environments containing visually creative stimuli provide opportunities for silent contemplation which in turn evoke neuropsychological mechanisms related to creative processes. Furthermore, the finding that the trait of "openness to experience" and exposure to a visually creative environment contributed to greater generation of novel metaphors suggests that creativity may be dependent on both individual and environmental factors., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The delivery of therapeutics across the cell membrane and into the cytoplasm is a major challenge that limits the development of new therapies. This challenge is compounded by the lack of a general assay for cytosolic delivery. Here we develop this assay based on the pro-fluorophore CrAsH-EDT2, and provide cytosolic penetration results for a variety of drug delivery agents (polyethyleneimine, poly-arginine, Ferritin, poly [maleic anhydride-alt-isobutene] grafted with dodecylamine, and cationic liposomes) into HeLa and T98G cells. Our results show that this method can be widely applicable to different cells and drug delivery agents, and yield statistically robust results. We later use this method to optimize and improve a model drug delivery agent's (Ferritin) cytosolic penetration., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Research Question: Do preimplantation genetic testing (PGT) pregnancies have higher post-partum complications compared with naturally conceived pregnancies?, Design: Retrospective cohort study conducted in 2008-2020 at the Shaare Zedek Medical Center (SZMC), including all patients aged 18-45 years old who conceived following PGT with a singleton live birth >24 weeks. Data were collected from computerized hospital databases and patient files. There were two control groups: (i) pregnancies following IVF-ICSI (intracytoplasmic sperm injection); (ii) four neighbourhood controls for each case delivery (two women delivered before and two after) of women with naturally conceived pregnancies., Results: Overall, 120 PGT, 779 IVF-ICSI and 3507 naturally conceived deliveries were included. Demographic variables were similar apart from slightly higher age in the PGT (P = 0.003) and ICSI (P = 0.002) groups (31.07 ± 4.38 PGT, 31.66 ± 5.03 ICSI, 28.77 ± 5.72 naturally conceived). Composite post-partum placental-related complications (manual lysis of placenta, revision of uterine cavity, haemoglobin drop ≥3 g/dl, post-partum haemorrhage, need for blood transfusion) were more prevalent in both the PGT and IVF-ICSI groups as opposed to naturally conceived (20.0% versus 18.9% versus 10.3%, respectively, P < 0.001, P = 0.007). In a multivariate regression model PGT was not found to be independently associated with composite post-partum placental-related complications (adjusted odds ratio [aOR] 1.44, 95% confidence interval [CI] 0.83-2.15), while IVF-ICSI pregnancies had increased risk (aOR 1.52, 95% CI 1.20-1.97) compared with natural conception. No difference was found between fresh and frozen cycles or between day 3 and day 5 embryo transfer., Conclusions: PGT pregnancies have a comparable risk of post-partum placental-related complications to naturally conceived pregnancies, unlike IVF-ICSI pregnancies. It is possible that infertility itself is the main mediator for post-partum complications in IVF-ICSI pregnancies., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

The gelatinases, a subgroup of the matrix metalloproteinases (MMPs) superfamily are composed of two members; MMP2 and MMP9. They are known to degrade gelatin among other components of the extracellular matrix. Recently, the two gelatinases were found to be necessary for neural crest cell migration and to compensate for each other loss in these cells. To characterize their involvement in the skeletal system, and to better reveal their individual or common roles, we have generated double knockout (dKO) mice, lacking both MMP2 and MMP9. Comprehensive analysis of the skeleton morphological and mechanical parameters at postnatal day (P) 0, P21, 3 months (M) and 8M of age, revealed an unexpected distinct role for each gelatinase; MMP2 was found to be involved merely in intramembranous ossification which led to a smaller skull and inferior cortical parameters upon its loss, while MMP9 was found to affect only the endochondral ossification process, which led to shorter long-bones in its absence. Importantly, the dKO mice demonstrated a combination of both the skull and long bone phenotypes as found in the single-KOs, and not a severer additive phenotype. Transcriptome analysis on the cortical bone, the growth plate and the skull frontal bone, found many genes that were differentially expressed as a direct or indirect result of MMP-loss, and reinforced the specific and distinct role of each gelatinase in each bone type. Altogether, these results suggest that although both gelatinases share the same substrates and are highly expressed in flat and long bones, they are indispensable and control separately the development of different bones., Competing Interests: Declaration of Competing Interest The authors have declared that no conflict of interest exists., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Research Question: Does inheritance of the fragile X mental retardation 1 (FMR1) premutation allele affect embryo morphokinetic development?, Design: A retrospective cohort analysis of 529 embryos from 126 IVF cycles of 39 FMR1 premutation female carriers undergoing preimplantation genetic testing for monogenic/single gene defects (PGT-M). Morphological and morphokinetic parameters obtained using a time-lapse monitoring system were compared between embryos that inherited the FMR1 premutation allele (FMR1 group, n = 271) and those who received the normal allele (normal group, n = 258). The following embryo outcome measures were compared: morphokinetic parameters up to day 3, start of blastulation time (tSB) for day 5 embryos and the rate of top-quality embryos on days 3 and 5., Results: No differences were found in morphokinetic parameters between the groups from the time of intracytoplasmic sperm injection (ICSI) until a biopsy on day 3. The blastulation rate in the two groups was comparable. However, the start of blastulation was delayed in FMR1 embryos compared to that in the genetically normal embryos (median tSB: 104.2 h [99.3-110.3] versus 101.6 h [94.5-106.7], P = 0.01). In addition, the rate of top-quality FMR1 embryos was lower than that of genetically normal embryos (25.6% versus 38.8%, P = 0.04)., Conclusion: Embryos that inherit the FMR1 premutation allele are of lower quality at the blastocyst stage compared with those that do not inherit the mutated allele., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

A psychedelic industrial complex is emerging as new research on these substances and their effects is being approved. These substances show promise, but much remains unknown about their potential for both benefit and harm. Despite the paucity of reliable mechanistic evidence, some entrepreneurs have already begun to market psychedelic advice. We draw on some critiques of the self-help industry to propose potential parallels in the psychedelic industry. Overstated claims, cultural lore, for-profit organizations, and spiritual gurus come with the territory of both industries aimed at selling solutions for mental health disorders. We offer some guidelines for responsible research, therapy, and policy to temper these concerns, focusing on evidence-based practices, decriminalization, and rigorous therapist training., Competing Interests: Declarations of Interest Rotem Petranker co-owns the Center for Psychadelic Science Inc. and Psychedelic Research Consultations Inc., both scientific consulting firms., (Copyright © 2022. Published by Elsevier B.V.)

Background: A growing body of literature reports associations between exposure to particulate matter with diameter ≤2.5 μm (PM 2.5 ) during pregnancy and birth outcomes. However, findings are inconsistent across studies., Objectives: To assess the association between PM 2.5 and birth outcomes of fetal growth in a cohort with high prevalence of siblings by multilevel models accounting for geographical- and mother-level correlations., Methods: In Israel, we used Maccabi Healthcare Services data to establish a population-based cohort of 381,265 singleton births reaching 24-42 weeks' gestation and birth weight of 500-5000 g (2004-2015). Daily PM 2.5 predictions from a satellite-based spatiotemporal model were linked to the date of birth and maternal residence. We generated mean PM 2.5 values for the entire pregnancy and for exposure periods during pregnancy. Associations between exposure and birth outcomes were modeled by using multilevel logistic regression with random effects for maternal locality of residence, administrative census area (ACA) and mother., Results: In fully adjusted models with a mother-level random intercept only, a 10-μg/m 3 increase in PM 2.5 over the entire pregnancy was positively associated with term low birth weight (TLBW) (Odds ratio, OR = 1.25, 95% confidence interval, CI: 1.09,1.43) and small for gestational age (SGA) (OR = 1.15, 95% CI: 1.06,1.26). Locality- and ACA-level effects accounted for <0.4% of the variance while mother-level effects explained ∼50% of the variability. Associations varied by exposure period, infants' sex, birth order, and maternal pre-pregnancy BMI., Conclusions: Consideration of mother-level variability in a region with high fertility rates provides new insights on the strength of associations between PM 2.5 and birth outcomes., (Copyright © 2022. Published by Elsevier Inc.)

Identifying the presence and extent of early ischemic changes (EIC) on Non-Contrast Computed Tomography (NCCT) is key to diagnosing and making time-sensitive treatment decisions in patients that present with Acute Ischemic Stroke (AIS). Segmenting EIC on NCCT is however a challenging task. In this study, we investigated a 3D CNN based on nnU-Net, a self-adapting CNN technique that has become the state-of-the-art in medical image segmentation, for segmenting EIC in NCCT of AIS patients. We trained and tested this model on a sizeable and heterogenous dataset of 534 patients, split into 438 for training and validation and 96 for testing. On this test set, we additionally assessed the inter-rater performance by comparing the proposed approach against two reference segmentation annotations by expert neuroradiologist readers, using this as the benchmark against which to compare our model. In terms of spatial agreement, we report median Dice Similarity Coefficients (DSCs) of 39.8% for the model vs. Reader-1, 39.4% for the model vs. Reader-2, and 55.6% for Reader-2 vs. Reader-1. In terms of lesion volume agreement, we report Intraclass Correlation Coefficients (ICCs) of 83.4% for model vs. Reader-1, 80.4% for model vs. Reader-2, and 94.8% for Reader-2 vs. Reader-1. Based on these results, we conclude that our model performs well relative to expert human performance and therefore may be useful as a decision-aid for clinicians., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Pneumonia in infancy has been linked to long-term consequences for the rapidly developing lung. We examined the impact of hospitalized community-acquired pneumonia (CAP) on subsequent respiratory health., Methods: We conducted a retrospective matched-cohort study using the Optum® de-identified Electronic Health Record Dataset (2009-2018). Study population comprised healthy infants hospitalized for CAP ("CAP patients"), and matched comparators without pneumonia ("comparison patients"), before age 2 years. Study outcomes included any chronic respiratory disorder, reactive airway disease (asthma, hyperactive airway disease, recurrent wheezing), and CAP hospitalization occurring between age 2-5 years, and were evaluated overall as well as by age and etiology at first CAP hospitalization., Results: Study population totaled 1,343 CAP patients and 6,715 comparison patients. Rates per 100 patient-years and relative rates (RR) of study outcomes from age 2-5 years for CAP patients versus comparison patients were: any chronic respiratory disorder, 11.6 vs. 4.9 (RR = 2.4 [95% CI: 2.1-2.6]); reactive airway disease, 6.1 vs 1.9 (RR = 3.2 [2.6-3.8]); and CAP hospitalization, 1.0 vs 0.2 (RR = 6.3 [3.6-10.9]). Rates of study outcomes were highest among CAP patients who had their initial hospitalization in the second year of life., Conclusions: Infant CAP foreshadows an increased risk of subsequent chronic respiratory disorders, which may be elevated when CAP occurs closer to pre-school age (i.e., age 2-5 years). These findings are most consistent with the hypothesis that inflammation persists beyond the acute stage of pneumonia and plays a role in the development of chronic respiratory sequelae., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) suggest carrier screening panel design criteria intended to ensure meaningful results. This study used a data-driven approach to interpret the criteria to identify guidelines-consistent panels., Methods: Carrier frequencies in >460,000 individuals across 11 races/ethnicities were used to assess carrier frequency. Other criteria were interpreted on the basis of published data. A total of 176 conditions were then evaluated. Stringency thresholds were set as suggested by ACOG and/or ACMG or by evaluating conditions already recommended by ACOG and ACMG., Results: Forty and 75 conditions had carrier frequencies of ≥1 in 100 and ≥1 in 200, respectively; 175 had a well-defined phenotype; and 165 met at least 1 severity criterion and had an onset early in life. Thirty-seven conditions met conservative thresholds, including a carrier frequency of ≥1 in 100, and 74 conditions met permissive thresholds, including a carrier frequency of ≥1 in 200; thus, both were identified as guidelines-consistent panels., Conclusion: Clear panel design criteria are needed to ensure quality and consistency among carrier screening panels. Evidence-based analyses of criteria resulted in the identification of guidelines-consistent panels of 37 and 74 conditions., Competing Interests: Conflict of Interest Rotem Ben-Shachar, Katherine Johansen Taber, and Dale Muzzey are current employees and shareholders of Myriad Genetics, Inc. Aishwarya Arjunan, James Goldberg, Kristjan E. Kaseniit, and Raul Torres are former employees of Myriad Genetics, Inc. Haywood Brown is the Executive Medical Director of the Access to Equitable Carrier Screening Coalition, for which he receives compensation. No funding was provided for the purpose of this study. All work was conducted by authors in the course of their respective employment., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Chironomids are aquatic insects that are known to be pollution tolerant. We have recently demonstrated that endogenous chironomid microbiota protects its host from toxic metals. Following these findings, we hypothesized that under different environmental conditions, a different bacterial consortium will evolve. Our aim was to explore the change in chironomid larval microbiota composition triggered by exposure to toxic copper and hexavalent chromium. Chironomid larvae were collected from the environment and treated in the laboratory with copper, hexavalent chromium, and no metal (control). After six days, the microbial composition of the surviving larvae was examined. We found a significant change in larval microbiota composition between the three treatments and for different copper concentrations. The abundance of specific taxa varied significantly between the treatments. At the genus level, the abundance of some genera (e.g. Yersinia, Acinetobacter) increased in the presence of copper, and some genera (e.g. Yersinia, Dysgonomonas, Delftia, Enterococcus) increased in the presence of hexavalent chromium, compared to the control. The change in the larval microbiota composition was rapid and metal-specific. We suggest that each larva hosts a consortium of bacterial species that can proliferate under a specific environmental change and thus, protect the insect under unstable environmental conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Study Objective: Bartholin's gland abscess may occur in up to 2% of the women. Surgical drainage using the Word catheter application or marsupialization is the treatment of choice in the management of Bartholin's gland abscess. We aimed to compare the abscess recurrence rates between these 2 surgical methods., Design: A retrospective cohort database study., Setting: A university-affiliated, high-volume teaching hospital in southern Israel., Patients: All women who were surgically treated for Bartholin's gland abscess., Interventions: Different clinical and postoperative characteristics were retrieved from the patients' records. A univariate analysis was conducted, and p <.05 was considered significant., Measurements and Main Results: During the study period, 321 women were admitted to our center with Bartholin's gland abscess and were managed surgically. Of these, 215 (67%) were treated using the Word catheter and 106 (33%) by drainage and marsupialization. No differences were found in clinical and microbiologic features between the study groups. In addition, recurrence rates as well as recurrent admissions did not differ significantly. Postoperative complications were similar between the groups., Conclusion: Our study reassures that both the Word catheter application and marsupialization are appropriate and safe when treating Bartholin's gland abscess., (Copyright © 2021 AAGL. Published by Elsevier Inc. All rights reserved.)

Nanoparticle assisted drug delivery to the cytoplasm is limited by sequestration of nanoparticles in endosomes. Endosomal escape through polymer-induced membrane destabilization is one of a few well characterized mechanisms to overcome it. Aiming to utilize this method in vivo, it is necessary to understand how modulating the structural and chemical features of the polymer and the presence of proteins in biological fluids can affect this activity. Here, as a model for the endosomal membrane, we use the membrane of red blood cells to evaluate the membrane destabilization ability of a model amphiphilic polymer in the presence of blood plasma using a hemolysis assay. This allows determination of red blood cells membrane permeabilization through the quantification of hemoglobin leakage. Our results showed a strong inhibitory effect of plasma, and that hemolytic activity can be improved by chemical modification of the polymeric micelle, reducing its interaction with plasma proteins. Finally, a second mechanism of pH-induced direct diffusion is proposed and tested using an oil/water partitioning model. These results offer a body of knowledge to improve delivery of drugs across biological membranes using carefully designed polymeric nanocarriers., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: RBFOX2, an RNA-binding protein, controls tissue-specific alternative splicing of exons in diverse processes of development. The progenitor cytotrophoblast of the human placenta differentiates into either the syncytiotrophoblast, formed via cell fusion, or the invasive extravillous trophoblast lineage. The placenta affords a singular system where a role for RBFOX2 in both cell invasion and cell fusion may be studied. We investigated a role for RBFOX2 in trophoblast cell differentiation, as a foundation for investigations of RBFOX2 in embryo implantation and placental development., Methods: Immunohistochemistry of RBFOX2 was performed on placental tissue sections from three trimesters of pregnancy and from pathological pregnancies. Primary trophoblast cell culture and immunofluorescence were employed to determine RBFOX2 expression upon cell fusion. Knockdown of RBFOX2 expression was performed with βhCG and syncytin-1 as molecular indicators of fusion., Results: In both normal and pathological placentas, RBFOX2 expression was confined to the cytotrophoblast and the extravillous trophoblast, but absent from the syncytiotrophoblast. Additionally, we showed that primary trophoblasts that spontaneously fused in cell culture downregulated RBFOX2 expression. In functional experiments, knockdown expression of RBFOX2 significantly upregulated βhCG, while the upregulation of syncytin-1 did not reach statistical significance., Discussion: RBFOX2, by conferring mRNA diversity, may act as a regulator switch in trophoblast differentiation to either the fusion or invasive pathways. By studying alternative splicing we further our understanding of placental development, yielding possible insights into preeclampsia, where expression of antiangiogenic isoforms produced through alternative splicing play a critical role in disease development and severity., (Copyright © 2020. Published by Elsevier Ltd.)

Background: There is controversy whether exposure to assisted reproductive technology (ART) is associated with increased risk of pediatric cancer. We aimed at calculating the overall risk of pediatric cancers after ART in a large cohort of exposed women; and to conduct a systematic review and meta- analysis of cohort studies examining overall risk of pediatric cancers after ART., Methods: All children born in Israel who were members of Maccabi Health Services (MHS) between 1999 and 2016 after ART, were linked to the Israeli Registry of Childhood Cancer (IGS) to identify those with cancer diagnosed before 16 years of age. In parallel we conducted a systematic review and meta-analysis of observational cohort studies with more than 5000 ART- exposed cases that measured pediatric cancer after ART., Results: In the cohort study, the risk ratio for pediatric cancer after ART in general was 0.95 (95% CI, 0.76-1.19). The RR was 1.09 (95% CI, 0.79-1.48) for IVF treatments. Meta- analysis of 13 cohort studies with a total of 750,138 women exposed to ART (with 1152 pediatric cancers) and 214,008,000 unexposed controls (with 30,458 pediatric cancers) did not reveal increased risk for pediatric cancers (RR 0.99; 95% CI, 0.85-1.15)., Conclusions: Based on very large numbers, ART in general, and IVF in particular, are not associated with overall increased risk of pediatric cancer., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Ribonucleotide reductase (RNR) catalyzes the rate limiting step in dNTP biosynthesis and is tightly regulated at the transcription and activity levels. One of the best characterized responses of yeast to DNA damage is up-regulation of RNR transcription and activity and consequently, elevation of the dNTP pools. Hydroxyurea is a universal inhibitor of RNR that causes S phase arrest. It is used in the clinic to treat certain types of cancers. Here we studied the response of the fungal plant pathogen Fusarium oxysporum to hydroxyurea in order to generate hypotheses that can be used in the future in development of a new class of pesticides. F. oxysporum causes severe damage to more than 100 agricultural crops and specifically threatens banana cultivation world-wide. Although the recovery of F. oxysporum from transient hydroxyurea exposure was similar to the one of Saccharomyces cerevisiae, colony formation was strongly inhibited in F. oxysporum in comparison with S. cerevisiae. As expected, genomic and phosphoproteomic analyses of F. oxysporum conidia (spores) exposed to hydroxyurea showed hallmarks of DNA replication perturbation and activation of recombination. Unexpectedly and strikingly, RNR was not induced by either hydroxyurea or the DNA-damaging agent methyl methanesulfonate as determined at the RNA and protein levels. Consequently, dNTP concentrations were significantly reduced, even in response to a low dose of hydroxyurea. Methyl methanesulfonate treatment did not induce dNTP pools in F. oxysporum, in contrast to the response of RNR and dNTP pools to DNA damage and hydroxyurea in several tested organisms. Our results are important because the lack of a feedback mechanism to increase RNR expression in F. oxysporum is expected to sensitize the pathogen to a fungal-specific ribonucleotide inhibitor. The potential impact of our observations on F. oxysporum genome stability and genome evolution is discussed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Emotional and cognitive impairments in Parkinson's disease (PD) are prevalent, hamper interpersonal relations and reduce quality of life. It is however unclear to what extent these domains interplay in PD-related deficits and how they are influenced by dopaminergic availability. This study examined the effect of cognitive impairment and dopaminergic medication on neural and behavioral mechanisms of facial emotion recognition in PD patients. PD patients on and off dopaminergic medication and matched healthy controls underwent an emotional face matching task during functional MRI. In addition, a comprehensive neuropsychological evaluation of cognitive function was conducted. Increased BOLD response to emotional faces was found in the visual cortex of PD patients relative to controls irrespective of cognitive function and medication status. Administration of dopaminergic medication in PD patients resulted in restored behavioral accuracy for emotional faces relative to controls and decreased retrosplenial cortex BOLD response to emotion relative to off-medication state. Furthermore, cognitive impairment in PD patients was associated with reduced behavioral accuracy for non-emotional stimuli and predicted BOLD response to emotion in the anterior and posterior cingulate cortices, depending on medication status. Findings of aberrant visual and retrosplenial BOLD response to emotion are suggested to stem from altered attentional and/or emotion-driven modulation from subcortical and higher cortical regions. Our results indicate neural disruptions and behavioral deficits in emotion processing in PD patients that are dependent on dopaminergic availability and independent of cognitive function. Our findings highlight the importance of dopaminergic treatment not only for the motor symptoms but also the emotional disturbances in PD., (Copyright © 2019 Elsevier B.V. and ECNP. All rights reserved.)

Purpose: The American College of Obstetricians and Gynecologists (ACOG) proposed seven criteria for expanded carrier screening (ECS) panel design. To ensure that screening for a condition is sufficiently sensitive to identify carriers and reduce residual risk of noncarriers, one criterion requires a per-condition carrier rate greater than 1 in 100. However, it is unestablished whether this threshold corresponds with a loss in clinical detection. The impact of the proposed panel design criteria on at-risk couple detection warrants data-driven evaluation., Methods: Carrier rates and at-risk couple rates were calculated in 56,281 patients who underwent a 176-condition ECS and were evaluated for panels satisfying various criteria. Condition-specific clinical detection rates were estimated via simulation., Results: Different interpretations of the 1-in-100 criterion have variable impact: a compliant panel would include between 3 and 38 conditions, identify 11-81% fewer at-risk couples, and detect 36-79% fewer carriers than a 176-condition panel. If the carrier rate threshold must be exceeded in all ethnicities, ECS panels would lack prevalent conditions like cystic fibrosis. Simulations suggest that the clinical detection rate remains >84% for conditions with carrier rates as low as 1 in 1000., Conclusion: The 1-in-100 criterion limits at-risk couple detection and should be reconsidered.

Objective: To examine the association between hypertensive disorders of pregnancy and third stage placental complications., Methods: A retrospective cohort study based on Soroka Medical Center institutional computerized database. All vaginal deliveries of women between the years 1998-2013 were included. Rates of third placental complications and other adverse pregnancy outcomes were compared between parturients with and without hypertensive disorders of pregnancy. Multivariate analysis models as well as generalized equations models (GEE) controlling for potential confounders were constructed., Results: Of 263,053 deliveries included, 14,754 (5.6%) were complicated by hypertensive disorders of pregnancy. Hypertensive parturients were older, had higher rates of: diabetes, previous cesarean section and induction of labor. Rates of third stage placental complications were significantly higher among hypertensive parturients (4.7% versus 4.0%, p value <0.001). Preeclampsia was found independently associated with third placental complication in the logistic regression and the GEE models constructed. Adjusted odds ratio, 95% confidence interval, respectively: 1.11 (1.00-1.24); 1.11 (1.00-1.25)., Conclusion: Our study was the first to demonstrate that an association between hypertensive disorders of pregnancy and third stage placental complications exists, suggesting a common pathological pathway. Further larger studies are needed in order to reinforce these findings., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Background: Spontaneous abortions are the most common complication of pregnancy. Clotrimazole and miconazole are widely used vaginal-antimycotic agents used for the treatment of vulvovaginal candidiasis. A previous study has suggested an increased risk of miscarriage associated with these azoles, which may lead health professionals to refrain from their use even if clinically indicated., Objective: The aim of the current study was to assess the risk for spontaneous abortions following first trimester exposure to vaginal antimycotics., Study Design: A historical cohort study was conducted including all clinically apparent pregnancies that began from January 2003 through December 2009 and admitted for birth or spontaneous abortion at Soroka Medical Center, Clalit Health Services, Beer-Sheva, Israel. A computerized database of medication dispensation was linked with 2 computerized databases containing information on births and spontaneous abortions. Time-varying Cox regression models were constructed adjusting for mother's age, diabetes mellitus, hypothyroidism, obesity, hypercoagulable or inflammatory conditions, recurrent miscarriages, intrauterine contraceptive device, ethnicity, tobacco use, and the year of admission., Results: A total of 65,457 pregnancies were included in the study: 58,949 (90.1%) ended with birth and 6508 (9.9%) with a spontaneous abortion. Overall, 3246 (5%) pregnancies were exposed to vaginal antimycotic medications until the 20th gestational week: 2712 (4.2%) were exposed to clotrimazole and 633 (1%) to miconazole. Exposure to vaginal antimycotics was not associated with spontaneous abortions as a group (crude hazard ratio, 1.11; 95% confidence interval, 0.96-1.29; adjusted hazard ratio, 1.11; 95% confidence interval, 0.96-1.29) and specifically for clotrimazole (adjusted hazard ratio, 1.05; 95% confidence interval, 0.89-1.25) and miconazole (adjusted hazard ratio, 1.34; 95% confidence interval, 0.99-1.80). Furthermore, no association was found between categories of dosage of vaginal antimycotics and spontaneous abortions., Conclusion: Exposure to vaginal antimycotics was not associated with spontaneous abortions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

One of the major challenges in cancer treatment today is that many patients develop resistance to the therapeutic agents, resulting in treatment failure. Alternative splicing can significantly alter the coding region of drug targets. Here, we highlight several reports that provide key examples of alternative splicing events that occur in various cancers and play a role in resistance to cancer therapy. These examples present prime targets for future study and development of splicing modulation therapy. Modulation of alternative splicing has recently been approved as treatment for several diseases, although not yet for cancer. We propose that a similar approach may be successfully adapted to combat cancer therapy resistance, in cases where alternative splicing is known to be the mechanism that contributes to the resistance., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. The authors have notified the Editor of a serious error in their initial assumptions and, therefore, the overall conclusions presented in this article. The causative mutation is essential for the analysis and, therefore, it is difficult to correct part of the article. Had the Editor been aware of the issues flagged by the authors, the article would not have been accepted for publication. The authors have requested that the article is retracted because their data and conclusions are incorrect, and the Editor has agreed to retract the article., (Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Objective: To examine the recovery from severe Preeclampsia toxemia (PET) in women treated with magnesium sulfate (MgSO 4 ) during the first 24h postpartum as reflected by the changes in various clinical and laboratory markers., Study Design: The study population included all women diagnosed with severe PET that gave birth at the Soroka University Medical center between 2013 and 2014, and were treated with MgSO 4 in the first 24h postpartum. Data were collected from the institutional computerized records. The different parameters were examined in 6h intervals and were compared using appropriate statistical tests., Main Outcomes Measures: Change in various postpartum laboratory and clinical parameters., Results: During the study period there were 132 singleton deliveries with severe PET treated with a 24-hours postpartum MgSO 4 regimen. Most of the women were primigravida and delivered vaginally. Both mean systolic and mean diastolic blood pressure values have shown recovery to normal values after the first 6h of treatment (P<0.001). Urine output and proteinuria have demonstrated later recovery (after 12h)., Conclusions: When assessing the natural recovery of severe PET features, the earliest parameter to recover during the first 24h postpartum is hypertension followed by urine output and the proteinuria. Further larger studies are needed in order to confirm these results. Moreover, the use of these parameters may allow using shorter MgSO 4 treatment regimens for appropriate women showing earlier recovery and facilitating quicker mother-baby bonding and emotional recovery., (Copyright © 2017 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

The emerging technique of real-time fMRI neurofeedback trains individuals to regulate their own brain activity via feedback from an fMRI measure of neural activity. Optimum feedback presentation has yet to be determined, particularly when working with clinical populations. To this end, we compared continuous against intermittent feedback in subjects with tinnitus. Fourteen participants with tinnitus completed the whole experiment consisting of nine runs (3 runs × 3 days). Prior to the neurofeedback, the target region was localized within the auditory cortex using auditory stimulation (1 kHz tone pulsating at 6 Hz) in an ON-OFF block design. During neurofeedback runs, participants received either continuous (n = 7, age 46.84 ± 12.01, Tinnitus Functional Index (TFI) 49.43 ± 15.70) or intermittent feedback (only after the regulation block) (n = 7, age 47.42 ± 12.39, TFI 49.82 ± 20.28). Participants were asked to decrease auditory cortex activity that was presented to them by a moving bar. In the first and the last session, participants also underwent arterial spin labeling (ASL) and resting-state fMRI imaging. We assessed tinnitus severity using the TFI questionnaire before all sessions, directly after all sessions and six weeks after all sessions. We then compared neuroimaging results from neurofeedback using a general linear model (GLM) and region-of-interest analysis as well as behavior measures employing a repeated-measures ANOVA. In addition, we looked at the seed-based connectivity of the auditory cortex using resting-state data and the cerebral blood flow using ASL data. GLM group analysis revealed that a considerable part of the target region within the auditory cortex was significantly deactivated during neurofeedback. When comparing continuous and intermittent feedback groups, the continuous group showed a stronger deactivation of parts of the target region, specifically the secondary auditory cortex. This result was confirmed in the region-of-interest analysis that showed a significant down-regulation effect for the continuous but not the intermittent group. Additionally, continuous feedback led to a slightly stronger effect over time while intermittent feedback showed best results in the first session. Behaviorally, there was no significant effect on the total TFI score, though on a descriptive level TFI scores tended to decrease after all sessions and in the six weeks follow up in the continuous group. Seed-based connectivity with a fixed-effects analysis revealed that functional connectivity increased over sessions in the posterior cingulate cortex, premotor area and part of the insula when looking at all patients while cerebral blood flow did not change significantly over time. Overall, these results show that continuous feedback is suitable for long-term neurofeedback experiments while intermittent feedback presentation promises good results for single session experiments when using the auditory cortex as a target region. In particular, the down-regulation effect is more pronounced in the secondary auditory cortex, which might be more susceptible to voluntary modulation in comparison to a primary sensory region.

Tremulous jaw movements (TJMs) have become a commonly used rat model of Parkinsonian tremor. TJMs can be induced by a number of neurochemical conditions that parallel those seen in human Parkinsonism, including DA depletion, DA antagonism, and cholinomimetic administration, and can be reduced by various antiparkinsonian agents. TJMs typically occur in bursts with the peak frequency in the range of 3-7.5 Hz, which is similar to the Parkinsonian tremor frequency range. While the vast majority of this work has been done using rats, current efforts have focused on extending the TJM model to mice. The aim of the present studies was to establish a mouse model of Parkinsonian resting tremor using the anticholinesterase galantamine, and to investigate the effects of adenosine A2A antagonism on galantamine-induced TJMs. Galantamine significantly induced TJMs in a dose-dependent manner (0.5, 1.0, 1.5, 2.0, 2.5 mg/kg IP). The TJMs tended to occur in bursts in the 3-7.5 Hz frequency range, with a peak frequency of approximately 6 Hz. Systemic administration of the adenosine A2A antagonist MSX-3 (2.5, 5.0, 10.0 mg/kg) significantly attenuated galantamine-induced TJMs. Co-administration of MSX-3 also altered the local frequency of galantamine-induced TJMs, decreasing the peak frequency from approximately 6 Hz to 5 Hz, though the vast majority of TJMs remained in the frequency range characteristic of Parkinsonian resting tremor. These results indicate that adenosine A2A antagonism is capable of reducing anticholinesterase-induced TJMs in mice. Extending the TJM model to mice gives researchers an additional avenue for investigating drug-induced Parkinsonism and tremorogenesis, and could be a useful addition to the study of motor abnormalities observed in mouse genetic models of Parkinsonism., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Ceramides are synthesized by six mammalian ceramide synthases (CerSs), each of which uses fatty acyl-CoAs of different chain lengths for N-acylation of the sphingoid long-chain base. We now describe a rapid and reliable CerS assay that uses a fluorescent N-[6-[(7-nitrobenzo-2-oxa-1,3-diazol-4-yl) (NBD) sphinganine substrate followed by separation of the NBD-lipid substrate and products using solid phase extraction (SPE) C18 chromatography. SPE chromatography is a quick and reliable alternative to TLC, and moreover, there is no degradation of either NBD-sphinganine or NBD-ceramide. We have optimized the assay for use with minimal amounts of protein in a minimal volume. This assay will prove useful for the analysis of CerS activity, which is of particular importance in light of the growing involvement of CerS in cell regulation and in the pathology of human diseases., (Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.)

Background: Recognition of specific individuals is fundamental to mammalian social behavior and is mediated in most mammals by the main and accessory olfactory systems. Both these systems innervate the medial amygdala (MeA), where activity of the neuropeptide oxytocin is thought to mediate social recognition memory (SRM). The specific contribution of the MeA to SRM formation and the specific actions of oxytocin in the MeA are unknown., Methods: We used the social discrimination test to evaluate short-term and long-term SRM in adult Sprague-Dawley male rats (n = 38). The role of protein synthesis in the MeA was investigated by local application of the protein synthesis blocker anisomycin (n = 11). Synaptic plasticity was assessed in vivo by recording the MeA evoked field potential responses to stimulation of the main (n = 21) and accessory (n = 56) olfactory bulbs before and after theta burst stimulation. Intracerebroventricular administration of saline, oxytocin, or oxytocin receptor antagonist was used to measure the effect of oxytocin on synaptic plasticity., Results: Anisomycin application to the MeA prevented the formation of long-term SRM. In addition, the responses of MeA neurons underwent long-term depression (LTD) after theta burst stimulation of the accessory olfactory bulb, but not the main accessory bulb, in an oxytocin-dependent manner. No LTD was found in socially isolated rats, which are known to lack long-term SRM. Finally, accessory olfactory bulb stimulation before SRM acquisition blocked long-term SRM, supporting the involvement of LTD in the MeA in formation of long-term SRM., Conclusions: Our results indicate that long-term SRM in rats involves protein synthesis and oxytocin-dependent LTD in the MeA., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Weekly gemcitabine therapy is the major treatment offered for patients with pancreatic adenocarcinoma cancer; however, relative resistance of tumor cells to chemotherapy, rapid regrowth, and metastasis are the main causes of death within a year. Recently, the daily continuous administration of chemotherapy in low doses--called metronomic chemotherapy (MC)--has been shown to inhibit primary tumor growth and delay metastases in several tumor types; however, its use as a single therapy is still in question due to its moderate therapeutic benefit. Here, we show that the combination of weekly gemcitabine with MC of the same drug delays tumor regrowth and inhibits metastasis in mice implanted orthotopically with pancreatic tumors. We further demonstrate that weekly gemcitabine, but not continuous MC gemcitabine or the combination of the two drug regimens, promotes rebound myeloid-derived suppressor cell (MDSC) mobilization and increases angiogenesis in this tumor model. Furthermore, Bv8 is highly expressed in MDSCs colonizing pancreatic tumors in mice treated with weekly gemcitabine compared to MC gemcitabine or the combination of the two regimens. Blocking Bv8 with antibodies in weekly gemcitabine-treated mice results in a significant reduction in tumor regrowth, angiogenesis, and metastasis. Overall, our results suggest that pro-tumorigenic effects induced by weekly gemcitabine are mediated in part by MDSCs expressing Bv8. Therefore, both Bv8 inhibition and MC can be used as legitimate 'add-on' treatments for preventing post-chemotherapy pancreatic cancer recurrence, progression, and metastasis following weekly gemcitabine therapy., (Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: Epigallocatechin-3-gallate (EGCG), a catechin gallate ester, is the major component of green tea and has been demonstrated to inhibit tumor growth as well as inhibit smooth muscle cell migration. We evaluated the effect of the phytochemicals resveratrol, allicin, sulforaphane (SFN), and EGCG on intimal hyperplasia in the carotid artery injury model., Methods: Intimal hyperplasia was induced in carotid arteries of adult Sprague-Dawley rats with a wire injury. Experimental animals received intraperitoneal injections of one of the four phytochemicals daily beginning 1 day prior to surgery and continued for up to 4 weeks. Control animals were administered saline. Carotid specimens were harvested at 2 weeks and subjected to quantitative image analysis. In addition, EGCG specimens were analyzed for cell proliferation, immunohistochemistry, and Western blot analysis., Results: Quantitative image analysis showed significant phytochemical suppression of intimal hyperplasia at 2 and 4 weeks postoperatively with EGCG (62% decrease in intimal area). Significant decreases were also noted at 2 weeks for SFN (56%) and resveratrol (44%), whereas the decrease with allicin (24%) was not significant. Quantification of intimal hyperplasia by intima:media ratio showed similar results. Cell proliferation assay of specimens demonstrated suppression by EGCG. Immunohistochemical staining of EGCG-treated specimens showed extracellular signal-regulated kinase (ERK) suppression but not of the c-jun N-terminal kinase or p38 pathways. Western blot analysis confirmed reduced ERK activation in arteries treated with EGCG., Conclusions: Intraperitoneal injection of the phytochemicals EGCG, SFN, resveratrol, and allicin have suppressive effects on the development of intimal hyperplasia in the carotid artery injury model, with maximal effect due to EGCG. The mechanism of EGCG action may be due to inhibition of ERK activation. EGCG may affect a common pathway underlying either neoplastic cellular growth or vascular smooth muscle cellular proliferation., (Copyright © 2013 Society for Vascular Surgery. All rights reserved.)

The barrier function of the human epidermis is supposed to be governed by lipid composition and organization in the stratum corneum. Disorders of keratinization, namely ichthyoses, are typically associated with disturbed barrier activity. Using autozygosity mapping and exome sequencing, we have identified a homozygous missense mutation in CERS3 in patients with congenital ichthyosis characterized by collodion membranes at birth, generalized scaling of the skin, and mild erythroderma. We demonstrate that the mutation inactivates ceramide synthase 3 (CerS3), which is synthesized in skin and testis, in an assay of N-acylation with C26-CoA, both in patient keratinocytes and using recombinant mutant proteins. Moreover, we show a specific loss of ceramides with very long acyl chains from C26 up to C34 in terminally differentiating patient keratinocytes, which is in line with findings from a recent CerS3-deficient mouse model. Analysis of reconstructed patient skin reveals disturbance of epidermal differentiation with an earlier maturation and an impairment of epidermal barrier function. Our findings demonstrate that synthesis of very long chain ceramides by CerS3 is a crucial early step for the skin barrier formation and link disorders presenting with congenital ichthyosis to defects in sphingolipid metabolism and the epidermal lipid architecture.

Though potentially linked to the basic physiology of stress response we still have no clear understanding of Gulf War Illness (GWI), a debilitating illness presenting with a complex constellation of immune, endocrine and neurological symptoms. Here we compared male GWI (n=20) with healthy veterans (n=22) and subjects with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) (n=7). Blood was drawn during a Graded eXercise Test (GXT) prior to exercise, at peak effort (VO2 max) and 4-h post exercise. Affymetrix HG U133 plus 2.0 microarray gene expression profiling in peripheral blood mononuclear cells (PBMCs) was used to estimate activation of over 500 documented pathways. This was cast against ELISA-based measurement of 16 cytokines in plasma and flow cytometric assessment of lymphocyte populations and cytotoxicity. A 2-way ANOVA corrected for multiple comparisons (q statistic <0.05) indicated significant increases in neuroendocrine-immune signaling and inflammatory activity in GWI, with decreased apoptotic signaling. Conversely, cell cycle progression and immune signaling were broadly subdued in CFS. Partial correlation networks linking pathways with symptom severity via changes in immune cell abundance, function and signaling were constructed. Central to these were changes in IL-10 and CD2+ cell abundance and their link to two pathway clusters. The first consisted of pathways supporting neuronal development and migration whereas the second was related to androgen-mediated activation of NF-κB. These exploratory results suggest an over-expression of known exercise response mechanisms as well as illness-specific changes that may involve an overlapping stress-potentiated neuro-inflammatory response., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Understanding the process of myeloid differentiation offers important insights into both normal and abnormal developmental processes but is limited by the dearth of experimental models. Here we show that myeloid progenitors can be derived from embryonic stem cells, immortalized, and applied to the study of the mechanisms underlying myeloid differentiation. The embryonic stem cell-derived myeloid progenitors, when immortalized with estrogen-regulated Hoxb8 protein, demonstrate normal karyotyping, are genetically tractable, and can be differentiated into functional neutrophils. Using this model, we identified mammalian target of rapamycin complex 1 as a critical regulator of myeloid differentiation. Together, our studies led to a convenient, karyotypically normal, and genetically manipulatable cellular system, which can be used to shed new light on the mechanisms for myeloid differentiation.