Temporal trends and predictors of gestational exposure to organophosphate ester flame retardants and plasticizers.

BACKGROUND: Organophosphate esters (OPEs), used as flame retardants and plasticizers, are chemicals of concern for maternal and infant health. Prior studies examining temporal trends and predictors of OPE exposure are primarily limited by small sample sizes. OBJECTIVES: Characterize temporal trends and predictors of OPE exposure biomarkers. METHODS: We determined urinary concentrations of eight biomarkers of OPE exposure at three timepoints during pregnancy for participants in the LIFECODES Fetal Growth Study (n = 900), a nested case-cohort recruited between 2007 and 2018. We examined biomarker concentrations, their variability during pregnancy, and temporal trends over the study period. In addition, we identified sociodemographic and pregnancy characteristics associated with biomarker concentrations. Analyses were conducted using both the within-subject pregnancy geometric means and biomarker concentrations measured at individual study visits. RESULTS: Five OPE biomarkers were detected in at least 60% of the study participants. Biomarkers were not strongly correlated with one another and intraclass correlation coefficients, measuring within-subject variability during pregnancy, ranged from 0.27 to 0.51. Biomarkers exhibited varying temporal trends across study years. For example, bis(1-chloro-2-propyl) phosphate (BCIPP) increased monotonically, whereas bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and diphenyl phosphate (DPHP), displayed non-monotonic trends with concentrations that peaked between 2011 and 2014. We observed associations between sociodemographic characteristics and OPE biomarkers. In general, concentrations of most OPE biomarkers were higher among participants from racial and ethnic minority populations, participants who were younger, had higher pre-pregnancy body mass index (BMI), and less than a college degree. We observed consistent results using either averaged or visit-specific biomarker concentrations. SIGNIFICANCE: We observed widespread exposure to several OPEs and OPE biomarkers displayed varying temporal trends in pregnant people from 2007 to 2018. Concentrations of most OPE biomarkers varied according to sociodemographic factors, suggesting higher burdens of exposure among participants with higher pre-pregnancy BMI, those belonging to racial and ethnic minority populations, and lower educational attainment.

Neuro-psychiatric symptoms in directly and indirectly blast exposed civilian survivors of urban missile attacks.

BACKGROUND: Blast-explosion may cause traumatic brain injury (TBI), leading to post-concussion syndrome (PCS). In studies on military personnel, PCS symptoms are highly similar to those occurring in post-traumatic stress disorder (PTSD), questioning the overlap between these syndromes. In the current study we assessed PCS and PTSD in civilians following exposure to rocket attacks. We hypothesized that PCS symptomatology and brain connectivity will be associated with the objective physical exposure, while PTSD symptomatology will be associated with the subjective mental experience. METHODS: Two hundred eighty nine residents of explosion sites have participated in the current study. Participants completed self-report of PCS and PTSD. The association between objective and subjective factors of blast and clinical outcomes was assessed using multivariate analysis. White-matter (WM) alterations and cognitive abilities were assessed in a sub-group of participants (n = 46) and non-exposed controls (n = 16). Non-parametric analysis was used to compare connectivity and cognition between the groups. RESULTS: Blast-exposed individuals reported higher PTSD and PCS symptomatology. Among exposed individuals, those who were directly exposed to blast, reported higher levels of subjective feeling of danger and presented WM hypoconnectivity. Cognitive abilities did not differ between groups. Several risk factors for the development of PCS and PTSD were identified. CONCLUSIONS: Civilians exposed to blast present higher PCS/PTSD symptomatology as well as WM hypoconnectivity. Although symptoms are sub-clinical, they might lead to the future development of a full-blown syndrome and should be considered carefully. The similarities between PCS and PTSD suggest that despite the different etiology, namely, the physical trauma in PCS and the emotional trauma in PTSD, these are not distinct syndromes, but rather represent a combined biopsychological disorder with a wide spectrum of behavioral, emotional, cognitive and neurological symptoms.

Impact of COVID-19 on clinical outcomes of robotic inguinal hernia repair.

PURPOSE: To investigate the impact of the COVID-19 pandemic on the clinical impact of the clinical outcomes of robotic inguinal hernia repair. METHODS: Patients who underwent RIHR 2 years before and after March 10, 2020, were included in this retrospective study and assigned accordingly to the pre- or post-COVID group. Pre-, intra-, and postoperative variables including patients' demographics, hernia characteristics, complications, and hernia recurrence rates were compared between groups. RESULTS: 183 (94.5% male) and 141 (96.4% male) patients were assigned to the pre- and post-COVID groups, respectively. Patient demographics and medical comorbidities did not differ between groups. Operative time was approximately 40 min longer in the post-COVID group (p < 0.001) with higher rates of bilateral IHR (pre-COVID: 30.1% vs. post-COVID: 46.4%, p = 0.003). Mesh material differed between groups with predominance of polyester mesh in the pre-COVID group vs. polypropylene in the post-COVID one. Median hospital length of stay (LOS) was 0 days in both groups, and same-day discharge rates were 93.4% pre-pandemic and 92.8% post-pandemic (p = 0.09). There were no pulmonary complications recorded in either group or no cases of COVID-19 detected within two weeks postoperatively in the post-COVID group. Seromas were more frequent in the post-COVID group (pre-COVID: 2 vs. post-COVID: 8, p = 0.018) and no hernia recurrences were recorded. CONCLUSION: This is the first study to describe the impact of COVID-19 on RIHR. Clinical outcomes and hernia-specific complications were not impacted by the COVID-19 pandemic.

Outcomes during delivery hospitalisations with inflammatory bowel disease.

OBJECTIVE: To characterise inflammatory bowel disease (IBD) trends and associated risk during delivery hospitalisations. DESIGN: Cross-sectional. SETTING: US delivery hospitalisations. POPULATION: Delivery hospitalisations in the 2000-2018 National Inpatient Sample. METHODS: This study analysed a nationally representative hospital discharge database based on the presence of IBD. Temporal trends in IBD were analysed using joinpoint regression to estimate the average annual percent change (AAPC). IBD severity was characterised by the presence of diagnoses such as penetrating and stricturing disease and history of bowel resection. Risks for adverse outcomes were analysed based on presence of IBD. Poisson regression models were performed with unadjusted and adjusted risk ratios (aRR) as measures of effect. MAIN OUTCOME MEASURE: Prevalence of IBD and associated adverse outcomes. RESULTS: Of 73 109 790 delivery hospitalisations, 89 965 had a diagnosis of IBD. IBD rose from 0.06% in 2000 to 0.21% in 2018 (AAPC 7.3%, 95% CI 6.7-7.9%). Among deliveries with IBD, IBD severity diagnoses increased from 4.1% to 8.1% from 2000 to 2018. In adjusted analysis, IBD was associated with increased risk for preterm delivery (aRR 1.50, 95% CI 1.47-1.53), severe maternal morbidity (aRR 1.93, 95% CI 1.83-2.04), venous thrombo-embolism (aRR 2.76, 95% CI 2.39-3.18) and surgical injury during caesarean delivery hospitalisation (aRR 5.03, 95% CI 4.76-5.31). In the presence of a severe IBD diagnosis, risk was further increased for all adverse outcomes. CONCLUSION: IBD is increasing in the obstetric population and is associated with adverse outcomes. Risk is increased in the presence of a severe IBD diagnosis. TWEETABLE ABSTRACT: Deliveries among women with inflammatory bowel disease are increasing. Disease severity is associated with adverse outcomes.

Population risk factors for nulliparous, term, singleton, vertex caesarean birth: a national cross-sectional study.

OBJECTIVE: To characterise medical, obstetric and demographic risk factors associated with nulliparous, term, singleton, vertex (NTSV) caesarean birth. STUDY DESIGN: Cross-sectional study. SETTING: United States delivery hospitalisations. POPULATION: NTSV births in 2016-18 US natality data. METHODS: This study analysed a national sample of natality data generated by the United States National Vital Statistics System. NTSV deliveries were identified. The primary outcome was caesarean birth. Risk factors including maternal age, body mass index (BMI) and pregestational diabetes were analysed. Multivariable log-linear regression models analysed factors associated with NTSV caesarean with adjusted risk ratios (aRR) as measures of effect. RESULTS: Of 11 622 400 deliveries, 3 764 707 met NTSV criteria, and their caesarean section rate was 25.9%. Maternal age 35-39 years (aRR 1.51, 95% CI 1.50-1.52) and 40-54 years (aRR 2.03, 95% 2.00-2.05) compared with age 19-34 years; BMI 25 to <30 kg/m2 (aRR 1.32, 95% CI 1.31-1.33), 30 to <35 kg/m2 (aRR 1.57 95% CI 1.56-1.58), 35 to <40 kg/m2 (aRR 1.82, 95% CI 1.80-1.83) and ≥40 kg/m2 (aRR 2.17, 95% CI 2.15-2.19) compared with BMI 18.5-24.9 kg/m2; and pregestational diabetes (aRR 1.54, 95% CI 1.51-1.57) were all associated with increased risk. Risk factors allowed stratification of patients into high-risk versus low-risk groups. The NTSV caesarean rate was 37.9% in women who had one or more of the following characteristics: age ≥35 years, BMI ≥30 kg/m2 or pregestational diabetes. In comparison, the NTSV caesarean rate was 20.8% among women without any of these three risk factors (P < 0.01). CONCLUSION: Among NTSV births, BMI, maternal age and medical conditions are important risk factors for caesarean delivery.

The potential role of microvascular pathology in the neurological manifestations of coronavirus infection.

Human coronaviruses are highly pathogenic viruses that pose a serious threat to human health. Examples include the severe acute respiratory syndrome outbreak of 2003 (SARS-CoV-1), the Middle East Respiratory Syndrome (MERS-CoV) outbreak of 2012, and the current SARS-CoV-2 (COVID-19) pandemic. Herein, we review the neurological manifestations of coronaviruses and discuss the potential pathogenic role of blood-brain barrier dysfunction. We present the hypothesis that pre-existing vascular damage (due to aging, cardiovascular disease, diabetes, hypertension or other conditions) facilitates infiltration of the virus into the central nervous system (CNS), increasing neuro-inflammation and the likelihood of neurological symptoms. We also discuss the role of a neuroinflammatory cytokine profile in both blood-brain barrier dysfunction and macrovascular disease (e.g. ischemic stroke and thromboembolism). Future studies are needed to better understand the involvement of the microvasculature in coronavirus neuropathology, and to test the diagnostic potential of minimally-invasive screening tools (e.g. serum biomarkers, fluorescein retinal angiography and dynamic-contrast MRI).

Correction to: Modulation of the cAMP Response by G[Formula: see text] and G[Formula: see text]: A Computational Study of G Protein Signaling in Immune Cells.

The original version of this article unfortunately contained mistakes.

Sildenafil Protects Endothelial Cells From Radiation-Induced Oxidative Stress.

INTRODUCTION: The etiology of radiation-induced erectile dysfunction (ED) is complex and multifactorial, and it appears to be mainly atherogenic. AIM: To focus on vascular aspects of radiation-induced ED and to elucidate whether the protective effects of sildenafil are mediated by attenuation of oxidative stress and apoptosis in the endothelial cells. METHODS: Bovine aortic endothelial cells (BAECs), with or without pretreatment of sildenafil (5 µM at 5 minutes before radiation), were used to test endothelial dysfunction in response to external beam radiation at 10-15 Gy. Generation of reactive oxygen species (ROS) was studied. Extracellular hydrogen peroxide (H2O2) was measured using the Amplex Red assay and intracellular H2O2 using a fluorescent sensor. In addition, ROS superoxide (O2•-) was measured using a O2•- chemiluminescence enhancer. Both H2O2 and O2•- are known to reduce the bioavailability of nitric oxide, which is the most significant chemical mediator of penile erection. Generation of cellular peroxynitrite (ONOO-) was measured using a chemiluminescence assay with the PNCL probe. Subsequently, we measured the activation of acid sphingomyelinase (ASMase) enzyme by radioenzymatic assay using [14C-methylcholine] sphingomyelin as substrate, and the generation of the proapoptotic C16-ceramide was assessed using the diacylglycerol kinase assay. Endothelial cells apoptosis was measured as a readout of these cells' dysfunction. MAIN OUTCOME MEASURES: Single high-dose radiation therapy induced NADPH oxidases (NOXs) activation and ROS generation via the proapoptotic ASMase/ceramide pathway. The radio-protective effect of sildenafil on BAECs was due to inhibition of this pathway. RESULTS: Here, we demonstrate for the first time that radiation activated NOXs and induced generation of ROS in BAECs. In addition, we showed that sildenafil significantly reduced radiation-induced O2•- and as a result there was reduction in the generation of peroxynitrite in these cells. Subsequently, sildenafil protected the endothelial cells from radiation therapy-induced apoptosis. STRENGTHS AND LIMITATIONS: This is the first study demonstrating that single high-dose radiation therapy induced NOXs activation, resulting in the generation of O2•- and peroxynitrite in endothelial cells. Sildenafil reduced ROS generation by inhibiting the ASMase/ceramide pathway. These studies should be followed in an animal model of ED. CONCLUSIONS: This study demonstrated that sildenafil protects BAECs from radiation-induced oxidative stress by reducing NOX-induced ROS generation, thus resulting in decreased endothelial dysfunction. Therefore, it provides a potential mechanism to better understand the atherogenic etiology of postradiation ED. Wortel RC, Mizrachi A, Li H, et al. Sildenafil Protects Endothelial Cells From Radiation-Induced Oxidative Stress. J Sex Med 2019;16:1721-1733.

Design and testing of a system for measuring high-frequency AC losses in superconducting wires and coils carrying DC and AC currents.

Development of high-power superconducting applications requires the accurate estimation of AC losses in the superconductor. In applications such as superconducting magnetic energy storage, the charge/discharge/persistent switching frequency of the coil, resulting from pulse width modulation control algorithms, is usually in the kilohertz regime. Therefore, a thorough investigation of the losses in the kilohertz regime of AC currents superimposed on large DC currents is essential in order to ensure the device stable operation at a predefined temperature. We describe here a unique experimental setup designed and built for characterizing AC losses in superconducting wires and coils under such special conditions. To minimize the eddy currents induced in the apparatus, a cryostat vacuum vessel was made of Delrin, an insulating synthetic polymer. The measurement setup allows driving DC currents up to 150 A and superimposed AC currents with amplitudes up to 10 Arms and frequencies up to 18 kHz. The system utilizes conduction cooling to reach a wide range of temperatures between 6 and 100 K and allows measurements of 10 cm long superconducting wires and coils with a diameter of 40 cm. The loss is measured by the electrical method, i.e., by direct voltage and current waveform measurement, achieving a resolution better than 100 nW. The system described here will assist in developing superconducting wires and coils for high-power applications.

Spaced training improves learning in Ts65Dn and Ube3a mouse models of intellectual disabilities.

Benefits of distributed learning strategies have been extensively described in the human literature, but minimally investigated in intellectual disability syndromes. We tested the hypothesis that training trials spaced apart in time could improve learning in two distinct genetic mouse models of neurodevelopmental disorders characterized by intellectual impairments. As compared to training with massed trials, spaced training significantly improved learning in both the Ts65Dn trisomy mouse model of Down syndrome and the maternally inherited Ube3a mutant mouse model of Angelman syndrome. Spacing the training trials at 1 h intervals accelerated acquisition of three cognitive tasks by Ts65Dn mice: (1) object location memory, (2) novel object recognition, (3) water maze spatial learning. Further, (4) spaced training improved water maze spatial learning by Ube3a mice. In contrast, (5) cerebellar-mediated rotarod motor learning was not improved by spaced training. Corroborations in three assays, conducted in two model systems, replicated within and across two laboratories, confirm the strength of the findings. Our results indicate strong translational relevance of a behavioral intervention strategy for improving the standard of care in treating the learning difficulties that are characteristic and clinically intractable features of many neurodevelopmental disorders.

Impact of timing of delivery on maternal and neonatal outcomes for women after three previous caesarean deliveries; a secondary analysis of the caesarean section registry.

BACKGROUND: As more women are presenting with three previous caesarean deliveries (CD), providers may suggest early term delivery as a means to avoid the risk of spontaneous labour and associated maternal morbidity. OBJECTIVE: To determine whether early term delivery is associated with lower maternal and neonatal morbidity for women with three previous CD. STUDY DESIGN: Secondary analysis of a prospective registry of CD at 19 US academic centres from 1999 to 2002. POPULATION: Women with three previous CD undergoing scheduled or emergent delivery with live, singleton gestations 37-41+ weeks of gestation were included. Women with non-low transverse incisions, antepartum stillbirth, previous myomectomy, fetal anomalies, more or fewer than three previous CD or attempting trial of labour after caesarean section were excluded. METHODS: Gestational age was categorised by week. We fitted logistic regression models to adjust for clinically relevant or statistically significant confounders. MAIN OUTCOME MEASURES: The primary and secondary outcomes were composites, respectively, of maternal and neonatal morbidity. RESULTS: In all, 821 women met the inclusion criteria; maternal morbidity composite occurred in 9.86% and neonatal morbidity occurred in 10.5%. After adjusting for confounding variables, maternal and neonatal morbidity occurred least frequently at 39 weeks. CONCLUSIONS: In women with three previous CDs, adverse maternal outcomes do not increase with increasing gestational age beyond 37 weeks but early term elective repeat CDs are associated with higher neonatal morbidity. Elective delivery of women with three previous CD at 39 weeks of gestation is safe in the absence of maternal or fetal indications for early term delivery. TWEETABLE ABSTRACT: Delivery of women with three previous caesarean deliveries at 39 weeks, in the absence of maternal or fetal indications for early term delivery, is associated with decreased maternal morbidity.

Design and implementation of a Thomson parabola for fluence dependent energy-loss measurements at the Neutralized Drift Compression eXperiment.

The interaction of ion beams with matter includes the investigation of the basic principles of ion stopping in heated materials. An unsolved question is the effect of different, especially higher, ion beam fluences on ion stopping in solid targets. This is relevant in applications such as in fusion sciences. To address this question, a Thomson parabola was built for the Neutralized Drift Compression eXperiment (NDCX-II) for ion energy-loss measurements at different ion beam fluences. The linear induction accelerator NDCX-II delivers 2 ns short, intense ion pulses, up to several tens of nC/pulse, or 1010-1011 ions, with a peak kinetic energy of ∼1.1 MeV and a minimal spot size of 2 mm FWHM. For this particular accelerator, the energy determination with conventional beam diagnostics, for example, time of flight measurements, is imprecise due to the non-trivial longitudinal phase space of the beam. In contrast, a Thomson parabola is well suited to reliably determine the beam energy distribution. The Thomson parabola differentiates charged particles by energy and charge-to-mass ratio, through deflection of charged particles by electric and magnetic fields. During first proof-of-principle experiments, we achieved to reproduce the average initial helium beam energy as predicted by computer simulations with a deviation of only 1.4%. Successful energy-loss measurements with 1 µm thick silicon nitride foils show the suitability of the accelerator for such experiments. The initial ion energy was determined during a primary measurement without a target, while a second measurement, incorporating the target, was used to determine the transmitted energy. The energy-loss was then determined as the difference between the two energies.

Higher serum levels of pro-hepcidin in patients with Parkinson's disease treated with deep brain stimulation.

Hepcidin is an essential hormone responsible for the systemic metabolism of iron and simultaneously belongs to the family of the protein mediators of the acute inflammatory response, primarily induced in response to interleukin 6. It can therefore be regarded as a link between the oxidative stress processes, where iron plays an important role, and the processes of neuroinflammation - both considered to be responsible for the neurodegeneration in Parkinson's disease. We assessed the serum level of pro-hepcidin in patients with Parkinson's disease treated only pharmacologically and those treated additionally with deep brain stimulation (DBS) as compared to the control group. Thirty-seven patients with Parkinson's disease (18 females, 19 males, mean age: 57 years) were treated only pharmacologically with optimal, individualized therapy for each patient, whereas 15 (7 females, 8 males, mean age: 54 years) were treated additionally with DBS. The control group consisted of 31 healthy volunteers (15 females, 16 males, mean age: 58 years). In the subgroup of patients with Parkinson's disease treated with DBS the serum concentration of pro-hepcidin was significantly higher and the result was statistically significantly higher than in the control group (p = 0.0003) and in patients with Parkinson's disease treated only pharmacologically (p = 0.025). The results suggested the possible immunomodulatory effect of prolonged high-frequency stimulation and the implantation of the electrodes into the brain tissue of the host, most likely in the form of the increasaed production of inflammatory mediators, associated with the activation of the astroglia and microglia. The rational justification for the purpose of our study was the evidences and hypothesis from studies on the potential immunomodulatory and neuroprotective effect of DBS in patients with Parkinson's disease, the systemic influence of the DBS procedure on the improvement of motor function, reduction of dopaminergic drugs, improvement of the quality of life of patients, and animal studies, which have proven the presence of regional neuroinflammation around implanted electrodes.

Randomised clinical trial: efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study).

BACKGROUND: Thiopurine hypermethylation towards 6-methylmercaptopurine (6MMP) instead of 6-thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation. AIMS: To prospectively determine efficacy of allopurinol-thiopurine combination and to compare 2 doses of allopurinol. DESIGN: In a multicentre, double-blind trial, patients with clinically active or steroid-dependent IBD and thiopurine shunting were randomised to 50 or 100 mg/d allopurinol and 25% of their screening thiopurine dose, which was subsequently optimised, aiming for 6TGN of 260-500 pmol/8x108 RBCs. The primary endpoint was steroid-free clinical remission at 24 weeks. RESULTS: Of 73 patients, 39 (53% [95% CI 42-65]) achieved steroid-free remission, (54% with 50 mg/d and 53% with 100 mg/d). 81% were able to discontinue steroids. Therapeutic 6TGN levels were achieved in both groups. Final thiopurine doses were lower with 100 mg/d allopurinol (P < 0.005). 6MMP: 6TGN ratio decreased from mean 64 to 4 (P < 0.001), being higher with 50 mg/d (6 ± 1.83) than for 100 mg/d ([1 ± 0.16], P = 0.003). Three patients on 50 mg/d failed to sustain low ratios at 24 weeks. Toxicity was minimal; three patients on 50 mg/d allopurinol developed transient leukopenia. Alanine aminotransferase concentrations decreased (P < 0.001) similarly in both arms. Faecal calprotectin levels at study end were lower in patients who achieved the primary endpoint (median 171 [85-541] vs 821[110-5892] ug/g, P = 0.03). CONCLUSIONS: Low-dose allopurinol-thiopurine combination safely reverses shunting and optimises 6TGN with associated improvement in disease activity. 100 mg/d allopurinol is preferable due to greater metabolite profile stability and lower thiopurine dose without additional toxicity.