Assessment of an AI-based tool for population-wide collection of placental morphological data.

OBJECTIVES: Automated placental assessment could allow accurate and timely morphological/pathological measurements at scale. We undertook a pilot study using an artificial intelligence-based assessment system (AI-PLAX) to ascertain the potential of a state-wide rollout as part of Generation Victoria, assessing the impact of time post-delivery, user, and technology used for image capture, on a range of derived placental data. STUDY DESIGN: Ten placentas were imaged by three different users and imaging technologies (iPad, iPhone, Samsung) at (0 h), 24 h, and 48 h post-delivery. Using AI-PLAX, disc size (short and long length, perimeter, area), shape (normal, abnormal), cord insertion type (central, eccentric), cord coiling, abruption (retroplacental hematoma), and meconium staining were determined. RESULTS: When analysing the maternal surface of the placenta, time in cold storage post-delivery had modest effects on placental dimensions, with decreases in the short length (24-48 h: -3.7 %), disc area (0-24 h: 4.7 % and 0-48 h: -7.4 %), and perimeter (0-48 h: -3.8 %) observed. There was marginal impact on placental dimensions when the placenta was imaged by different users, including long length (+1.9 %), disc area (+2.9 %), and perimeter (+2.0 %). Measures of placental size were not impacted by the type of technology used to capture the images. When analysing the fetal surface of the placenta, more variance in placental size measures were observed between users. Abruption detection was not affected by any parameter. Time between delivery and imaging impacted apparent meconium staining - likely reflecting changes in fetal surface colour over time. Meconium staining was not affected by technology or user. CONCLUSIONS: This study supports the feasibility of the collection of placenta images for later morphological analysis by AI-PLAX, with measures obtained minimally influenced by time in cold storage, user imaging the placenta, or technology to capture the images.

Health care access, psychosocial outcomes and mental health in adults living with epilepsy during the COVID-19 pandemic.

PURPOSE: People living with epilepsy (PLWE) have a higher prevalence of mental health comorbidities and poorer psychosocial outcomes compared to the general population. The aim of this study was to examine psychosocial outcomes, mental health, healthcare accessibility, and seizure burden in PLWE during the COVID-19 pandemic. METHODS: We conducted a cross-sectional study of adults with epilepsy treated in an urban multicenter health system from 2021 to 2022. A standardized questionnaire assessed for COVID-19 history, comorbidities, access to antiseizure medications (ASMs) and neurological care, seizure burden, and psychosocial outcomes (e.g., employment, social and financial support). The Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) were administered to evaluate for depression and anxiety. Frequency and proportions for categorical variables and median and interquartile ranges for continuous variables were calculated. RESULTS: Fifty-five PLWE participated (95 % response rate). Median age was 40 years (IQR 31.5-66.5), 61.8 % were women, 47.3 % had a bachelor's degree or higher and 29.1 % each had Medicaid and Medicare insurance. Race (from highest to lowest %) was: 32.7 % White, 20 % Black, 20 % Latinx, 14.5 % Asian, and 12.7 % selected "other" or "prefer not to say." COVID-19 had been diagnosed in 21.8 % of participants. Symptoms of anxiety and depression were self-reported by 43.6 % and 34.5 % of patients, respectively, with many describing this symptom as new post-pandemic (37.5 % and 31.6 %, respectively). Using validated scales, 52.7 % had depression (PHQ-9 score ≥ 5) with 30.9 % having moderate/severe depression (PHQ-9 score ≥ 10), while 29.1 % had probable generalized anxiety disorder (GAD-7 score ≥ 8). Seizure burden increased in 21.8 % of participants, while 20 % reported fewer seizures and 29.1 % were seizure free since the COVID-19 pandemic. Economic impacts of the pandemic included job loss (25 % amongst those employed at onset of pandemic), new or worsened financial difficulties (40 %), and new or worsened social support issues (30.9 %). Of all participants, 18.2 % reported difficulties accessing ASMs and 25.5 % cancelled visits, but of those with cancelled visits, 78.6 % had their appointments rescheduled as a telehealth visit. CONCLUSION: Our cohort of PLWE experienced some challenges during the COVID-19 pandemic including poorer mental health and financial and employment-related stressors. Encouragingly, healthcare access was relatively spared during the COVID-19 crisis, with some patients even reporting a reduction in seizure burden. However, PLWE require ongoing psychosocial support with particular attention to decompensation of mental health and social stressors that may be exacerbated by the COVID-19 pandemic.

Distinct and shared genetic architectures of Gestational diabetes mellitus and Type 2 Diabetes Mellitus.

Gestational diabetes mellitus (GDM) affects more than 16 million pregnancies annually worldwide and is related to an increased lifetime risk of Type 2 diabetes (T2D). The diseases are hypothesized to share a genetic predisposition, but there are few GWAS studies of GDM and none of them is sufficiently powered to assess whether any variants or biological pathways are specific to GDM. We conducted the largest genome-wide association study of GDM to date in 12,332 cases and 131,109 parous female controls in the FinnGen Study and identified 13 GDM-associated loci including 8 novel loci. Genetic features distinct from T2D were identified both at the locus and genomic scale. Our results suggest that the genetics of GDM risk falls into two distinct categories - one part conventional T2D polygenic risk and one part predominantly influencing mechanisms disrupted in pregnancy. Loci with GDM-predominant effects map to genes related to islet cells, central glucose homeostasis, steroidogenesis, and placental expression. These results pave the way for an improved biological understanding of GDM pathophysiology and its role in the development and course of T2D.

A Prospective Study to Examine Responsiveness and Minimally Important Differences (MIDs) for the CLEFT-Q Scales Following Three Cleft-Specific Operations.

The aim of this study was to examine internal responsiveness and estimate minimally important differences (MIDs) for CLEFT-Q scales.In this prospective cohort study, participants completed the CLEFT-Q appearance and health-related quality of life (HRQL) scales before and six months after cleft-related surgery.Seven cleft centres in Canada, USA and UK participated.Patients were ages 8-29 years with CL/P.Patients underwent rhinoplasty, orthognathic or cleft lip scar revision surgery.Internal responsiveness was examined using Cohen's d effect sizes (ESs) based on the following interpretation: 0.20-0.49 small, 0.50-0.79 moderate and ≥ 0.80 large. MIDs were estimated using two distribution-based approaches.Participants had a rhinoplasty (n = 31), orthognathic (n = 21) or cleft lip scar revision (n = 18) surgery. Most participants were males (56%) and aged 8-11 years (41%). Following rhinoplasty, ESs were larger for the nose (0.92, p = 0.001) and nostrils (0.94, p < 0.001) scales than for the face scale (0.51, p = 0.003). MIDs ranged between 6.2-10.4. For orthognathic surgery, larger ES was observed for the jaws scale (1.80, p < 0.001) compared with the teeth (1.16, p < 0.001), face (1.15, p = 0.001) and lips (0.94, p < 0.001) scales. MIDs ranged between 5.9-14.4. In the cleft lip scar revision sample, the largest ES was observed for the nose scale (0.76, p = 0.03), followed by lips (0.58, p = 0.009) and cleft lip scar (0.50, p = 0.043) scales. MIDs ranged between 6.4-12.3.CLEFT-Q detected change in key outcomes for three cleft-specific surgeries, providing evidence of its responsiveness. Estimated MIDs will aid in interpreting this PROM.

Multi-Instrument Characterization of Magnetospheric Cold Plasma Dynamics in the June 22, 2015 Geomagnetic Storm.

We present a comparison of magnetospheric plasma mass/electron density observations during an 11-day interval which includes the geomagnetic storm of June 22, 2015. For this study we used: Equatorial plasma mass density derived from geomagnetic field line resonances (FLRs) detected by Van Allen Probes and at the ground-based magnetometer networks EMMA and CARISMA; in situ electron density inferred by the Neural-network-based Upper hybrid Resonance Determination algorithm applied to plasma wave Van Allen Probes measurements. The combined observations at L ∼ 4, MLT ∼ 16 of the two longitudinally separated magnetometer networks show a temporal pattern very similar to that of the in situ observations: A density decrease by an order of magnitude about 1 day after the Dst minimum, a partial recovery a few hours later, and a new strong decrease soon after. The observations are consistent with the position of the measurement points with respect to the plasmasphere boundary as derived by a plasmapause test particle simulation. A comparison between plasma mass densities derived from ground and in situ FLR observations during favorable conjunctions shows a good agreement. We find however, for L < âˆ¼3, the spacecraft measurements to be higher than the corresponding ground observations with increasing deviation with decreasing L, which might be related to the rapid outbound spacecraft motion in that region. A statistical analysis of the average ion mass using simultaneous spacecraft measurements of mass and electron density indicates values close to 1 amu in plasmasphere and higher values (∼2-3 amu) in plasmatrough.

Partnering with survivors & families to determine research priorities for adult out-of-hospital cardiac arrest: A James Lind Alliance Priority Setting Partnership.

BACKGROUND: Research priority setting in health care has historically been done by expert health care providers and researchers and has not involved patients, family or the public. Survivors & family members have been particularly absent from this process in the field of resuscitation research and specifically adult out of hospital cardiac arrest (OHCA). As such, we sought to conduct a priority setting exercise in partnership with survivors, lay responders and their families in order to ensure that their priorities were visible. We partnered with the James Lind Alliance (UK) and used their commonly used consensus methodology for Public Priority Setting Partnerships (PSPs) to identify research priorities that reflected the perspectives of all stakeholders. METHODS: We used two rounds of public and health care professional surveys to create the initial priority lists. The initial survey collected open-ended questions while the second round consolidated the list of initial questions into a refined list for prioritization. This was done by reviewing existing evidence and thematic categorization by the multi-disciplinary steering committee. An in-person consensus workshop was conducted to come to consensus on the top ten priorities from all perspectives. The McMaster PPEET tool was used to measure engagement. RESULTS: The initial survey yielded more than 425 responses and 1450 "questions" from survivors and family members (18%), lay responders, health care providers and others. The second survey asked participants to rank a short list of 125 questions. The final top 25 questions were brought to the in-person meeting, and a top ten were selected through the JLA consensus process. The final list of top ten questions included how to improve the rate of lay responder CPR, what interventions used at the scene of an arrest can improve resuscitation and survival, how survival can be improved in rural areas of Canada, what resuscitation medications are most effective, what care patient's family members need, what post-discharge support is needed for survivors, how communication should work for everyone involved with a cardiac arrest, what factors best predict neurologically intact survival, whether biomarkers/genetic tests are effective in predicting OHCA and more research on the short and long-term psycho-social impacts of OHCA on survivors. The PPEET showed overwhelmingly positive results for the patient and family engagement experience during the final workshop. CONCLUSIONS: This inclusive research priority setting provides essential information for those doing resuscitation research internationally. The results provide a guide for priority areas of research and should drive our community to focus on questions that matter to survivors and their families in our work. In particular the Canadian Resuscitation Outcomes Consortium will be incorporating the top ten list into its strategic plan for the future.

Sex-dependent associations of maternal androgen levels with offspring BMI and weight trajectory from birth to early childhood.

CONTEXT: In preclinical studies, high androgen levels during pregnancy are associated with low birth weight and rapid postnatal weight gain in the offspring. However, human data linking prenatal androgens with birth weight and early life weight gain in the offspring are scarce. DESIGN: We evaluated 516 mother-child pairs enrolled in the New England birth cohorts of the Collaborative Perinatal Project (1959-1966). We assayed androgen bioactivity in maternal sera during third-trimester using a receptor-mediated luciferase expression bioassay. Age and sex-specific BMI Z-scores (BMIz), defined using established standards, were assessed at birth, 4 months, 1 year, 4 years, and 7 years. We used linear mixed models to evaluate the relation of maternal androgens with childhood BMIz overall and by sex. We examined the association of maternal androgens with fetal growth restriction. The association of weight trajectories with maternal androgens was examined using multinomial logistic regression. RESULTS: Higher maternal androgen levels associated with lower BMIz at birth (ß = - 0.39, 95% CI: - 0.73, - 0.06); this relation was sex-dependent, such that maternal androgens significantly associated with BMIz at birth in girls alone (ß = - 0.72, 95% CI: - 1.40, - 0.04). The relation of maternal androgens with fetal growth restriction revealed dose threshold effects that differed by sex. There was no significant association between maternal androgens and weight trajectory overall. However, we found a significant sex interaction (p = 0.01); higher maternal androgen levels associated with accelerated catch-up growth in boys (aOR = 2.14, 95% CI: 1.14, 4.03). CONCLUSION: Our findings provide evidence that maternal androgens may have differential effects on the programming of intrauterine growth and postnatal weight gain depending on fetal sex.

Oxygen torus and its coincidence with EMIC wave in the deep inner magnetosphere: Van Allen Probe B and Arase observations.

We investigate the longitudinal structure of the oxygen torus in the inner magnetosphere for a specific event found on 12 September 2017, using simultaneous observations from the Van Allen Probe B and Arase satellites. It is found that Probe B observed a clear enhancement in the average plasma mass (M) up to 3-4 amu at L = 3.3-3.6 and magnetic local time (MLT) = 9.0 h. In the afternoon sector at MLT ~ 16.0 h, both Probe B and Arase found no clear enhancements in M. This result suggests that the oxygen torus does not extend over all MLT but is skewed toward the dawn. Since a similar result has been reported for another event of the oxygen torus in a previous study, a crescent-shaped torus or a pinched torus centered around dawn may be a general feature of the O+ density enhancement in the inner magnetosphere. We newly find that an electromagnetic ion cyclotron (EMIC) wave in the H+ band appeared coincidently with the oxygen torus. From the lower cutoff frequency of the EMIC wave, the ion composition of the oxygen torus is estimated to be 80.6% H+, 3.4% He+, and 16.0% O+. According to the linearized dispersion relation for EMIC waves, both He+ and O+ ions inhibit EMIC wave growth and the stabilizing effect is stronger for He+ than O+. Therefore, when the H+ fraction or M is constant, the denser O+ ions are naturally accompanied by the more tenuous He+ ions, resulting in a weaker stabilizing effect (i.e., larger growth rate). From the Probe B observations, we find that the growth rate becomes larger in the oxygen torus than in the adjacent regions in the plasma trough and the plasmasphere.

Multiple ipsilateral femoral stress fractures in a patient taking denosumab for osteoporosis-a case report.

This is the first report describing three ipsilateral femoral stress fractures in a patient taking denosumab. INTRODUCTION: Multiple reports of atypical femur fractures (AFF) in patients receiving denosumab have emerged recently. Denosumab is an anti-resorptive agent approved for treatment of osteoporosis. It is a human monoclonal antibody which blocks osteoclast activation, maturation, and function. METHODS: This is a case report of a 74-year-old female patient who sustained three stress fractures of her left femur. RESULTS: The patient healed her fractures after intramedullary nailing of the femur and was able to return to her activities. CONCLUSIONS: High index of suspicion is needed in any patient with osteoporosis on denosumab complaining of thigh or groin pain. Careful examination and radiographic studies of both femurs are warranted if AFF is discovered.

Predictors of Need for First and Recurrent Emergency Medical Service Transport to Emergency Department after Dialysis Initiation.

Background: Dialysis patients are frequently transported to the emergency department (ED) by Emergency Medical Services (EMS) due to acute and severe illness. However, little is known about predictors of first and recurrent transport to the ED (EMS-ED), based on characteristics at the time of dialysis initiation.Methods: We analyzed a cohort of adult (≥18 years) patients affiliated with a large quaternary care center who initiated chronic dialysis from 2009 to 2013 (last follow-up: 2015). Data on patient characteristics at the time of dialysis initiation were linked to regional EMS data. Candidate predictors of first and recurrent EMS-ED transport included comorbid conditions, dialysis characteristics and frailty severity (using the first version of the clinical frailty scale score; CFS). Time to first EMS-ED was analyzed using a multivariable sub-hazards regression model accounting for competing events (transplantation or death). Time to recurrent EMS-ED was analyzed using the Anderson-Gill counting approach, accounting for competing risks.Results: A total of 455 patients were included in the study, 243 (53%) had 1+ EMS-ED events, 90 (20%) never required an EMS-ED at last follow-up, and 69 (15%) and 53 (12%) experienced transplant or death as their first event, respectively. The mean age of the cohort was 62 ± 15 years, 89% were Caucasian, and 35% were female sex. Patients were highly comorbid and 97/381 (25.5%) with available data on frailty severity had a CFS score of ≥5, inclusive of CFS scores ranging from mildly to severely frail. After adjustment, a CFS score of ≥5 (relative to 1-2) was associated with a > 2-fold increase in the risk of first EMS-ED (subdistribution relative hazard; SHR 2.28, 95% confidence interval; CI 1.30-3.98). A history of peripheral vascular disease (SHR 1.43, 95% CI 1.00-2.03) and rheumatologic disease (SHR 1.84, 95% CI 1.00-3.38) was also associated with first EMS-ED. Frailty severity was the only factor associated with recurrent EMS-ED.Conclusion: Patients are at a high risk of EMS-ED after dialysis initiation. Frailty severity (at the time of dialysis initiation) is a strong predictor of first and recurrent EMS-ED and this may be important to guide informed decision making and resource planning for dialysis patients who require EMS.

Initiation of a fixed-dose four-factor prothrombin complex concentrate protocol.

Patients who require urgent warfarin reversal often receive four-factor prothrombin complex concentrate (4F-PCC), which is traditionally dosed according to weight and initial INR. Our institution implemented a fixed-dose 4F-PCC strategy, using an initial dose of 1500 units. We evaluated the frequency with which the initial fixed dose 4F-PCC was inadequate, as defined by need for supplemental dosing. As part of the protocol, if the initial fixed-dose 4F-PCC is administered and does not achieve INR goal, then the remainder of the standard weight- and INR-based dosing can be given. During the study period, 63 patients on warfarin received 4F-PCC using the fixed-dose protocol. Based on the INR following 4F-PCC administration, 11 patients (17%) were eligible to receive a supplemental dose based on failure to achieve their specified INR goal. Two of the 11 patients eligible for supplemental 4F-PCC dosing received the second dose, both with initial supratherapeutic INRs > 3.5. We found that most patients given an initial fixed-dose 4F-PCC achieved their INR goals, and of those who did not, most did not receive supplemental dosing, suggesting that clinical providers felt that adequate hemostasis had been achieved. In addition, fixed-dose 4F-PCC was able to be given rapidly, with few dosing errors, suggesting that this is a reasonable option for 4F-PCC delivery.

Automated ASPECTS in Acute Ischemic Stroke: A Comparative Analysis with CT Perfusion.

BACKGROUND AND PURPOSE: Automated ASPECTS has the potential of reducing interobserver variability in the determination of early ischemic changes. We aimed to assess the performance of an automated ASPECTS software against the assessment of a neuroradiologist in a comparative analysis with concurrent CTP-based CBV ASPECTS. MATERIALS AND METHODS: Patients with anterior circulation stroke who had baseline NCCT and CTP and underwent successful mechanical thrombectomy were included. NCCT-ASPECTS was assessed by 2 neuroradiologists, and discrepancies were resolved by consensus. CTP-CBV ASPECTS was assessed by a different neuroradiologist. Automated ASPECTS was provided by Brainomix software. ASPECTS was dichotomized (ASPECTS ≥6 or <6) and was also based on the time from onset (>6 or ≤6 hours). RESULTS: A total of 58 patients were included. The interobserver agreement for NCCT ASPECTS was moderate (κ = 0.48) and marginally improved (κ = 0.64) for dichotomized data. Automated ASPECTS showed excellent agreement with consensus reads (κ = 0.84) and CTP-CBV ASPECTS (κ = 0.84). Intraclass correlation coefficients for ASPECTS across all 3 groups were 0.84 (95% CI, 0.76-0.90, raw scores) and 0.94 (95% CI, 0.91-0.96, dichotomized scores). Automated scores were comparable with consensus reads and CTP-CBV ASPECTS in patients when grouped on the basis of time from symptom onset (>6 or ≤6 hours). There was significant (P < .001) negative correlation with final infarction volume and the 3 ASPECTS groups (r = -0.52, consensus reads; -0.58, CTP-CBV; and -0.66, automated). CONCLUSIONS: ASPECTS derived from an automated software performs equally as well as consensus reads of expert neuroradiologists and concurrent CTP-CBV ASPECTS and can be used to standardize ASPECTS reporting and minimize interpretation variability.

Abnormalities in thalamo-cortical connections in patients with first-episode schizophrenia: a two-tensor tractography study.

The "cognitive dysmetria" hypothesis suggests that impairments in cognition and behavior in patients with schizophrenia can be explained by disruptions in the cortico-cerebellar-thalamic-cortical circuit. In this study we examine thalamo-cortical connections in patients with first-episode schizophrenia (FESZ). White matter pathways are investigated that connect the thalamus with three frontal cortex regions including the anterior cingulate cortex (ACC), ventrolateral prefrontal cortex (VLPFC), and lateral oribitofrontal cortex (LOFC). We use a novel method of two-tensor tractography in 26 patients with FESZ compared to 31 healthy controls (HC), who did not differ on age, sex, or education. Dependent measures were fractional anisotropy (FA), Axial Diffusivity (AD), and Radial Diffusivity (RD). Subjects were also assessed using clinical functioning measures including the Global Assessment of Functioning (GAF) Scale, the Global Social Functioning Scale (GF: Social), and the Global Role Functioning Scale (GF: Role). FESZ patients showed decreased FA in the right thalamus-right ACC and right-thalamus-right LOFC pathways compared to healthy controls (HCs). In the right thalamus-right VLPFC tract, we found decreased FA and increased RD in the FESZ group compared to HCs. After correcting for multiple comparisons, reductions in FA in the right thalamus- right ACC and the right thalamus- right VLPC tracts remained significant. Moreover, reductions in FA were significantly associated with lower global functioning scores as well as lower social and role functioning scores. We report the first diffusion tensor imaging study of white matter pathways connecting the thalamus to three frontal regions. Findings of white matter alterations and clinical associations in the thalamic-cortical component of the cortico-cerebellar-thalamic-cortical circuit in patients with FESZ support the cognitive dysmetria hypothesis and further suggest the possible involvement of myelin sheath pathology and axonal membrane disruption in the pathogenesis of the disorder.

Undiagnosed hypertrophic obstructive cardiomyopathy during transcatheter aortic valve replacement: a case report.

BACKGROUND: Transcatheter aortic valve replacement is indicated for severe symptomatic aortic stenosis in patients who have a very high or prohibitive surgical risk as assessed pre-procedurally by the Society of Thoracic Surgery Risk Score, EuroSCORE (II), frailty testing, and other predictors. When combined with another left ventricular outflow tract obstruction, careful consideration must be taken prior to proceeding with transcatheter aortic valve replacement because an additional masked left ventricular outflow tract pathology can lead to challenging hemodynamics in the peri-deployment phase, as reported in this case. CASE PRESENTATION: A 56-year-old Caucasian man with multiple comorbidities and severe aortic stenosis underwent transcatheter aortic valve replacement under monitored anesthesia care. During the deployment phase, he developed dyspnea that progressed to pulmonary edema requiring emergent conversion to general anesthesia, orotracheal intubation, acute respiratory distress syndrome-type ventilation, and vasopressor medications. Intraoperative transesophageal echocardiography was performed and hypertrophic obstructive cardiomyopathy with systolic anterior motion of the mitral valve was discovered as an underlying pathology, undetected on preoperative imaging. After treatment with beta blockers, fluid resuscitation, and alpha-1 agonists, he stabilized and was eventually discharged from our hospital without any lasting sequelae. CONCLUSIONS: Patients with aortic stenosis most often develop symmetric hypertrophy; however, a small subset has asymmetric septal hypertrophy leading to left ventricular outflow tract obstruction. In cases of severe aortic stenosis, however, evidence of left ventricular outflow tract obstruction via both symptoms and echocardiographic findings may be minimized due to extremely high afterload on the left ventricle. Diagnosing a left ventricular outflow tract obstruction as the cause of hemodynamic instability during transcatheter aortic valve replacement, in the absence of abnormal findings on echocardiogram preoperatively, requires a high index of clinical suspicion. The management of acute onset left ventricular outflow tract obstruction intraoperatively consists primarily of medical therapy, including rate control, adequate volume resuscitation, and avoidance of inotropes. With persistently elevated gradients, interventional treatments may be considered.

Wave Phenomena and Beam-Plasma Interactions at the Magnetopause Reconnection Region.

This paper reports on Magnetospheric Multiscale observations of whistler mode chorus and higher-frequency electrostatic waves near and within a reconnection diffusion region on 23 November 2016. The diffusion region is bounded by crescent-shaped electron distributions and associated dissipation just upstream of the X-line and by magnetic field-aligned currents and electric fields leading to dissipation near the electron stagnation point. Measurements were made southward of the X-line as determined by southward directed ion and electron jets. We show that electrostatic wave generation is due to magnetosheath electron beams formed by the electron jets as they interact with a cold background plasma and more energetic population of magnetospheric electrons. On the magnetosphere side of the X-line the electron beams are accompanied by a strong perpendicular electron temperature anisotropy, which is shown to be the source of an observed rising-tone whistler mode chorus event. We show that the apex of the chorus event and the onset of electrostatic waves coincide with the opening of magnetic field lines at the electron stagnation point.

Factors associated with treatment delays in pediatric refractory convulsive status epilepticus.

OBJECTIVE: To identify factors associated with treatment delays in pediatric patients with convulsive refractory status epilepticus (rSE). METHODS: This prospective, observational study was performed from June 2011 to March 2017 on pediatric patients (1 month to 21 years of age) with rSE. We evaluated potential factors associated with increased treatment delays in a Cox proportional hazards model. RESULTS: We studied 219 patients (53% males) with a median (25th-75th percentiles [p25-p75]) age of 3.9 (1.2-9.5) years in whom rSE started out of hospital (141 [64.4%]) or in hospital (78 [35.6%]). The median (p25-p75) time from seizure onset to treatment was 16 (5-45) minutes to first benzodiazepine (BZD), 63 (33-146) minutes to first non-BZD antiepileptic drug (AED), and 170 (107-539) minutes to first continuous infusion. Factors associated with more delays to administration of the first BZD were intermittent rSE (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.14-2.09; p = 0.0467) and out-of-hospital rSE onset (HR 1.5, 95% CI 1.11-2.04; p = 0.0467). Factors associated with more delays to administration of the first non-BZD AED were intermittent rSE (HR 1.78, 95% CI 1.32-2.4; p = 0.001) and out-of-hospital rSE onset (HR 2.25, 95% CI 1.67-3.02; p < 0.0001). None of the studied factors were associated with a delayed administration of continuous infusion. CONCLUSION: Intermittent rSE and out-of-hospital rSE onset are independently associated with longer delays to administration of the first BZD and the first non-BZD AED in pediatric rSE. These factors identify potential targets for intervention to reduce time to treatment.

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.

This corrects the article DOI: 10.1038/mp.2016.97.

Challenges in the implementation of EAACI guidelines on allergen immunotherapy: A global perspective on the regulation of allergen products.

Regulatory approaches for allergen immunotherapy (AIT) products and the availability of high-quality AIT products are inherently linked to each other. While allergen products are available in many countries across the globe, their regulation is very heterogeneous. First, we describe the regulatory systems applicable for AIT products in the European Union (EU) and in the United States (US). For Europe, a depiction of the different types of relevant procedures, as well as the committees involved, is provided and the fundamental role of national agencies of the EU member states in this complex and unique network is highlighted. Furthermore, the regulatory agencies from Australia, Canada, Japan, Russia, and Switzerland provided information on the system implemented in their countries for the regulation of allergen products. While AIT products are commonly classified as biological medicinal products, they are made available by varying types of procedures, most commonly either by obtaining a marketing authorization or by being distributed as named patient products. Exemptions from marketing authorizations in exceptional cases, as well as import of allergen products from other countries, are additional tools applied by countries to ensure availability of needed AIT products. Several challenges for AIT products are apparent from this analysis and will require further consideration.