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AIM To investigate the association between circulating anti-dopamine D2 receptor (D2R) autoantibodies and the exacerbation of tics in children with chronic tic disorders (CTDs). METHOD One hundred and thirty-seven children with CTDs (108 males, 29 females; mean age [SD] 10y 0mo [2y 7mo], range 4-16y) were recruited over 18 months. Patients were assessed at baseline, at tic exacerbation, and at 2 months after exacerbation. Serum anti-D2R antibodies were evaluated using a cell-based assay and blinded immunofluorescence microscopy scoring was performed by two raters. The association between visit type and presence of anti-D2R antibodies was measured with McNemar's test and repeated-measure logistic regression models, adjusting for potential demographic and clinical confounders. RESULTS At exacerbation, 11 (8%) participants became anti-D2R-positive ('early peri-exacerbation seroconverters'), and nine (6.6%) became anti-D2R-positive at post-exacerbation ('late peri-exacerbation seroconverters'). The anti-D2R antibodies were significantly associated with exacerbations when compared to baseline (McNemar's odds ratio=11, p=0.003) and conditional logistic regression confirmed this association (Z=3.49, p

Risk assessments of air pollution impacts on human health and ecosystems would ideally consider a broad set of climate and emission scenarios and the role of natural internal climate variability wi...

A central strategy in achieving greenhouse gas mitigation targets is the transition of vehicles from internal combustion engines to electric power. However, due to complex emission sources and nonlinear chemistry, it is unclear how such a shift might impact air quality. Here we apply a prototype version of the new-generation NOAA GFDL global Atmospheric Model, version 4 (GFDL AM4) to investigate the impact on U.S. air quality from an aggressive conversion of internal combustion vehicles to battery-powered electric vehicles (EVs). We examine a suite of scenarios designed to quantify the effect of both the magnitude of EV market penetration and the source of electricity generation used to power them. We find that summer surface ozone (O3) decreases in most locations due to widespread reductions of traffic NOx emissions. Summer fine particulate matter (PM2.5) increases on average and largest in areas with increased coal-fired power generation demands. Winter O3 increases due to reduced loss via traffic NOx while PM2.5 decreases since larger ammonium nitrate reductions offset increases in ammonium sulfate. The largest magnitude changes are simulated at the extremes of the probability distribution. Increasing the fraction of vehicles converted to EVs further decreases summer O3, while increasing the fraction of electricity generated by “emission-free” sources largely eliminates the increases in summer PM2.5 at high EV adoption fractions. Ultimately, the number of conventional vehicles replaced by EVs has a larger effect on O3 than PM2.5, while the source of the electricity for those EVs exhibit greater control on PM2.5.

Infectious pathogens may represent an environmental risk factor for chronic tic disorders (CTD). This cross-sectional study aimed to determine whether Mycoplasma pneumoniae (M. pneumoniae) IgG positivity is associated with the presence or severity of tics. We compared M. pneumoniae IgG positivity across three groups: children and adolescents (3–16 years) with CTD (CTD group; n = 302); siblings (3–10 years) of people with CTD who developed tics within a seven-year follow-up period (tic onset group; n = 51); siblings (4–10 years) who did not develop tics within the study period and were ≥10-years-old at their last assessment (unaffected group; n = 88). The relationship between M. pneumoniae IgG positivity and the presence and severity of tics was analysed using multilevel models controlling for site, family relatedness, sex, age, presence of comorbid obsessive–compulsive and/or attention-deficit/hyperactivity disorder and use of psychotropic medication. M. pneumoniae IgG positivity was not associated with the presence of CTD, or the first onset of tics as compared to siblings who remained unaffected. M. pneumoniae IgG positivity was associated with a higher tic severity score within the CTD group (β = 2.64, s.e. = 1.15, p = 0.02). It is possible that M. pneumoniae infection influences tic severity in CTD or, that having more severe tics, increases the risk of infection. However, it is more likely that the association observed in this study reflects a propensity toward enhanced immune responses in people with CTD and that, rather than a causal relationship, infection and greater tic severity are indirectly linked via shared underlying immune mechanisms.

Objective To evaluate the diagnostic performance of the antimullerian hormone (AMH) level determined using the Access AMH assay for predicting poor ovarian response (POR) defined as ≤4 oocytes retrieved, including the validation of the predefined AMH cutoff of 0.93 ng/mL in both serum and plasma. Design Prospective cohort study. Setting Fifteen private and academic fertility centers (14 in the United States and 1 in Canada). Patient(s) Women aged 21–45 years planning controlled ovarian stimulation for in vitro fertilization. Intervention(s) None. Main Outcome Measure(s) Number of oocytes retrieved, categorized as POR and normal-to-high ovarian response (non-POR). The correlation of AMH level and antral follicle count. Result(s) Data were available for 472 participants who completed the study (74 with POR and 398 non-POR). The mean AMH serum level among those with POR was 0.99 ng/mL (median 0.76 ng/mL) compared with 2.83 ng/mL (median 2.36 ng/mL) among the normal-to-high responders. For confirmation of the 0.93 ng/mL AMH level cutoff as a predictor of POR, a receiver operating characteristic analysis gave an area under the curve of 0.852, with corresponding sensitivity and specificity of 63.5% and 89.2%, respectively. The associated positive predictive value was 52.2% and the negative predictive value was 92.9%. The AMH plasma values demonstrated a strong correlation with AMH serum values with an r value = 0.9980. The previously established AMH cutoff of 1.77 ng/mL for antral follicle count >15 resulted in a sensitivity of 83.8% (95% confidence interval [CI] 77.7–88.5) and a specificity of 59.9% (95% CI 54.2–65.4). Conclusion(s) This study validated the previously established AMH cut-point for the prediction of POR. Because this cut-point may vary depending on the assay used, the specific AMH assay should be reported in the literature whenever possible.

EMTICS Collaborative Group., Genetic predisposition, autoimmunity and environmental factors [e.g. pre- and perinatal difficulties, Group A Streptococcal (GAS) and other infections, stress-inducing events] might interact to create a neurobiological vulnerability to the development of tics and associated behaviours. However, the existing evidence for this relies primarily on small prospective or larger retrospective population-based studies, and is therefore still inconclusive. This article describes the design and methodology of the EMTICS study, a longitudinal observational European multicentre study involving 16 clinical centres, with the following objectives: (1) to investigate the association of environmental factors (GAS exposure and psychosocial stress, primarily) with the onset and course of tics and/or obsessive–compulsive symptoms through the prospective observation of at-risk individuals (ONSET cohort: 260 children aged 3–10 years who are tic-free at study entry and have a first-degree relative with a chronic tic disorder) and affected individuals (COURSE cohort: 715 youth aged 3–16 years with a tic disorder); (2) to characterise the immune response to microbial antigens and the host’s immune response regulation in association with onset and exacerbations of tics; (3) to increase knowledge of the human gene pathways influencing the pathogenesis of tic disorders; and (4) to develop prediction models for the risk of onset and exacerbations of tic disorders. The EMTICS study is, to our knowledge, the largest prospective cohort assessment of the contribution of different genetic and environmental factors to the risk of developing tics in putatively predisposed individuals and to the risk of exacerbating tics in young individuals with chronic tic disorders., This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under Grant agreement no. 278367. Schrag was supported by the National Institute for Health Research UCLH Biomedical Research Centre, and Müller, Burger, Schnell and Weidinger by Stiftung Immunität und Seele. This research was supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London (Heyman); partially sponsored by GSK Vaccines (Margarit, Bartolini); and Deutsche Forschungsgemeinschaft (DFG): projects 1692/3-1, 4-1 (Münchau).

Der 39-jahrige Lagerist stellt sich bei seinem Hausarzt vor und berichtet bei diesem erstmals von „Zuckungen und Gerauschen“ seit dem Grundschulalter. Eine Blutkontrolle, EEG und cMRT seien regelrecht gewesen. Aktuelle motorische Tics umfassen Kopfnicken, Bauchschlagen und Beruhrtics, vokale Tics ausern sich in Rauspern, Husten und die Silbe „prp“.

BackgroundHypovitaminosis-D has been linked to neuropsychiatric conditions, but little is known about vitamin D status in individuals with chronic tic disorders (CTD). This study sought to determine whether vitamin D levels are associated with the severity of tics and presence and severity of comorbid obsessive-compulsive disorder (OCD) and/ or attention-deficit/hyperactivity disorder (ADHD).MethodsThis is a cross-sectional sub-study of the European Multicentre Tics in Children Studies (EMTICS). Vitamin D [25(OH)D] levels (ng/ml) were obtained for 327 participants with CTD at study entry and tic severity was measured using the Yale Global Tic Severity Scale (YGTSS). An association between tic severity and presence and severity of comorbid OCD and/or ADHD symptoms was analysed using multilevel models controlling for season, site, sex, age and presence of comorbid OCD and/or ADHD.ResultsThe participants comprised 247 boys and 80 girls (4-16 years, mean [SD], 10.9 [2.72]). Hypovitaminosis-D ([25(OH)D] < 20ng/ml) was present in 33% of participants with CTD and/ or comorbid OCD and/ or ADHD. The authors found no association between 25(OH)D levels and tic severity or OCD symptom severity. However, lower 25(OH)D levels were significantly associated with increased severity of ADHD symptoms in participants with CTD (β = -0.25, s.e. = 0.08, 95% CI, -0.42 to -0.09; p < 0.01).ConclusionAdditional research is needed to confirm these findings and assess whether hypovitaminosis-D may represent an underlying biological vulnerability for comorbid ADHD symptoms in CTD as it may signpost novel strategies for prevention and treatment.

Objective To evaluate a new fully automated antimullerian hormone (AMH) assay for prediction of poor ovarian response (POR) to ovarian stimulation defined as four or fewer oocytes retrieved. Design Prospective cohort study. Setting Thirteen private and academic fertility centers in the United States. Patients(s) A total of 178 women undergoing their first in vitro fertilization (IVF) cycle eligible for the study were consented and enrolled, with data available from 160 women for prediction of POR and 164 women for AMH correlation with antral follicle count (AFC). Intervention(s) None. Main Outcome Measure(s) Cutoff point for AMH that predicts POR. Correlation of AMH with AFC, and cutoff point for AMH that correlates with antral follicle count >15. Result(s) The mean AMH among the poor responders was 0.74 ng/mL, compared with 3.20 ng/mL for normal to high responders. The AMH cutoff at 90% specificity for predicting POR with the use of the receiver operating characteristic (ROC) curve was 0.93 ng/mL, with an associated sensitivity of 74.1%. For prediction of POR, ROC analysis showed that AMH (area under the ROC curve [AUC] = 0.929) was significantly better than FSH (AUC = 0.615; P 15 was 1.75, with specificity of 59.1%. Conclusion(s) A fully automated AMH assay can be a useful biomarker for predicting POR in IVF cycles. Because AMH cutoff points vary depending on the assay used, future studies should continue to calibrate test results to clinically important outcomes.

This paper contrasts the current Chinese “Belt and Road Initiative” (BRI) against the opening of the U.S. west in the 19 th century using principles of western rhetoric as basis for interpretation. Most specifically, Kenneth Burke’s Dramatistic Pentad is used for initial clarification along with explanation of how further understanding can be realized via Fantasy Theme Analysis to better appreciate the expression of rhetorical vision. Recognition of how BRI can be understood differently, depending on the cultural context, is stressed as a strategic intelligence perspective. This is couched in the contextual framing of mass media influences as explained by Marshall McLuhan.

Objective To assess the efficacy and safety of a vaginal progesterone (P4) insert (Endometrin) for luteal support for assisted reproductive technology (ART). Design Multicenter, randomized, open-label (assessor-blinded) phase III clinical trial. Setting Twenty-five U.S. ART centers. Patient(s) A total of 1,211 ART patients randomized to three groups: Endometrin 100 mg twice daily (n = 404), Endometrin 100 mg three times daily (n = 404), and P4 90 mg 8% gel daily (n = 403). Intervention(s) In vitro fertilization and ET were performed according to site-specific protocols. The day after oocyte retrieval, Endometrin or vaginal P4 gel was begun for luteal support and continued for up to 10 weeks of pregnancy. Main Outcome Measure(s) Biochemical, clinical, and ongoing pregnancy and live birth rates. Result(s) Pregnancy rates were high and similar in all treatment groups, with biochemical rates exceeding 50%, clinical and ongoing rates ≥40%, and live birth rates at 35%–38%. The adverse event profiles were similar across groups. Conclusion(s) Pregnancy rates and live birth rates for Endometrin (twice daily and three times daily) were high and similar to those for P4 gel. The adverse event profiles for both were similar to that for P4 gel and primarily due to IVF stimulation and oocyte retrieval. Endometrin was safe and well tolerated.

Purpose With ethical requirements to the enrollment of lower risk subjects, osteoporosis trials are underpowered to detect reduction in hip fractures. Different skeletal sites have different levels of fracture risk and response to treatment. We sought to identify fracture sites which cluster with hip fracture at higher than expected frequency; if these sites respond to treatment similarly, then a composite fracture endpoint could provide a better estimate of hip fracture reduction. Methods Cohort study using Veterans Affairs and Medicare administrative data. Male Veterans (n = 5,036,536) aged 50–99 years receiving VA primary care between 1999 and 2009 were included. Fractures were ascertained using ICD9 and CPT codes and classified by skeletal site. Pearson correlation coefficients, logistic regression and kappa statistics were used to describe the correlation between each fracture type and hip fracture within individuals, without regard to the timing of the events. Results 595,579 (11.8%) men suffered 1 or more fractures and 179,597 (3.6%) suffered 2 or more fractures during the time under study. Of those with one or more fractures, the rib was the most common site (29%), followed by spine (22%), hip (21%) and femur (20%). The fracture types most highly correlated with hip fracture were pelvic/acetabular (Pearson correlation coefficient 0.25, p Conclusions Pelvic, acetabular, femur, and shoulder fractures cluster with hip fractures within individuals at greater than expected frequency. If we observe similar treatment risk reductions within that cluster, subsequent trials could consider the use of a composite endpoint to better estimate hip fracture risk.

Objective To compare corifollitropin alfa with recombinant FSH treatment in terms of the vital pregnancy rate in older patients undergoing IVF. Design Phase 3 randomized, double-blind, noninferiority trial. Setting Multicenter trial. Patient(s) A total of 1,390 women aged 35–42 years. Intervention(s) A single injection of 150 μg of corifollitropin alfa or daily 300 IU of recombinant FSH for the first 7 days then daily recombinant FSH until three follicles reach ≥17 mm in size. Ganirelix was started on stimulation day 5 up to and including the day of recombinant hCG administration. If available, two good quality embryos were transferred on day 3. Main Outcome Measure(s) Vital pregnancy rate (PR), number of oocytes, and live birth rate. Result(s) Vital PRs per started cycle were 23.9% in the corifollitropin alfa group and 26.9% in the recombinant FSH group, with an estimated difference (95% confidence interval) of -3.0% (−7.4 to 1.4). The mean (SD) number of recovered oocytes per started cycle was 10.7 (7.2) and 10.3 (6.8) in the corifollitropin alfa and the recombinant FSH groups, respectively, with an estimated difference of 0.5 (−0.2 to 1.2). The live birth rates per started cycle were 21.3% in the corifollitropin alfa group and 23.4% in the recombinant FSH group, with an estimated difference (95% confidence interval) −2.3% (−6.5 to 1.9). The incidence of serious adverse events was 0.4% versus 2.7% in the corifollitropin alfa and recombinant FSH groups, respectively, and of ovarian hyperstimulation syndrome (OHSS; all grades) was 1.7% in both groups. Conclusion(s) Treatment with corifollitropin alfa was proven noninferior to daily recombinant FSH with respect to vital PRs, number of oocytes retrieved, and live birth rates, and was generally well tolerated. Clinical Trial Registration Number NCT01144416.

Objective To compare the efficacy and safety of three different ratios of human-derived follicle-stimulating hormone/human menopausal gonadotropin (human-derived FSH:hMG, Bravelle and Repronex) mixed together in the same syringe and administered subcutaneously once daily, to in vitro fertilization (IVF) patients Design Two randomized, prospective, age stratified, IVF studies. Setting Twenty-one academic and private clinics with experience in IVF/embryo transfer (ET). Patient(s) Infertile premenopausal women undergoing IVF-ET. Intervention(s) Pituitary suppression with leuprolide acetate, randomization to one of three treatment groups, followed by gonadotropin stimulation (GS) for up to 15 days. The human-derived FSH:hMG ratios were the following: Group 1, a 1:1 ratio throughout; Group 2, a 3:0 ratio that was changed to 1:1 after GS day 5; Group 3, a 2:1 ratio that was increased to 3:1, 4:1, or 5:1 after GS day 5, as needed. Main outcome measure(s) Mean number of oocytes retrieved; peak estradiol levels; dose and duration of stimulation; implantation rates; adverse events; injection site pain; and pregnancy and live birth rates. Result(s) Overall, women 2 levels, more oocytes retrieved, and improved implantation and live birth rates compared with women 34 to 40 years old. Nonetheless, each ratio of human-derived FSH:hMG produced comparable implantation rates, and continuing pregnancy and take-home baby rates. Conclusion(s) All three ratios of human-derived FSH:hMG in both age groups produced comparable pregnancy and live birth rates with similar safety results.

Different compartments in the central nervous system mount distinct inflammatory responses. The meninges and choroid plexus respond to pro-inflammatory stimuli in a manner reminiscent of a peripheral inflammatory response, whereas the brain parenchyma is refractory. Trauma-induced lesions in brain and in spinal cord are associated with leukocyte infiltration, blood-brain barrier (BBB) breakdown, and secondary tissue destruction. Unexpectedly, these phenomena are generally more pronounced in the parenchyma of the spinal cord than in the parenchyma of the brain. To investigate whether these differences between brain and spinal cord can be attributed, at least in part, to differing sensitivities to proinflammatory cytokines, we stereotactically injected recombinant rat (rr) TNFalpha or rrIL-1beta into the striatum or the spinal cord of Wistar rats. In the brain, the injection of rrTNFalpha failed to evoke BBB breakdown or leukocyte recruitment, whereas in the spinal cord injection of TNFalpha resulted in marked BBB breakdown and leukocyte recruitment. Similarly, the injection of rrIL-1beta into the brain parenchyma failed to induce BBB breakdown and gave rise to only minimal neutrophil recruitment, whereas the injection of rrIL-1beta into the spinal cord induced significant BBB breakdown and recruitment of neutrophils and lymphocytes. Thus, using a minimally invasive injection technique, equivalent in both circumstances, we have shown that there are marked differences in the inflammatory response between the brain parenchyma and spinal cord parenchyma. This observation has important implications for the treatment of spinal cord injuries.

Charlotte Whitton’s influence in professionalizing Canadian social work cannot be overestimated. As Director of the Canadian Welfare Council, she was instrumental in establishing a social work network by recommending appointments to key positions across the country. This network assisted Whitton in implementing the recommendations of more than a score of CWC social surveys that bore her imprimatur. Determined to standardize social work, she transformed ad hoe child care practices into cohesive child welfare policies. Her promotion of central Canadian models of child welfare drew hostile regional responses, especially in Alberta. Her commitment to the boarding-out principle contributed to the de-institutionalization of dependent children.