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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

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.

Background: Children with Tourette syndrome (TS) often have comorbid disorders, particularly attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). While subtle premorbid symptoms have been described in various psychiatric disorders, the presence of clinical precursors that may exist before the onset of tics is unknown. This longitudinal study aimed to find clinical precursors of tics by assessing a range of clinical characteristics prior to tic onset in comparison with children without onset of tics.Methods: A sample of 187 3- to 10-year-old first-degree unaffected relatives of children with TS were followed up to 7 years in the European Multicentre Tics in Children Study (EMTICS). We investigated whether clinical characteristics assessed at baseline predicted tic onset, comparing 126 children without tic onset to 61 children who developed tics. We used the least absolute shrinkage and selection operator (LASSO) method, a penalised logistic regression approach. We also explored sex differences and repeated our analyses in an age- and sex-matched subsample.Results: Children with tic onset were more frequently male (beta = -0.36), had higher baseline severity of conduct problems (beta = 0.23), autism spectrum disorder symptoms (ASD; beta = 0.08), compulsions (beta = 0.02) and emotional problems (beta = 0.03) compared to children without tic onset. Conduct and ASD problems were male-specific predictors, whereas severity of compulsions and oppositional (beta = 0.39) and emotional problems were female-specific predictors.Conclusion: This study supports the presence of clinical precursors prior to tic onset and highlights the need of sex-specific monitoring of children at risk of developing tics. This may aid in the earlier detection of tics, particularly in females. We moreover found that tics most often persisted one year after tic onset, in contrast to the common belief that tics are mostly transient.

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).

Tic disorders typically start in early childhood and can be classified into provisional tic disorder (tics last12 months) and chronic tic disorders (tics last 12 months). The widely known chronic tic disorder Tourette's syndrome is featuring multiple motor and vocal tics. Tics are typically waxing and waning in frequency and intensity. Concentration and relaxation might decrease tics, whereas stress and excitement might increase tics. Psychiatric comorbidities, like obsessive-compulsive disorder, ADHD, depression and anxiety are common. The etiology is multifactorial with genetic and environmental interactions leading to a dysregulation of cortico-striato-pallido-thalamo-cortical networks.A correct diagnosis and psychoeducation are essential for patients as well as their relatives. Additional therapies are needed for patients with severe tics that cause physical impairment or great psychosocial stress. It is crucial to also treat psychiatric comorbidities. Psychotherapeutic interventions for tics include progressive muscle relaxation, habit reversal training, exposure and response prevention and comprehensive behavioral intervention for tics. First-line psychopharmacological treatment in Europe contains aripiprazole, tiapride and risperidone, which are all used off-label for tic disorders. Haloperidol remains the only approved medication for the pharmacotherapy of tics in Germany, but is rarely used due to its side effects. Cannabinoids gain interest as a new pharmacological option, but are mainly offered within the frame of studies.Das Bewusstsein der Öffentlichkeit für Tic-Störungen und insbesondere für das Tourette-Syndrom ist durch zahlreiche Medienbeiträge in den letzten Jahren gestiegen. Immer wieder wird in TV- oder Printmedien jedoch lediglich von schweren Fällen des Tourette-Syndroms berichtet, die nicht dem durchschnittlichen Krankheitsverlauf entsprechen. Eine umfangreiche Aufklärung über Symptome, Verlauf, Ursachen und Behandlungsmöglichkeiten ist daher wünschenswert 1.

Heat waves and air pollution episodes pose a serious threat to human health and may worsen under future climate change. In this paper, we use 15 years (1999-2013) of commensurately gridded (1° x 1°) surface observations of extended summer (April-September) surface ozone (O3), fine particulate matter (PM2.5), and maximum temperature (TX) over the eastern United States and Canada to construct a climatology of the coincidence, overlap, and lag in space and time of their extremes. Extremes of each quantity are defined climatologically at each grid cell as the 50 d with the highest values in three 5-y windows (∼95th percentile). Any two extremes occur on the same day in the same grid cell more than 50% of the time in the northeastern United States, but on a domain average, co-occurrence is approximately 30%. Although not exactly co-occurring, many of these extremes show connectedness with consistent offsets in space and in time, which often defy traditional mechanistic explanations. All three extremes occur primarily in large-scale, multiday, spatially connected episodes with scales of >1,000 km and clearly coincide with large-scale meteorological features. The largest, longest-lived episodes have the highest incidence of co-occurrence and contain extreme values well above their local 95th percentile threshold, by +7 ppb for O3, +6 µg m-3 for PM2.5, and +1.7 °C for TX. Our results demonstrate the need to evaluate these extremes as synergistic costressors to accurately quantify their impacts on human health.

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.

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.

Without active engagement, many adults with serious mental illnesses remain untreated in the community and commit criminal offenses, resulting in their placement in the jails rather than mental health facilities. A mental health treatment court (MHTC) with an assertive community treatment (ACT) model of case management was developed through the cooperative efforts of the criminal justice and mental health systems. Participants were 235 adults with a serious mental illness who were booked into the county jail, and who volunteered for the study. An experimental design was used, with participants randomly assigned to MHTC or treatment as usual (TAU), consisting of adversarial criminal processing and less intensive mental health treatment. Results were reported for 6 and 12 month follow-up periods. Clients in both conditions improved in life satisfaction, distress, and independent living, while participants in the MHTC also showed reductions in substance abuse and new criminal activity. Outcomes are interpreted within the context of changes brought about in the community subsequent to implementation of the MHTC.

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.

Two strategies have been shown by others to improve CST regeneration following thoracic spinal cord injury: 1) the administration of a monoclonal antibody, IN-1, raised against a myelin-associated, neurite growth inhibitory protein, and 2) the delivery of acidic fibroblast growth factor (aFGF) in fibrin glue in association with peripheral nerve grafts. Because autologous transplantation of human Schwann cells (SCs) is a potential strategy for CNS repair, we evaluated the ability of these two molecular agents to induce CST regeneration into human SC grafts placed to span a midthoracic spinal cord transection in the adult nude rat, a xenograft tolerant strain. IN-1 or control (HRP) antibodies were delivered to the injury/graft region by encapsulated hybridoma cells ("IN-1 ravioli") or daily infusion of hybridoma culture supernatant; aFGF-fibrin glue was placed in the same region in other animals. Anterograde tracing from the motor cortex using the dextran amine tracers, Fluororuby (FR) and biotinylated dextran amine (BDA), was performed. Thirty-five days after grafting, the CST response was evaluated qualitatively by looking for regenerated CST fibers in or beyond grafts and quantitatively by constructing camera lucida composites to determine the sprouting index (SI), the position of the maximum termination density (MTD) rostral to the GFAP-defined host/graft interface, and the longitudinal spread (LS) of bulbous end terminals. The latter two measures provided information about axonal die-back. In control animals (graft only), the CST did not enter the SC graft and underwent axonal die-back [SI = 1.4 +/- 0.1, MTD = 2.0 +/- 0.2, LS = 1.3 +/- 0.3, (n = 3)]. Results of IN-1 delivery from ravioli did not differ from controls, but injections of IN-1-containing supernatant resulted in a significant degree of sprouting but did not prevent axonal die-back [SI = 1.9 +/- 0.1, MTD = 1.5 +/- 0.2, LS = 1.1 +/- 0.1, (n = 7)] and traced fibers did not enter grafts. Acidic FGF dramatically reduced axonal die-back and caused sprouting [SI = 2.0 +/- 0.1 (n = 5), MTD = 0.5 +/- 0.04 (n = 6), LS = 0.4 +/- 0.1 (n = 6)]. Some traced fibers entered SC grafts and in 2/6 cases entered the distal interface. We conclude that 1) human SC grafts alone do not support the regeneration of injured CST fibers and do not prevent die-back, 2) grafts plus IN-1 antibody-containing supernatant support some sprouting but die-back continues, and 3) grafts plus aFGF-fibrin glue support regeneration of some fibers into the grafts and reduce die-back.

Chronic pelvic inflammatory disease is a common gynecologic diagnosis in women with chronic pelvic pain. When standard antimicrobial therapy does not improve the clinical status, uncommon diagnoses such as Enterobius vermicularis should be considered. In this case, E vermicularis presented as acute and chronic salpingitis in a patient who had had E vermicularis-related appendicitis 5 years earlier.