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Background Disuse decreases muscle size and is predictive of mortality across multiple pathologies. Detriments to mitochondrial function are hypothesized to underlie disuse‐induced muscle atrophy. Little data exist on early mechanisms contributing to onset of these pathologies, nor is it known how they differ between sexes. The purpose of this study was to examine differential and conserved responses to mitochondrial quality control in male and female mice during the development and progression of disuse‐induced atrophy. Methods One hundred C57BL/6J mice (50 male and 50 female) were hindlimb unloaded to induce disuse atrophy for 0 (con), 24, 48, 72, or 168 h. At designated time‐points, extensor digitorum longus, gastrocnemius, and soleus muscles were collected for analysis of mitochondrial quality control markers. Results One hundred sixty‐eight hours of disuse resulted in ~25% lower oxidative muscle fibre CSA in both male (P = 0.003) and female (P = 0.02) mice without any differences due to disuse in glycolytic fibres. In male mice, 48 h of unloading was sufficient to result in ~67% greater mitochondrial oxidative stress as assessed by the reporter gene pMitoTimer compared with 0 h (P = 0.002), this mitochondrial stress preceded detectable muscle loss. However in female mice, mitochondrial oxidative stress did not occur until 168 h of disuse (~40% greater mitochondrial oxidative stress in 168 h compared with 0 h of disuse, P

Introduction Tourette syndrome (TS) is a complex neurodevelopmental disorder characterized by chronic motor and vocal tics. While consistently effective treatment is lacking, evidence indicates that the modulation of endocannabinoid system is potentially beneficial. Lu AG06466 (previously ABX-1431) is a highly selective inhibitor of monoacylglycerol lipase, the primary enzyme responsible for the degradation of the endocannabinoid ligand 2-arachidonoylglycerol. This exploratory study aimed to determine the effect of Lu AG06466 versus placebo on tics and other symptoms in patients with TS. Methods In this phase 1b cross-over study, 20 adult patients with TS on standard-of-care medications were randomized to a single fasted dose of Lu AG06466 (40 mg) or placebo in period 1, followed by the other treatment in period 2. The effects on tics, premonitory urges, and psychiatric comorbidities were evaluated using a variety of scaled approaches at different time points before and after treatment. Results All scales showed an overall trend of tic reduction, with two out of three tic scales (including the Total Tic Score of the Yale Global Tic Severity Score) showing a significant effect of a single dose of Lu AG06466 versus placebo at various timepoints. Treatment with Lu AG06466 resulted in a significant reduction in premonitory urges versus placebo. Single doses of Lu AG06466 were generally well-tolerated, and the most common adverse events were headache, somnolence, and fatigue. Conclusion In this exploratory trial, a single dose of Lu AG06466 showed statistically significant positive effects on key measures of TS symptoms.

A standardized definition of treatment failure in the management of tics is currently lacking. Such definition would prevent persistent use of unnecessary interventions and help clinicians to determine when to offer less established treatments (e.g., deep brain stimulation surgery). To achieve an expert consensus-based definition of failure of medical treatments for tics, we used a multi-step, multi-round, web-based Delphi approach involving international specialist clinicians with specific expertise in tic disorders. These experts were identified through professional networks or consortia related to chronic tic disorders. We created a survey and reviewed the questions with stakeholders prior to two rounds of Delphi surveys, followed by a final review and discussion among research team members. Both survey rounds were completed using a sample of 36 expert stakeholders from 14 countries, including neurologists, psychiatrists, and clinical psychologists. The Delphi process led to consensus on 10 statements which formed the final definition of treatment failure. The definition was structured and operationalized according to two separate sections, one for behavioral and one for pharmacological treatments. Core components of the definition and its operationalization included lack of efficacy, adherence, and tolerability, as well as a definition of failure of behavioral therapies as a whole, and of pharmacological therapies as a whole. The group concluded that the components of this specific definition reflect the range and complexity of characteristics to consider in establishing tic-related treatment failure. Future research should assess the feasibility of this operational definition and whether it will change clinical decision-making and improve management outcomes.

OBJECTIVE: To investigate the effect of restriction measures implemented to mitigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission during the coronavirus disease 2019 (COVID-19) pandemic on pregnancy duration and outcome. METHODS: A before-and-after study was conducted with cohort sampling in three maternity hospitals in Melbourne, Australia, including women who were pregnant when restriction measures were in place during the COVID-19 pandemic (estimated conception date between 1 November 2019 and 29 February 2020) and women who were pregnant before the restrictions (estimated conception date between 1 November 2018 and 28 February 2019). The primary outcome was delivery before 34 weeks' gestation or stillbirth. The main secondary outcome was a composite of adverse perinatal outcomes. Pregnancy outcomes were compared between women exposed to restriction measures and unexposed controls using the χ-square test and modified Poisson regression models, and duration of pregnancy was compared between the groups using survival analysis. RESULTS: In total, 3150 women who were exposed to restriction measures during pregnancy and 3175 unexposed controls were included. Preterm birth before 34 weeks or stillbirth occurred in 95 (3.0%) exposed pregnancies and in 130 (4.1%) controls (risk ratio (RR), 0.74 (95% CI, 0.57-0.96); P = 0.021). Preterm birth before 34 weeks occurred in 2.4% of women in the exposed group and in 3.4% of women in the control group (RR, 0.71 (95% CI, 0.53-0.95); P = 0.022), without evidence of an increase in the rate of stillbirth in the exposed group (0.7% vs 0.9%; RR, 0.83 (95% CI, 0.48-1.44); P = 0.515). Competing-risks regression analysis showed that the effect of the restriction measures on spontaneous preterm birth was stronger and started earlier (subdistribution hazard ratio (HR), 0.81 (95% CI, 0.64-1.03); P = 0.087) than the effect on medically indicated preterm birth (subdistribution HR, 0.89 (95% CI, 0.70-1.12); P = 0.305). The effect was stronger in women with a previous preterm birth (RR, 0.42 (95% CI, 0.21-0.82); P = 0.008) than in parous women without a previous preterm birth (RR, 0.93 (95% CI, 0.63-1.38); P = 0.714) (P for interaction = 0.044). Composite adverse perinatal outcome was less frequent in the exposed group than in controls (all women: 2.1% vs 2.9%; RR, 0.73 (95% CI, 0.54-0.99); P = 0.042); women with a previous preterm birth: 4.5% vs 8.4%; RR, 0.54 (95% CI, 0.25-1.18); P = 0.116). CONCLUSIONS: Restriction measures implemented to mitigate SARS-CoV-2 transmission during the COVID-19 pandemic were associated with a reduced rate of preterm birth before 34 weeks. This reduction was mainly due to a lower rate of spontaneous prematurity. The effect was more substantial in women with a previous preterm birth and was not associated with an increased stillbirth rate. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

NEW FINDINGS What is the central question of this study? Is the oestrous cycle affected during disuse atrophies and, if so, how are oestrous cycle changes related to musculoskeletal outcomes? What is the main finding and its importance? Rodent oestrous cycles were altered during disuse atrophy, which was correlated with musculoskeletal outcomes. However, the oestrous cycle did not appear to be changed by Lewis lung carcinoma, which resulted in no differences in muscle size in comparison to healthy control animals. These findings suggest a relationship between the oestrous cycle and muscle size during atrophic pathologies. ABSTRACT Recent efforts have focused on improving our understanding of female muscle physiology during exposure to muscle atrophic stimuli. A key feature of female rodent physiology is the oestrous cycle. However, it is not known how such stimuli interact with the oestrous cycle to influence muscle health. In this study, we investigated the impact of muscle atrophic stimuli on the oestrous cycle and how these alterations are correlated with musculoskeletal outcomes. A series of experiments were performed in female rodents, including hindlimb unloading (HU), HU followed by 24 h of reloading, HU combined with dexamethasone treatment, and Lewis lung carcinoma. The oestrous cycle phase was assessed throughout each intervention and correlated with musculoskeletal outcomes. Seven or 14 days of HU increased the duration in dioestrus or metoestrus (D/M; low hormones) and was negatively correlated with gastrocnemius mass. Time spent in D/M was also negatively correlated with changes in grip strength and bone density after HU, and with muscle recovery 24 h after the cessation of HU. The addition of dexamethasone strengthened these relationships between time in D/M and reduced musculoskeletal outcomes. However, in animals with Lewis lung carcinoma, oestrous cyclicity did not differ from that of control animals, and time spent in D/M was not correlated with either gastrocnemius mass or tumour burden. In vitro experiments suggested that enhanced protein synthesis induced by estrogen might protect against muscle atrophy. In conclusion, muscle atrophic insults are correlated with changes in the oestrous cycle, which are associated with deterioration in musculoskeletal outcomes. The magnitude of oestrous cycle alterations depends on the atrophic stimuli.

Objective:To compare the effect of comorbidities on the phenotype and outcomes of preeclampsia.Methods: A matched retrospective cohort study of women delivering at a tertiary maternity center following a diagnosis of preeclampsia. We collected data on signs and symptoms, biochemical markers, and maternal and perinatal outcomes.Results:We studied 474 women; 158 women with and 316 without comorbidities. Compared to women without comorbidities, women with comorbidities delivered earlier. They suffered fewer maternal but more neonatal complications.Conclusion: Women with comorbidities receive earlier intervention than women without comorbidities, which may lead to fewer maternal complications but worse neonatal outcomes.

COVID‐19 has resulted in unprecedented changes to maternity care across Australia. This study aims to analyse trends in maternity consultations and the uptake of telehealth in Victoria and New South Wales (NSW) since the first restrictions to reduce COVID‐19 transmission were implemented. From March 2020 to April 2021, a higher proportion of antenatal care consultations was delivered via telehealth in Victoria compared to NSW (13.8% vs 7.4%, P

We report the first outbreak of a new type of mass sociogenic illness that in contrast to all previously reported episodes is spread solely via social media. Accordingly, we suggest the more specific term ‘mass social media-induced illness’. In Germany, the current outbreak of mass social media-induced illness is initiated by a ‘virtual’ index case, who is the second most successful YouTube creator in Germany and enjoys enormous popularity among young people. Affected teenagers present with similar or identical functional ‘Tourette-like’ behaviours, which can be clearly differentiated from tics in Tourette syndrome. Functional ‘Tourette-like’ symptoms can be regarded as the ‘modern’ form of the well-known motor variant of mass sociogenic illness. Moreover, they can be viewed as the 21st century expression of a culture-bound stress reaction of our post-modern society emphasizing the uniqueness of individuals and valuing their alleged exceptionality, thus promoting attention-seeking behaviours and aggravating the permanent identity crisis of modern man. We wish to raise awareness of the current global Tourette-like mass social media-induced illness outbreak. A large number of young people across different countries are affected, with considerable impact on health care systems and society as a whole, since spread via social media is no longer restricted to specific locations such as local communities or school environments spread via social media is no longer restricted to specific locations such as schools or towns.

The rapid development and roll-out of coronavirus disease 2019 (COVID-19) vaccines is providing hope for a way to control the pandemic. As pregnant and lactating women are generally excluded from clinical trials, the vaccination programme was launched without adequate safety and efficacy data for pregnant women. Yet many professional organizations have recognized the need for administration of COVID-19 vaccines in pregnancy and have issued their own set of recommendations. The lack of evidence, however, has often led to confused messaging, inconsistent language and differing recommendations across organizations, potentially contributing to delay or refusal to accept vaccination by pregnant women. We summarize those differences and recommend that leaders collaborate at a country level to produce joint recommendations. We use the example of Australia, where two professional authorities along with the government and partners in New Zealand worked towards one message, consistent language and a unified recommendation. The aim was to help health professionals and women who are planning pregnancy or who are currently pregnant or breastfeeding to make an informed decision about COVID-19 vaccination. National advisory groups for immunization, professional obstetric organizations and government bodies should be encouraged to coordinate their statements on COVID-19 vaccination for pregnant and lactating women and to use similar language and phrasing for greater clarity.La rapidité de développement et de déploiement des vaccins contre la maladie à coronavirus 2019 (COVID-19) entretient l'espoir d'un jour pouvoir contrôler la pandémie. Étant donné que les femmes enceintes et allaitantes sont généralement exclues des essais cliniques, le programme de vaccination a été lancé en l'absence de données adéquates sur l'efficacité et l'innocuité du vaccin au sein de cette catégorie. Pourtant, de nombreuses associations professionnelles ont reconnu la nécessité de vacciner contre la COVID-19 durant la grossesse, et ont émis leurs propres recommandations. L'absence de preuves a toutefois souvent donné lieu à une communication incohérente, à un discours contradictoire et à des recommandations divergentes d'une organisation à l'autre, ce qui pourrait avoir conduit certaines femmes enceintes à retarder ou refuser la vaccination. Dans le présent document, nous exposons ces différences et exhortons les dirigeants à collaborer au niveau national pour formuler des recommandations communes. Nous utilisons l'exemple de l'Australie, où deux autorités professionnelles ont travaillé avec le gouvernement et des partenaires en Nouvelle-Zélande afin de transmettre un message unique, d'adopter un langage cohérent et de fournir des directives homogènes. L'objectif était d'aider les soignants et les femmes enceintes, allaitantes ou planifiant une grossesse à prendre une décision éclairée en matière de vaccination contre la COVID-19. Les organes consultatifs nationaux sur la vaccination, les associations professionnelles d'obstétrique et les pouvoirs publics devraient être encouragés à aligner leurs déclarations concernant la vaccination contre la COVID-19 chez les femmes enceintes et allaitantes, ainsi qu'à employer des termes et énoncés similaires pour davantage de clarté.El rápido desarrollo y puesta en marcha de las vacunas contra el coronavirus de la enfermedad por coronavirus (COVID-19) está dando esperanzas sobre una forma de controlar la pandemia. Como las mujeres embarazadas y lactantes suelen estar excluidas de los ensayos clínicos, el programa de vacunación se puso en marcha sin datos adecuados de seguridad y eficacia para las mujeres embarazadas. Sin embargo, muchas organizaciones profesionales han reconocido la necesidad de administrar las vacunas contra la COVID-19 durante el embarazo y han emitido su propio conjunto de recomendaciones. Sin embargo, la falta de pruebas a menudo ha ocasionado mensajes confusos, un lenguaje incoherente y recomendaciones diferentes en las distintas organizaciones, lo que puede contribuir a retrasar o rechazar la vacunación de las mujeres embarazadas. Resumimos esas diferencias y recomendamos que los líderes colaboren a nivel de país para elaborar recomendaciones conjuntas. Utilizamos el ejemplo de Australia, donde dos autoridades profesionales, junto con el gobierno y los socios de Nueva Zelanda, trabajaron para lograr transmitir un único mensaje con un lenguaje coherente y una recomendación unificada. El objetivo era ayudar a los profesionales sanitarios y a las mujeres que planean un embarazo o embarazadas o en periodo de lactancia a tomar una decisión informada sobre la vacunación contra la COVID-19. Hay que animar a los grupos consultivos nacionales de inmunización, a las organizaciones profesionales de obstetricia y a los organismos gubernamentales a que coordinen sus declaraciones sobre la vacunación contra la COVID-19 para las mujeres embarazadas y lactantes y a que utilicen un lenguaje y una redacción similares para mayor claridad.إن التطور والطرح السريع للقاحات مرض فيروس كورونا 2019 (كوفيد 19)، يمنحان الأمل في توفير طريقة للسيطرة على الجائحة. ونظرًا لأن النساء الحوامل والمرضعات يتم استبعادهن عمومًا من التجارب الإكلينيكية، فقد تم إطلاق برنامج التطعيم دون توفر بيانات كافية عن السلامة والفعالية بالنسبة للحوامل. إلا أن العديد من المنظمات المهنية قد أدركت الحاجة إلى إعطاء لقاحات كوفيد 19 أثناء الحمل، وأصدرت مجموعة من التوصيات الخاصة بها. ومع ذلك، فقد أدى الافتقار لوجود أدلة في كثير من الأحيان إلى رسائل مربكة، ولغة غير متناغمة، وتوصيات مختلفة من المنظمات المختلفة، وهو ما قد يساهم في تأخير أو رفض قبول التطعيم من جانب النساء الحوامل. نحن نلخص هذه الاختلافات، ونوصي بأن يقوم القادة بالتعاون على مستوى الدولة لوضع توصيات مشتركة. نحن نستخدم المثال الخاص بأستراليا، حيث عملت سلطتان مهنيتان، جنبًا إلى جنب، مع الحكومة، والشركاء في نيوزيلندا معًا، من أجل صياغة رسالة واحدة، ولغة متناغمة، وتوصية موحدة. كان الهدف هو مساعدة أخصائيي الصحة والنساء اللواتي يخططن للحمل، أو الحوامل أو المرضعات حاليًا، لاتخاذ قرار مستنير بشأن تطعيم كوفيد 19. يجب تشجيع المجموعات الاستشارية الوطنية للتحصين، ومنظمات التوليد المهنية، والهيئات الحكومية على تنسيق بياناتها بشأن تطعيم كوفيد 19 للنساء الحوامل والمرضعات، واستخدام لغة وصياغة مماثلة لتحقيق مزيد من الوضوح.新型冠状病毒肺炎疫苗的快速研发和推广为疫情防控工作带来了希望。由于临床试验通常不纳入孕期和哺乳期妇女,所以疫苗接种计划的推行并没有充足的针对孕期妇女的安全和疗效数据。不过,众多专业组织已经意识到在孕期接种新冠疫苗的必要性,并且发布了自己的一套推荐程序。然而,证据的缺乏往往导致不同组织之间的信息混乱、语言不一致和意见分歧,从而有可能导致孕妇推迟或拒绝接种疫苗。我们总结了这些差异并建议各个组织的领导能够在国家层面开展合作以提出意见统一的推荐程序。我们以澳大利亚为例,该国两个专业的权威机构与政府和新西兰的合作伙伴联合提出以一致的语言,传递统一的讯息和推荐程序。其目的在于帮助医护工作者和打算怀孕或者正处于孕期或哺乳期的妇女针对新冠疫苗接种作出明智的决策。我们应鼓励国家免疫咨询小组、专业的产科机构和政府单位统一他们针对孕期和哺乳期妇女接种新冠疫苗方面的陈述,并使用类似的语言和措辞以便更加明确地阐述其意见。.Быстрая разработка и внедрение вакцин против коронавирусной инфекции 2019 года (COVID-19) вселяет надежду в борьбе с этой пандемией. Поскольку беременные и кормящие женщины обычно не участвуют в клинических испытаниях, программа вакцинации была запущена без надлежащих данных о безопасности и эффективности для беременных женщин. Тем не менее многие профессиональные организации признали необходимость применения вакцины против COVID-19 во время беременности и выпустили свой собственный набор рекомендаций. Однако отсутствие доказательств часто приводило к путанице в информационных сообщениях, противоречащим формулировкам и несогласованным рекомендациям в разных организациях, что потенциально способствовало задержке вакцинации или отказу беременных женщин от вакцинации. Авторы приводят сводку этих различий и рекомендуют руководителям сотрудничать на уровне страны для подготовки совместных рекомендаций. В качестве примера использован опыт Австралии, где два профессиональных органа вместе с правительством и партнерами в Новой Зеландии работали над согласованным информированием, едиными формулировками и рекомендациями. Цель заключалась в том, чтобы помочь медицинским работникам и женщинам, планирующим беременность, беременным или кормящим грудью, принять обоснованное решение по поводу вакцинации против COVID-19. Следует поощрять национальные консультативные группы по иммунизации, профессиональные акушерские организации и государственные органы согласовывать свои заявления о вакцинации против COVID-19 для беременных и кормящих женщин, а также использовать схожие формулировки и выражения для обеспечения большей ясности.

Aim Dual enkephalinase inhibitors (DENKIs) are involved in the regulation of nociception via opioid receptors. The novel compound STR-324 belongs to the DENKI pharmacological class. This first-in-human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of STR-324 in healthy male participants. Methods This was a randomised, double-blind, placebo-controlled ascending dosing study in two parts: in part 1, 30 participants received 0.004-11.475 mg h(-1) of STR-324 or placebo (ratio 4:1) by 4 h intravenous infusion in a two-group, partial crossover design with four treatment periods separated by 1 month wash-out, and in part 2, 48 participants divided into three groups received either the active drug (1.25-11.25 mg h(-1)) or placebo (ratio 3:1) by 48 h intravenous infusion. Safety and tolerability parameters, pharmacokinetics and pharmacodynamic effects on neurocognitive and neurophysiological tasks and on a nociceptive test battery were evaluated. Results No clinically relevant changes in safety parameters were observed. All treatment-emergent adverse events were mild and transient. The pharmacokinetics of STR-324 could not be determined due to most concentrations being below quantifiable limits. STR-324 metabolite concentrations were measurable, showing dose proportionality of C-max and AUC(inf) with an estimated t(1/2) of 0.2-0.5 h. Significant changes in pharmacodynamic parameters were observed, but these were not consistent or dose-dependent. Conclusion STR-324 displayed favourable safety and tolerability profiles at all doses up to 11.475 mg h(-1). Although pharmacokinetic characterisation of STR-324 was limited, dose proportionality could be assumed based on major metabolite data assayed as proxy. No clear effects on nociceptive thresholds or other pharmacodynamic measures were observed. Trial registry: EudraCT (2014-002402-21) and toetsingonline.nl (63085).

In 2011 a working group of the European Society for the Study of Tourette syndrome (ESSTS) developed the first European Guidelines for Tourette syndrome (TS) published in the ECAP journal. After a decade ESSTS now presents updated guidelines, divided into four sections: Part I: assessment, Part II: psychological interventions, Part III: pharmacological treatment and Part IV: deep brain stimulation (DBS). In this paper, we summarise new developments described in the guidelines with respect to assessment and treatment of tics. Further, summary findings from a recent survey conducted amongst TS experts on these same topics are presented, as well as the first European patient representative statement on research. Finally, an updated decision tree is introduced providing a practical algorithm for the treatment of patients with TS. Interestingly, in the last decade there has been a significant shift in assessment and treatment of tics, with more emphasis on non-pharmacological treatments.

Summary Background Little evidence is available on the use of telehealth for antenatal care. In response to the COVID-19 pandemic, we developed and implemented a new antenatal care schedule integrating telehealth across all models of pregnancy care. To inform this clinical initiative, we aimed to assess the effectiveness and safety of telehealth in antenatal care. Methods We analysed routinely collected health data on all women giving birth at Monash Health, a large health service in Victoria (Australia), using an interrupted time-series design. We assessed the impact of telehealth integration into antenatal care from March 23, 2020, across low-risk and high-risk care models. Allowing a 1-month implementation period from March 23, 2020, we compared the first 3 months of telehealth integrated care delivered between April 20 and July 26, 2020, with conventional care delivered between Jan 1, 2018, and March 22, 2020. The primary outcomes were detection and outcomes of fetal growth restriction, pre-eclampsia, and gestational diabetes. Secondary outcomes were stillbirth, neonatal intensive care unit admission, and preterm birth (birth before 37 weeks' gestation). Findings Between Jan 1, 2018, and March 22, 2020, 20 031 women gave birth at Monash Health during the conventional care period and 2292 women gave birth during the telehealth integrated care period. Of 20 154 antenatal consultations provided in the integrated care period, 10 731 (53%) were delivered via telehealth. Overall, compared with the conventional care period, no significant differences were identified in the integrated care period with regard to the number of babies with fetal growth restriction (birthweight below the 3rd percentile; 2% in the integrated care period vs 2% in the conventional care period, p=0·72, for low-risk care models; 5% in the integrated care period vs 5% in the conventional care period, p=0·50 for high-risk care models), number of stillbirths (1% vs 1%, p=0·79; 2% vs 2%, p=0·70), or pregnancies complicated by pre-eclampsia (3% vs 3%, p=0·70; 9% vs 7%, p=0·15), or gestational diabetes (22% vs 22%, p=0·89; 30% vs 26%, p=0·06). Interrupted time-series analysis showed a significant reduction in preterm birth among women in high-risk models (–0·68% change in incidence per week [95% CI −1·37 to −0·002]; p=0·049), but no significant differences were identified in other outcome measures for low-risk or high-risk care models after telehealth integration compared with conventional care. Interpretation Telehealth integrated antenatal care enabled the reduction of in-person consultations by 50% without compromising pregnancy outcomes. This care model can help to minimise in-person interactions during the COVID-19 pandemic, but should also be considered in post-pandemic health-care models. Funding None.

This study investigated whether vitamin D is associated with the presence or severity of chronic tic disorders and their psychiatric comorbidities. This cross-sectional study compared serum 25-hydroxyvitamin D [25(OH)D] (ng/ml) levels among three groups: children and adolescents (3–16 years) with CTD (n = 327); first-degree relatives (3–10 years) of individuals with CTD who were assessed for a period of up to 7 years for possible onset of tics and developed tics within this period (n = 31); and first-degree relatives who did not develop tics and were ≥ 10 years old at their last assessment (n = 93). The relationship between 25(OH)D and the presence and severity of tics, as well as comorbid obsessive–compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD), were analysed controlling for age, sex, season, centre, latitude, family relatedness, and comorbidities. When comparing the CTD cohort to the unaffected cohort, the observed result was contrary to the one expected: a 10 ng/ml increase in 25(OH)D was associated with higher odds of having CTD (OR 2.08, 95% CI 1.27–3.42, p p = 0.01) and was inversely associated with ADHD symptom severity (β = − 2.52, 95% CI − 4.16–0.88, p

BACKGROUND Prenatal exposure to alcohol leads to a greater incidence of many cardiovascular-related diseases, presumably via a mechanism that may involve increased oxidative stress. An agonist of peroxisome proliferator-activated receptor gamma (PPARγ; rosiglitazone) has been shown to suppress alcohol-induced neuroinflammation and oxidative stress. The goal of this study was to determine whether acute and chronic treatment with rosiglitazone could restore or prevent impaired nitric oxide synthase (NOS)-dependent responses of cerebral arterioles in male and female adult (14-16 weeks old) rats exposed to alcohol in utero. METHODS We fed Sprague-Dawley dams a liquid diet with or without 3% ethanol for the duration of their pregnancy (21-23 days). In the first series of studies, we examined the reactivity of cerebral arterioles to eNOS- (ADP), nNOS-dependent (NMDA), and NOS-independent agonists in male and female adult rats before and during acute (1 hour) topical application of rosiglitazone (1 µM). In a second series of studies, we examined the influence of chronic treatment with rosiglitazone (3 mg/kg/day in drinking water for 2-3 weeks) on the responses of cerebral arterioles in male and female adult rats exposed to alcohol in utero. RESULTS We found that in utero exposure to alcohol similarly reduced responses of cerebral arterioles to ADP and NMDA, but not to nitroglycerin in male and female adult rats. In addition, acute treatment of the male and female adult rats with rosiglitazone similarly restored this impairment in cerebral vascular function to that observed in controls. We also found that chronic treatment with rosiglitazone prevented impaired vascular function in male and female adult rats that were exposed to alcohol in utero. CONCLUSIONS PPARγ activation may be an effective and relevant treatment to reverse or prevent cerebral vascular abnormalities associated with prenatal exposure to alcohol.

Lockdown drills are routinely conducted in schools across the U.S., yet little is known about the impact of such practices on participants—particularly for the faculty, staff, and administrators charged with student safety. The present study considers the effects of lockdown drills and associated emergency response training on perceived safety and preparedness at school for a sample of 3,000 school-based personnel in a large urban school district. After participating in drills and training, significant gains were made in perceived emergency preparedness, particularly among faculty and staff members, while perceived school safety—which already was particularly high—remained unaffected compared to ratings at baseline. Additionally, significant differences were found based upon respondent demographics, highlighting the importance in assessing subgroups’ needs during planning and implementation. Implications for school administration and relevant policymakers related to lockdown drills and training are considered within the context of creating a culture of preparedness.

Background There are still no sufficient data regarding the use of deep brain stimulation (DBS) in Gilles de la Tourette syndrome (GTS) and no agreement on optimal target. Objective To compare efficacy and safety of bilateral DBS of thalamus (centromedian-ventro-oral internus, CM-Voi) versus posteroventral lateral globus pallidus internus (pvl GPi)) versus sham stimulation, and baseline in severe medically refractory GTS. Methods In this randomized double-blind sham stimulation-controlled trial (RCT), 10 patients (3 women, mean age = 29.4 ± 10.2 SD, range 18–47) underwent three blinded periods each lasting three months including (i) sham, (ii) pvl GPi (on-GPi), and (iii) thalamic stimulation (on-thal) followed by an open uncontrolled long-term follow-up (up to 9 years) with individually determined target and stimulation settings. Results Nine patients completed the RCT. At group level, on-GPi – but not on-thal – resulted in a significant tic reduction compared to baseline, but had no effect on premonitory urges and psychiatric comorbidities. Direct comparisons of targets resulted in inconsistent or negative (compared to sham) findings. During follow-up, we found no improvement of tics, comorbidities, and quality of life at group level, however, single patients benefitted continuously from thalamic DBS. At last follow-up 89.9 months (mean) after surgery, 50% of patients had discontinued DBS. Hardware infections occurred in 3/10 patients. Conclusion Our data suggest that the initial effect of pvl GPi DBS is superior to thalamic (CM-Voi) DBS. While half of the patients discontinued treatment, single patients benefitted from thalamic DBS even after years. It is likely that outcome is influenced by various factors beyond the mere change in tic severity.

Tourette syndrome (TS) is characterized by the presence of vocal and motor tics with an onset in childhood. In almost 80% of patients psychiatric comorbidities coexist, particularly, attention deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD) or behavior (OCB), depression, anxiety, rage attacks, and self-injurious behaviour (SIB). In this review, we discuss current state of the art regarding diagnosis and assessment of tics and OCD in patients with TS as well as challenges related to differential diagnosis between tics and OCD-related phenomena based on a systematic literature search. While in most cases clinical symptoms can be easily classified as either tics or OCB/OCD, some phenomena lay on the frontier between tics and compulsions/obsessions. For example, compulsions may resemble tics and, vice versa, sequences of motor tics may be misdiagnosed as compulsions. Accordingly, the terms “compulsive tics” and “cognitive tics” have been introduced. The most common and typical OCD symptom in patients with TS are “just right” phenomena, which also may show an overlap with tics, since patients may perform tics repeatedly until this feeling is achieved. Similarly, repetitive behaviors in patients with TS may manifest in a more “tic-like” or a more “OCD-like” type. Furthermore, SIB shows similarities with both tics and OCD. Until today, it is unclear how to classify this symptom best, although from most recent research a closer relationship between SIB and tics is suggested. In this review, in addition, we illustrate differences of the clinical spectrum of OCD in patients with TS compared to those with “pure OCD” without tics. To assess tics, the revised version of the Yale Global Tic Severity Scale (YGTSS-R) should be used, while for the assessment of OCD, the Yale Brown Obsessive Compulsive Disorder Scale (Y-BOCS) is recommended. Finally, we briefly summarize treatment strategies for tics and OCB/OCD in patients with TS.

Objective To compare the effectiveness and safety of Foley catheter and oral misoprostol for induction of labor (IOL). Methods The Cochrane Review on Mechanical Methods for Induction of Labour and Ovid MEDLINE, EMBASE via Ovid, Ovid Emcare, CINAHL Plus, ClinicalTrials.gov and Scopus, from inception to April 2019, were searched for randomized controlled trials (RCTs) comparing Foley catheter to oral misoprostol for IOL in viable singleton gestations. Eligible trials for which raw data were obtained were included and individual participant data meta-analysis was performed. Primary outcomes were vaginal birth, a composite of adverse perinatal outcome (including stillbirth, neonatal death, neonatal seizures, admission to the neonatal intensive care unit, severe respiratory compromise or meconium aspiration syndrome) and a composite of adverse maternal outcome (including admission to the intensive care unit, maternal infection, severe postpartum hemorrhage, maternal death or uterine rupture). The quality of the included RCTs was assessed using the Cochrane Risk of Bias 2 tool and the certainty of evidence was evaluated using the GRADE approach. A two-stage random-effects model was used for meta-analysis according to the intention-to-treat principle and interactions between treatment and baseline characteristics were assessed. Results Of seven eligible trials, four provided individual participant data for a total of 2815 participants undergoing IOL, of whom 1399 were assigned to Foley catheter and 1416 to oral misoprostol. All four trials provided data for each of the primary outcomes in all 2815 women. Compared with those receiving oral misoprostol, Foley catheter recipients had a slightly decreased chance of vaginal birth (risk ratio (RR), 0.95 (95% CI, 0.91-0.99); I2 , 2.0%; moderate-certainty evidence). A trend towards a lower rate of composite adverse perinatal outcome was found in women undergoing IOL using a Foley catheter compared with oral misoprostol (RR, 0.71 (95% CI, 0.48-1.05); I2 , 14.9%; low-certainty evidence). Composite adverse maternal outcome did not differ between the groups (RR, 1.00 (95% CI, 0.97-1.03); I2 , 0%; moderate-certainty evidence). Meta-analyses of effect modifications did not show significant interactions between intervention and parity or gestational age for any of the primary outcomes. Conclusions For women undergoing IOL, Foley catheter is less effective than oral misoprostol, as it was associated with fewer vaginal births. However, while we found no significant difference in maternal safety, Foley catheter induction may reduce adverse perinatal outcomes. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Aim To determine the prevalence of atypical general movements (GMs) in the general population, to examine its time trend and associated factors.Methods Participants consisted of 300 infants born in 2016-2018 (current cohort; gestational age 39.4 weeks (27-42); 162 boys), representative of the Dutch population. GMs were assessed at 2-4 months corrected age in terms of GM-complexity (definitely abnormal (DA) or not) and fidgety movements (present or absent). GM-complexity data from a cohort of 455 Dutch infants born in 2001-2002 were used to investigate the time trend.Results In the current cohort, 10 infants (3%) showed DA GM-complexity and 8 (3%) absent fidgety movements. Only one infant had both GM-impairments (0.3%). The prevalence of DA GM-complexity did not differ from that in the 2001-2002 cohort (adjusted odds ratio (OR) = 1.47 [0.53, 4.06]). DA GM-complexity was associated with maternal smoking (adjusted OR = 3.59 [1.56, 8.28]) and marginally with prematurity (adjusted OR = 2.78 [1.00, 7.74]); absence of fidgety movements was curvilinearly associated with assessment age only (OR = 1.06 [1.01, 1.12]).Conclusion In the general population, the prevalence of DA GM-complexity and absent fidgety movements is 3%. The finding that they rarely co-occur and are associated with different factors indicates that GM-assessment needs to address both aspects.

ASP8232 is a novel inhibitor of vascular adhesion protein-1 that was under evaluation for reducing residual albuminuria in patients with diabetic kidney disease. To characterize the pharmacokinetics (PK) of ASP8232 and its effect on vascular adhesion protein 1 (VAP-1) plasma activity and VAP-1 concentrations (pharmacodynamics, PD) in an integrated and quantitative manner, a target mediated drug disposition model was developed based on pooled data from four completed clinical trials with ASP8232 in healthy volunteers, and in patients with diabetic kidney disease and diabetic macular edema, respectively. In this model, the binding of ASP8232 to its soluble and membrane-bound target in the central and peripheral compartments were included. The model was able to adequately describe the non-linear PK and PD of ASP8232. The observed difference in PK between healthy volunteers and renally impaired patients could be explained by an effect of baseline estimated glomerular filtration rate on ASP8232 clearance and relative bioavailability. The relationship between ASP8232 concentration and VAP-1 inhibition was successfully established and can be applied to simulate drug exposure and degree of VAP-1 inhibition for any given dose of ASP8232 across the spectrum of renal function. Electronic supplementary material The online version of this article (10.1007/s10928-020-09717-w) contains supplementary material, which is available to authorized users.

The vascular adhesion protein-1 (VAP-1) inhibitor ASP8232 reduces albuminuria in patients with type 2 diabetes and chronic kidney disease. A mechanism-based model was developed to quantify the effects of ASP8232 on renal markers from a placebo-controlled Phase 2 study in diabetic kidney disease with 12 weeks of ASP8232 treatment. The model incorporated the available pharmacokinetic, pharmacodynamic (plasma VAP-1 concentration and activity), serum and urine creatinine, serum cystatin C, albumin excretion rate, urinary albumin-to-creatinine ratio, and urine volume information in an integrated manner. Drug-independent time-varying changes and different drug effects could be quantified for these markers using the model. Through simulations, this model provided the opportunity to dissect the relationship and longitudinal association between the estimated glomerular filtration rate and albuminuria and to quantify the pharmacological effects of ASP8232. The developed drug-independent model may be useful as a starting point for other compounds affecting the same biomarkers in a similar time scale. Electronic supplementary material The online version of this article (10.1007/s10928-020-09716-x) contains supplementary material, which is available to authorized users.

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

Pharmacological cardioversion of atrial fibrillation (AF) is frequently inefficacious. AP30663, a small conductance Ca2+ activated K+ (KCa2) channel blocker, prolonged the atrial effective refractory period in preclinical studies and subsequently converted AF into normal sinus rhythm. This first-in-human study evaluated the safety and tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects were explored. Forty-seven healthy male volunteers (23.7 ± 3.0 years) received AP30663 intravenously in ascending doses. Due to infusion site reactions, changes to the formulation and administration were implemented in the latter 24 volunteers. Extractions from a 24-hour continuous electrocardiogram were used to evaluate the PD effect of AP30663. Data were analyzed with a repeated measure analysis of covariance, noncompartmental analysis, and concentration-effect analysis. In total, 33 of 34 adverse events considered related to AP30663 exposure were related to the infusion site, mild in severity, and temporary in nature, although full recovery took up to 110 days. After formulation and administration changes, the local infusion site reaction remained, but the median duration was shorter despite higher dose levels. AP30663 displayed a less than dose proportional increase in peak plasma concentration (Cmax) and a terminal half-life of around 5 hours. In healthy volunteers, no effect of AP30663 was observed on electrocardiographic parameters, other than a concentration-dependent effect on the corrected QT Fridericia’s formula interval (+18.8 ± 4.3 ms for the highest dose level compared with time matched placebo). In conclusion, administration of AP30663, a novel KCa2 channel inhibitor, was safe and well-tolerated systemically in humans, supporting further development in patients with AF undergoing cardioversion.

ZUSAMMENFASSUNGDie Behandlung von Patienten mit Gilles-de-la-Tourette-Syndrom (GTS) ist bis heute unbefriedigend, da etablierte Therapien nur zu einer partiellen Reduktion der Tics und nicht zu einer Verbesserung psychiatrischer Komorbiditäten führen. Die medikamentöse Behandlung mit Antipsychotika führt oft zu relevanten Nebenwirkungen. Daher besteht großes Interesse, neue Behandlungsstrategien zu entwickeln. Basierend auf anekdotischen Berichten und kleinen Studien, in denen über positive Effekte durch Cannabis und cannabisbasierte Medikamente bei Patienten mit GTS berichtet wurde, wird in kontrollierten Studien untersucht, ob Medikamente, die durch unterschiedliche Mechanismen zu einer Stimulation des Endocannabinoidsystems führen, wirksam und verträglich in der Therapie von Tics und Komorbiditäten sind. In dieser Übersicht werden bisherige Studienergebnisse vorgestellt. Es werden Hypothesen diskutiert, warum Cannabinoide in der Behandlung des GTS wirksam sein könnten. Schließlich werden praktische Empfehlungen zur Therapie mit cannabisbasierten Medikamenten gegeben.

Few studies have examined factors associated with the timing of identification of hearing loss within a cohort of infants identified as deaf or hard of hearing (DHH) and what factors are associated with delayed identification. Minnesota Early Hearing Detection and Intervention (EHDI) personnel studied deidentified data from 729 infants with confirmed congenital hearing loss (i.e., hearing loss identification after not passing newborn hearing screening) born in Minnesota during 2012-2016. Differences in likelihood of delayed identification of congenital hearing loss (defined as not passing newborn hearing screening and age >3 months at the time of identification as DHH) based on multiple variables were analyzed. Overall, 222 (30.4%) infants identified as DHH had delayed identification. Multivariate regression showed that infants identified as DHH were significantly more likely to have delayed identification if they had 1) low birthweight, 2) public insurance, 3) a residence outside the metropolitan area, 4) a mother with a lower level of education, 5) a mother aged

Purpose Spontaneous venous pulsation (SVP) has a high negative predictive value for raised intracranial pressure and is a useful sign when assessing patients with headache. The objective was to determine if smartphone-based video ophthalmoscopy can detect SVP. Patients and methods In total 233 patients and 291 eyes were recruited from the Dunedin Hospital eye clinic from July to November 2018. Patients were examined by a clinician and graded for SVP with a slit lamp and 78 Dioptre lens. Videos were taken with a smartphone ophthalmoscope and graded by two separate clinicians blinded to the slit lamp findings. Results Only 272 eyes of 215 patients were included, as others failed in the inclusion criteria for overall video quality. Sensitivity was calculated as how likely the presence of SVP on video was indicative of the presence of SVP on slit lamp. Sensitivity was 84.77% for Observer 1, with 128 videos graded as positive for SVP on video ophthalmoscopy of the 151 identified as positive on slit lamp examination. Sensitivity was 76.82% for Observer 2 with 116 videos correctly identified. The false positive rate was calculated as the number of videos graded positive for SVP that had been graded as negative on slit lamp examination. This was 10.74% for observer 1 and 31.40% for observer 2. Conclusion This study demonstrates that SVP is detected by video ophthalmoscopy. This may be a useful triage, telemedicine and referral tool to be used for patients with headache in a primary care setting.

Introduction: 9–20% of the patients with an external ventricular drain develop a catheter-associated infection. Areas covered: This review summarizes the diagnostic process and management of bacterial external ventricular catheter-associated infection. Expert commentary: Current literature shows that no single CSF-, blood- or microbiological measure can be used to differentiate between an infection and sterile inflammation. The gold standard of diagnosis remains CSF culture. Empiric antimicrobial treatment consists of vancomycin combined with an anti-pseudomonal β-lactam. The increase in multi-drug resistant Gram-negative bacteria is an emerging problem in the treatment. Preventive measures and antibiotic-impregnated drains have shown to contribute to reducing incidence of external ventricular drain-associated infections.

Aim: To determine the prevalence of prevailing head position to one side (PHP) in young infants and to evaluate its associations with reaching performance, neurological condition and perinatal and socio-economic factors. Methods: Observational study in 500 infants (273 boys) 2-6 months corrected age, representative of the Dutch population (median gestational age 39.7 weeks (27-42); birthweight 3438 g (1120-4950). Prevailing head position to one side and reaching performance were assessed with the Infant Motor Profile; neurological condition with the Standardized Infant NeuroDevelopmental Assessment. Socio-economic information and perinatal information were obtained by questionnaire and medical records. Associations were analysed with uni- and multivariable statistics. Results: Prevailing head position to one side was observed in 100 infants (20%), and its prevalence decreased from 49% at 2 months to 0% at 6 months. Only in infants aged 4-5 months PHP was significantly associated with worse reaching and an at-risk neurological score. Prevailing head position to one side was weakly associated with prenatal substance exposure, post-natal admission to a paediatric ward and paternal native Dutch background. Conclusion: Prevailing head position to one side at 2-3 months is a frequently occurring sign with limited clinical significance. Yet, PHP at 4-5 months is associated with a worse functional and neurological condition. Therefore, PHP at 4-5 months could serve as a red flag indicating possible challenges in later development.

Part II of the European clinical guidelines for Tourette syndrome and other tic disorders (ECAP journal, 2011) provides updated information and recommendations for psychological interventions for individuals with tic disorders, created by a working group of the European Society for the Study of Tourette Syndrome (ESSTS). A systematic literature search was conducted to obtain original studies of psychological interventions for tic disorders, published since the initial European clinical guidelines were issued. Relevant studies were identified using computerized searches of the MEDLINE and PsycINFO databases for the years 2011–2019 and a manual search for the years 2019–2021. Based on clinical consensus, psychoeducation is recommended as an initial intervention regardless of symptom severity. According to a systematic literature search, most evidence was found for Habit Reversal Training (HRT), primarily the expanded package Comprehensive Behavioral Intervention for Tics (CBIT). Evidence was also found for Exposure and Response Prevention (ERP), but to a lesser degree of certainty than HRT/CBIT due to fewer studies. Currently, cognitive interventions and third-wave interventions are not recommended as stand-alone treatments for tic disorders. Several novel treatment delivery formats are currently being evaluated, of which videoconference delivery of HRT/CBIT has the most evidence to date. To summarize, when psychoeducation alone is insufficient, both HRT/CBIT and ERP are recommended as first-line interventions for tic disorders. As part of the development of the clinical guidelines, a survey is reported from ESSTS members and other tic disorder experts on preference, use and availability of psychological interventions for tic disorders.

In 2011 the European Society for the Study of Tourette Syndrome (ESSTS) published its first European clinical guidelines for the treatment of Tourette Syndrome (TS) with part IV on deep brain stimulation (DBS). Here, we present a revised version of these guidelines with updated recommendations based on the current literature covering the last decade as well as a survey among ESSTS experts. Currently, data from the International Tourette DBS Registry and Database, two meta-analyses, and eight randomized controlled trials (RCTs) are available. Interpretation of outcomes is limited by small sample sizes and short follow-up periods. Compared to open uncontrolled case studies, RCTs report less favorable outcomes with conflicting results. This could be related to several different aspects including methodological issues, but also substantial placebo effects. These guidelines, therefore, not only present currently available data from open and controlled studies, but also include expert knowledge. Although the overall database has increased in size since 2011, definite conclusions regarding the efficacy and tolerability of DBS in TS are still open to debate. Therefore, we continue to consider DBS for TS as an experimental treatment that should be used only in carefully selected, severely affected and otherwise treatment-resistant patients.

To investigate whether earlier “post-term” monitoring of South Asian (SA) pregnancies from 39 weeks’ gestation with amniotic fluid index (AFI) and cardiotocography (CTG) detected suspected fetal compromise. Retrospective cohort study of all SA-born women at an Australian health service with uncomplicated, singleton pregnancies following the introduction of twice-weekly AFI and CTG monitoring from 39 weeks. Monitoring results, and their association with a perinatal compromise composite (including assisted delivery for fetal compromise, stillbirth, and NICU admission) were determined. 771 SA-born women had earlier monitoring, triggering delivery in 82 (10.6%). 31 (4%) had a non-reassuring antepartum CTG (abnormal fetal heart rate or variability, or decelerations) and 21 (2.7%) had an abnormal AFI (≤ 5 cm). Women with abnormal monitoring were 53% (95% CI 1.2–1.9) more likely to experience perinatal compromise and 83% (95% CI 1.2–2.9) more likely to experience intrapartum compromise than women with normal monitoring. Monitoring from 39 weeks identified possible fetal compromise earlier than it otherwise would have been, and triggered intervention in 10% of women. Without robust evidence to guide timing of birth in SA-born women to reduce rates of stillbirth, earlier monitoring provides an alternative to routine induction of labour.

Cancer cachexia (CC) results in impaired muscle function and quality of life and is the primary cause of death for ∼20%–30% of patients with cancer. We demonstrated mitochondrial degeneration as a precursor to CC in male mice; however, whether such alterations occur in females is currently unknown. The purpose of this study was to elucidate muscle alterations in CC development in female tumor-bearing mice. Sixty female C57BL/6J mice were injected with PBS or Lewis lung carcinoma at 8 wk of age, and tumors developed for 1, 2, 3, or 4 wk to assess the time course of cachectic development. In vivo muscle contractile function, protein fractional synthetic rate (FSR), protein turnover, and mitochondrial health were assessed. Three- and four-week tumor-bearing mice displayed a dichotomy in tumor growth and were reassigned to high tumor (HT) and low tumor (LT) groups. HT mice exhibited lower soleus, tibialis anterior, and fat weights than PBS mice. HT mice showed lower peak isometric torque and slower one-half relaxation time than PBS mice. HT mice had lower FSR than PBS mice, whereas E3 ubiquitin ligases were greater in HT than in other groups. Bnip3 (mitophagy) and pMitoTimer red puncta (mitochondrial degeneration) were greater in HT mice, whereas Pgc1α1 and Tfam (mitochondrial biogenesis) were lower in HT mice than in PBS mice. We demonstrate alterations in female tumor-bearing mice where HT exhibited greater protein degradation, impaired muscle contractility, and mitochondrial degeneration compared with other groups. Our data provide novel evidence for a distinct cachectic development in tumor-bearing female mice compared with previous male studies. NEW & NOTEWORTHY Our study demonstrates divergent tumor development and tissue wasting within 3- and 4-wk mice, where approximately half the mice developed large tumors and subsequent cachexia. Unlike previous male studies, where metabolic perturbations precede the onset of cachexia, females appear to exhibit protections from the metabolic perturbations and cachexia development. Our data provide novel evidence for divergent cachectic development in tumor-bearing female mice compared with previous male CC studies, suggesting different mechanisms of CC between sexes.

In 2011, the European Society for the Study of Tourette Syndrome (ESSTS) published the first European guidelines for Tourette Syndrome (TS). We now present an update of the part on pharmacological treatment, based on a review of new literature with special attention to other evidence-based guidelines, meta-analyses, and randomized double-blinded studies. Moreover, our revision took into consideration results of a recent survey on treatment preferences conducted among ESSTS experts. The first preference should be given to psychoeducation and to behavioral approaches, as it strengthens the patients’ self-regulatory control and thus his/her autonomy. Because behavioral approaches are not effective, available, or feasible in all patients, in a substantial number of patients pharmacological treatment is indicated, alone or in combination with behavioral therapy. The largest amount of evidence supports the use of dopamine blocking agents, preferably aripiprazole because of a more favorable profile of adverse events than first- and second-generation antipsychotics. Other agents that can be considered include tiapride, risperidone, and especially in case of co-existing attention deficit hyperactivity disorder (ADHD), clonidine and guanfacine. This view is supported by the results of our survey on medication preference among members of ESSTS, in which aripiprazole was indicated as the drug of first choice both in children and adults. In treatment resistant cases, treatment with agents with either a limited evidence base or risk of extrapyramidal adverse effects might be considered, including pimozide, haloperidol, topiramate, cannabis-based agents, and botulinum toxin injections. Overall, treatment of TS should be individualized, and decisions based on the patient’s needs and preferences, presence of co-existing conditions, latest scientific findings as well as on the physician’s preferences, experience, and local regulatory requirements.

Based on its prevalence, Tourette syndrome cannot be considered a rare condition. However, in this opinion article, we make the claim that it should nonetheless be considered as an orphan or neglected disease.

BackgroundThe COVID-19 pandemic has resulted in a range of unprecedented disruptions to maternity care with documented impacts on perinatal outcomes such as stillbirth and preterm birth. Metropolitan Melbourne has endured one of the longest and most stringent lockdowns in globally. This paper presents the protocol for a multicentre study to monitor perinatal outcomes in Melbourne, Australia, during the COVID-19 pandemic.MethodsMulticentre observational study analysing monthly deidentified maternal and newborn outcomes from births >20 weeks at all 12 public maternity services in Melbourne. Data will be merged centrally to analyse outcomes and create run charts according to established methods for detecting non-random ‘signals’ in healthcare. Perinatal outcomes will include weekly rates of total births, stillbirths, preterm births, neonatal intensive care admissions, low Apgar scores and fetal growth restriction. Maternal outcomes will include weekly rates of: induced labour, caesarean section, births before arrival to hospital, postpartum haemorrhage, length of stay, general anaesthesia for caesarean birth, influenza and COVID-19 vaccination status, and gestation at first antenatal visit. A prepandemic median for all outcomes will be calculated for the period of January 2018 to March 2020. A significant shift is defined as ≥6 consecutive weeks, all above or below the prepandemic median. Additional statistical analyses such as regression, time series and survival analyses will be performed for an in-depth examination of maternal and perinatal outcomes of interests.Ethics and disseminationEthics approval for the collaborative maternity and newborn dashboard project has been obtained from the Austin Health (HREC/64722/Austin-2020) and Mercy Health (ref. 2020-031).Trial registration numberACTRN12620000878976; Pre-results.

ObjectivesThe COVID-19 pandemic has been associated with a worsening of perinatal outcomes in many settings due to the combined impacts of maternal COVID-19 disease, disruptions to maternity care, and overloaded health systems. In 2020, Melbourne endured a unique natural experiment where strict lockdown conditions were accompanied by very low COVID-19 case numbers and the maintenance of health service capacity. The aim of this study was to compare stillbirth and preterm birth rates in women who were exposed or unexposed to lockdown restrictions during pregnancy.DesignRetrospective multi-centre cohort study of perinatal outcomes before and during COVID-19 lockdownSettingBirth outcomes from all 12 public maternity hospitals in metropolitan MelbourneInclusion criteriaSingleton births without congenital anomalies from 24 weeks’ gestation. The lockdown-exposed cohort were those women for whom weeks 20- 40 of gestation would have occurred during the lockdown period of 23 March 2020 to 14 March 2021. The control cohort comprised all pregnancies in the corresponding periods one and two years prior to the exposed cohort.Main outcome measuresOdds of stillbirth, preterm birth (PTB), birth weight < 3rd centile, and iatrogenic PTB for fetal compromise, adjusting for multiple covariates.ResultsThere were 24,017 births in the exposed and 50,017 births in the control group. There was a significantly higher risk of preterm, but not term, stillbirth in the exposed group compared with the control group (0.26% vs 0.18%, aOR 1.49, 95%CI 1.08 to 2.05, P = 0.015). There was also a significant reduction in preterm birth < 37 weeks (5.93% vs 6.23%, aOR 0.93, 95%CI 0.87 to 0.99, P=0.03), largely mediated by a reduction in iatrogenic PTB for live births (3.01% vs 3.27%, aOR 0.89, 95%CI 0.81 to 0.98, P = 0.015), including iatrogenic PTB for suspected fetal compromise (1.25% vs 1.51%, aOR 0.79, 95%CI 0.69 to 0.91, P= 0.001). There was no significant difference in the spontaneous PTB rate between the exposed and control groups (2.69% vs 2.82%, aOR 0.94, 95%CI 0.86 to 0.1.03, P=0.25).ConclusionsLockdown restrictions in a high-income setting, in the absence of high rates of COVID-19 disease, were associated with a significant increase in preterm stillbirths, and a significant reduction in iatrogenic PTB for suspected fetal compromise.Trial registrationThis study was registered as an observational study with the Australian and New Zealand Clinical Trials Registry (ACTRN12620000878976).

BackgroundCommunity lockdowns during the COVID-19 pandemic may influence preterm birth rates, but mechanisms are unclear.MethodsWe compared neonatal outcomes of preterm infants born to mothers exposed to community lockdowns in 2020 (exposed group) to those born in 2019 (control group). Main outcome studied was composite of significant neonatal morbidity or death.ResultsMedian gestational age was 35+4 weeks (295 infants, exposed group) vs. 35+0 weeks (347 infants, control group) (p = 0.108). The main outcome occurred in 36/295 (12.2%) infants in exposed group vs. 46/347 (13.3%) in control group (p = 0.69). Continuous positive airway pressure (CPAP) use, jaundice requiring phototherapy, hypoglycaemia requiring treatment, early neonatal white cell and neutrophil counts were significantly reduced in the exposed group.ConclusionsCOVID-19 community lockdowns did not alter composite neonatal outcomes in preterm infants, but reduced rates of some common outcomes, and early white cell and neutrophil counts.

Low rates of preterm birth were observed during the coronavirus disease 2019 (COVID-19) lockdown in Melbourne, Australia.

Background Universal screening has been proposed as a strategy to identify asymptomatic individuals infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mitigate transmission. Aim To investigate the rate of positive tests among pregnant women in Melbourne, Australia. Methods We performed a cross-sectional prevalence study at three maternity hospitals (one tertiary referral hospital and two secondary maternities) in Melbourne, Australia. SARS-CoV-2 testing was offered to all pregnant women attending face-to-face antenatal visits and to those attending the hospital with symptoms of possible coronavirus disease, between 6th and 19th of May 2020. Testing was performed by multiplex-tandem polymerase chain reaction (PCR) on combined oropharyngeal and nasopharyngeal swabs. The primary outcome was the proportion of positive SARS-CoV-2 tests. Findings SARS-CoV-2 testing was performed in 350 women, of whom 19 had symptoms of possible COVID-19. The median maternal age was 32 years (IQR 28–35 years), and the median gestational age at testing was 33 weeks and four days (IQR 28 weeks to 36 weeks and two days). All 350 tests returned negative results (p = 0%, 95% CI 0–1.0%). Conclusion In a two-week period of low disease prevalence, the rate of asymptomatic coronavirus infection among pregnant women in Australia during the study period was negligible, reflecting low levels of community transmission.

Rage Attacks (RA) represent a clinically relevant symptom in patients with different psychiatric disorders. However, only recently the Rage Attack Questionnaire Revised (RAQ-R, 22 items, range, 0–66) has been developed as a new instrument for the assessment of RA. This study aimed to validate the RAQ-R in a large mixed psychiatric and psychosomatic sample. We tested internal consistency, convergent and discriminant validity as well as factor structure. In order to further explore the relationship of RA to other psychiatric symptoms, we calculated Pearson correlations between the RAQ-R and several other self-assessments including measurements for general psychological distress, quality of life, depression, anxiety, attention deficit/hyperactivity disorder (ADHD), impulsivity, and self-regulation abilities. Most relevant predictors of RA were examined in a multiple regression with stepwise elimination. In order to assess the manifestation of RA in different psychiatric disorders, group differences between diagnostic categories and healthy controls were calculated. Additionally, psychiatric patients were compared to patients with Tourette syndrome along RAQ-R scores. Data from healthy subjects and patients with Tourette syndrome were obtained from a previous study of our group. In this study, we included 156 patients with a wide and typical spectrum of psychiatric diseases. The RAQ-R was found to have excellent internal consistency and strong construct validity in this sample (Cronbach's α = 0.97, Average Variance Extracted = 0.58). Thus, the RAQ-R was shown to be a psychometrically sound assessment of RA in patients with different psychiatric disorders. Close constructs to RA were found to be aggression and hostility (r = 0.68) as well as low frustration tolerance and impulse control (r = 0.69). Compared to healthy controls, RA were significantly more common in the psychiatric sample (p < 0.001). More specifically, RAQ-R scores in all diagnostic categories assessed were higher compared to controls. Highest scores and effect sizes were found in patients with ADHD and borderline personality disorder (p < 0.001). Our results suggest that RA are a common and relevant symptom in many psychiatric disorders. As depression and RA showed only a moderate relation, RA should be distinguished from the concept of anger attacks, which are described as a core symptom of depression.

Introduction: Speech dysfluency, often referred to as stuttering, is a frequent speech disorder encountered in about 5% of children. Although in the majority of people affected, symptoms improve in adulthood, in some patients, stuttering persists and significantly impairs everyday functioning and quality of life. Treatment for stuttering includes speech therapy, cognitive behavioral therapy, and relaxation techniques. However, a substantial number of patients do not benefit sufficiently from these treatment strategies or are even treatment resistant. Methods: We present the case of a 20-year-old male with treatment-resistant stuttering, who markedly improved after treatment with medicinal cannabis. Results: Besides improved speech fluency as assessed by several phoniatric tests, we observed remission of (social) anxiety, improved mood, and reduced stress, resulting in an overall improvement of quality of life after cannabis therapy. The patient, in addition, reported improved attention, concentration, and sleep, increased self-confidence, and better social life. No side effects occurred. Over a time period of more than a year, treatment was equally effective. In an interview, the patient describes his personal view and the influence of cannabis-based treatment on his life. Conclusions: Medicinal cannabis could be effective in treatment of refractory stuttering, but these preliminary data have to be confirmed in controlled studies.

BackgroundThe COVID-19 pandemic has resulted in a range of unprecedented disruptions to the delivery of maternity care globally and has been associated with regional changes in perinatal outcomes such as stillbirth and preterm birth. Metropolitan Melbourne endured one of the longest and most stringent lockdowns in 2020. This paper presents the protocol for a collaborative maternity dashboard project to monitor perinatal outcomes in Melbourne, Australia, during the COVID-19 pandemic.MethodsDe-identified maternal and newborn outcomes will be collected monthly from all public maternity services in Melbourne, allowing rapid analysis of a multitude of perinatal indicators. Weekly outcomes will be displayed as run charts according to established methods for detecting non-random ‘signals’ in health care. A pre-pandemic median for all indicators will be calculated for the period of January 2018 to March 2020. A significant shift is defined as ≤ six consecutive weeks, all above or below the pre-pandemic median. Additional statistical analyses such as regression, time-series, and survival analyses will be performed for an in-depth examination of maternal and perinatal outcomes of interests.Ethics and DisseminationThis study has been registered as an observational study with the Australian and New Zealand Clinical Trials Registry (ACTRN12620000878976).Strengths and weaknesses of this study⍰ This project is the first clinician-led, multi-centre perinatal data collection system for metropolitan Melbourne.⍰ It complements the state government data collection, with the significant benefits of more timely and flexible reporting of outcomes, and granular detail on emerging areas of concern.⍰ The study relies on primary source coding of exposure and outcomes from each hospital that have not been internally validated during the study period.⍰ Data from private maternity hospitals, containing 25% of Melbourne births, are not available.⍰ This resource will support data-informed hospital pandemic responses through to the end of 2022.

Introduction Gilles de la Tourette syndrome (GTS) is a childhood onset disorder characterised by the presence of motor and vocal tics. The guidelines of both the American Academy of Neurology (AAN) as well as the European Society for the Study of Tourette Syndrome (ESSTS) recommend behavioural therapy and pharmacotherapy, mainly with antipsychotics, as first line treatments for tics. In spite of these well-established therapeutic approaches, a significant number of patients are dissatisfied because of insufficient tic reduction or intolerable side effects. Previous studies have suggested that cannabis-based medicine (CBM) might be an alternative treatment in these patients. Material and methods Two reviewers (KS, NS) searched the electronic database of PubMed on 1 July, 2021 for relevant studies using the search terms: ('Tourette syndrome' [MeSH Terms] OR 'Gilles de la Tourette syndrome' [MeSH Terms] OR 'tic disorders' [MeSH Terms] OR 'tics' [MeSH Terms] OR 'tic disorders'[Title/Abstract]) AND ('cannabis-based medicine' [Title/Abstract] OR 'cannabis' [Title/Abstract] OR 'dronabinol' [Title/Abstract] OR 'nabiximols' [Title/Abstract] OR 'tetrahydrocannabinol' [Title/Abstract] OR 'THC' [Title/Abstract] OR 'cannabidiol' [Title/Abstract], limit: 'humans'. These studies were further reviewed for additional relevant citations. The titles and abstracts of the studies obtained through this search were examined by two reviewers (KS, NS) in order to determine article inclusion. Discrepancies were addressed by the reviewers through discussion and eventually conversation with the senior reviewer (KMV). Results Although the amount of evidence supporting the use of CBM in GTS is growing, the majority of studies are still limited to case reports, case series, and open uncontrolled studies. To date, only two small randomised controlled trials (RCTs) using tetrahydrocannabinol (THC, dronabinol) have been published demonstrating the safety and efficacy of this intervention in the treatment of tics in patients with GTS. On the other hand, another RCT with Lu AG06466 (formerly known as ABX-1431), a modulator of endocannabinoid neurotransmission, has failed to prove effective in the therapy of GTS. Accordingly, under the guidelines of both the ESSTS and the AAN, treatment with CBM is categorised as an experimental intervention that should be applied to patients who are otherwise treatment-resistant. Conclusions Increasing evidence suggests that CBM is efficacious in the treatment of tics and psychiatric comorbidities in patients with GTS. The results of ongoing larger RCTs, such as CANNA-TICS (ClinicalTrials.gov Identifier: NCT03087201), will further clarify the role of CBM in the treatment of patients with GTS.

With this study, we aim to test the hypothesis that the effect of cannabidiol on drop-seizure frequency in patients with Lennox-Gastaut syndrome and Dravet syndrome could be attributed to a drug-drug interaction with clobazam. We performed clinical trial simulations for the effect of 20 mg/kg/day cannabidiol on drop-seizure frequency in patients with Lennox-Gastaut syndrome. We assumed that patients taking 10 or 20 mg clobazam would have a 2- to 7-fold increase in N-desmethylclobazam exposure, whereas patients not taking clobazam would have a median reduction in drop-seizure frequency and a variability in the percent reduction similar to the placebo group. The results show that the effect of cannabidiol on the median reduction in drop-seizure frequency in patients with Lennox-Gastaut syndrome may be explained by a drug-drug interaction with clobazam. This may have important implications for the use of cannabidiol and its Food and Drug Administration registration.

Introduction: Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder that is characterized by motor and vocal tics and psychiatric comorbidities, including attention deficit/hyperactivity disorder (ADHD) and obsessive-compulsive behavior/disorder (OCB/OCD). From anecdotal reports and preliminary controlled studies, it is suggested that cannabis-based medicine (CBM) may improve tics and comorbidities in adults with GTS. This study was designed to further investigate efficacy and safety of CBM in GTS and specifically compare effects of different CBM. Materials and Methods: First, we performed a retrospective data analysis including all those adult patients seen at our clinic, who had used CBM for the treatment of GTS at some time. All these patients were asked to complete an online survey (second study part) to receive more detailed data about treatment with CBM. Results: From medical records, we identified 98 patients who had used CBM (most often street cannabis followed by nabiximols, dronabinol, medicinal cannabis) for the treatment of GTS: Of the 38 patients who were able to judge, 66% preferred treatment with medicinal cannabis, 18% dronabinol, 11% nabiximols, and 5% street cannabis. Altogether, CBM resulted in a subjective improvement of tics (of about 60% in 85% of treated cases), comorbidities (55% of treated cases, most often OCB/OCD, ADHD, and sleeping disorders), and quality of life (93%). The effects of CBM appear to persist in the long term. Adverse events occurred in half of the patients, but they were rated as tolerable. Dosages of all CBM varied markedly. Patients assessed cannabis (with a preference for tetrahydrocannabinol [THC]-rich strains) as more effective and better tolerated compared with nabiximols and dronabinol. These data were confirmed by results obtained from the online survey (n=40). Conclusion: From our results, it is further supported that CBM might be effective and safe in the treatment of tics and comorbidities at least in a subgroup of adult patients with GTS. In our sample, patients favored THC-rich cannabis over dronabinol and nabiximols, which might be related to the entourage effect of cannabis. However, several limitations of the study have to be taken into considerations such as the open uncontrolled design and the retrospective data analysis.

Purpose: Delays in diagnosis and treatment are regularly discussed as potential poor prognostic factors for adolescent and young adult (AYA) cancer patients. We aimed to determine whether AYA cancer patients (15-24 years of age) in the South Island of New Zealand had longer times to diagnosis and treatment than pediatric ( 24 years) with the same diagnosis. Methods: A retrospective review of medical records was undertaken for 201 recently diagnosed sarcoma, Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL) patients in the South Island. An age stratified analysis was undertaken with a number of intervals related to the time to diagnosis (TTD) and total interval (TI) being determined. Results: Overall, the AYA group's TTD and TI was longer than the pediatric group, but shorter than the adult group. No age-based differences in patient interval (PI) were identified. AYA and adult sarcoma patients had longer TTD and TI than pediatric sarcoma. AYA and pediatric NHL patients had a shorter TTD and TI than adult NHL. No significant age-related interval differences were found in the HL group. Conclusions: AYA patients had a longer TTD and TI when compared with the pediatric group, but not when compared with the adult group. The impact of established AYA barriers to presentation are questioned, given no age-based differences in PI were found. The influence of tumor biology and cancer service delivery is an important consideration. Improved applicability of this type of research will be enabled by international collaboration.

Tics sind definiert als unwillkurlich auftretende Bewegungen und Lautauserungen. Die Klassifikation der Tic-Storungen erfolgt in Abhangigkeit von der Art und Dauer der Tics. Die Behandlung richtet sich nach der Schwere der Tics und der individuellen Beeintrachtigung. Am Anfang jeder Therapie sollte eine Psychoedukation stehen. Daruber hinaus stehen verhaltenstherapeutische, medikamentose und operative Therapien zur Verfugung.