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Education teams continue to place students with extensive support needs (ESN) in segregated settings despite nearly 50 years of research culminating in the conclusion that students with ESN have better outcomes when educated in general education contexts. This article uses Bronfenbrenner’s ecological systems theory to explain how social systems influence the beliefs, attitudes, and decisions made by education team members about the educational placement of students with ESN. This article describes: (a) Bronfenbrenner’s ecological systems theory to explain how each social system influences decisions made about the educational placement of students with ESN; (b) the history of educational segregation of students with disabilities; (c) macrosystems of education team members and how they perpetuate segregated placement decisions of students with ESN; and (d) actions to disrupt the education system and segregated placement decisions.

After an anterior cruciate ligament (ACL) injury, people need secondary prevention strategies to identify osteoarthritis at its earliest stages so that interventions can be implemented to halt or slow the progression toward its long-term burden. The Osteoarthritis Action Alliance formed an interdisciplinary Secondary Prevention Task Group to develop a consensus on recommendations to provide clinicians with secondary prevention strategies that are intended to reduce the risk of osteoarthritis after a person has an ACL injury. The group achieved consensus on 15 out of 16 recommendations that address patient education, exercise and rehabilitation, psychological skills training, graded-exposure therapy, cognitive-behavioral counseling (lacked consensus), outcomes to monitor, secondary injury prevention, system-level social support, leveraging technology, and coordinated care models. We hope this statement raises awareness among clinicians and researchers on the importance of taking steps to mitigate the risk of osteoarthritis after an ACL injury.

Background Three-dimensional (3D) human brain spheroids are instrumental to study central nervous system (CNS) development and (dys)function. Yet, in current brain spheroid models the limited variety of cell types hampers an integrated exploration of CNS (disease) mechanisms. Methods Here we report a 5-month culture protocol that reproducibly generates H9 embryonic stem cell-derived human cortical spheroids (hCSs) with a large cell-type variety. Results We established the presence of not only neuroectoderm-derived neural progenitor populations, mature excitatory and inhibitory neurons, astrocytes and oligodendrocyte (precursor) cells, but also mesoderm-derived microglia and endothelial cell populations in the hCSs via RNA-sequencing, qPCR, immunocytochemistry and transmission electron microscopy. Transcriptomic analysis revealed resemblance between the 5-months-old hCSs and dorsal frontal rather than inferior regions of human fetal brains of 19–26 weeks of gestational age. Pro-inflammatory stimulation of the generated hCSs induced a neuroinflammatory response, offering a proof-of-principle of the applicability of the spheroids. Conclusions Our protocol provides a 3D human brain cell model containing a wide variety of innately developing neuroectoderm- as well as mesoderm-derived cell types, furnishing a versatile platform for comprehensive examination of intercellular CNS communication and neurological disease mechanisms.

Between 2019 and 2022, there was a marked rise in adolescents/young adults seeking urgent help for functional tic-like behaviours (FTLBs). Given the global scale of this phenomenon, we aimed to pool cases from different institutions in an international registry to better characterize this spectrum and facilitate future longitudinal observation.An international collaborative group from 10 tertiary referral centres for tic disorders collected retrospective data on FTLB patients who sought specialists' attention between the last quarter of 2019 and June 2022. An audit procedure was used for collection of data, which comprised demographics, course of presentation and duration, precipitating and predisposing factors, phenomenology, comorbidities, and pharmacological treatment outcome.During the study period, we collected data on 294 patients with FTLBs, 97% of whom were adolescents and young adults and 87% of whom were female. FTLBs were found to have a peak of severity within 1 month in 70% of patients, with spontaneous remissions in 20%, and a very high frequency of complex movements (85%) and vocalizations (81%). Less than one-fifth of patients had pre-existing primary tic disorder, 66% had comorbid anxiety disorders, 28% comorbid depressive disorders, 24% autism spectrum disorder and 23% attention deficit/hyperactivity disorder. Almost 60% explicitly reported exposure to tic-related social media content. The vast majority of pharmacologically treated patients did not report benefit with tic-suppressing medications.Our data from the largest multicentre registry of FTLBs to date confirm substantial clinical differences from primary tic disorders. Social modelling was the most relevant contributing factor during the pandemic. Future longitudinal analyses from this database may help understand treatment approaches and responsiveness.

Since 2019, a global increase in patients presenting with functional Tourette-like behaviors (FTB) has been observed. This has been related to the exposure of tic-related content in social media, although other factors seem to further fuel this phenomenon. Recently, we, therefore, proposed the term mass social media-induced illness (MSMI) as, in our opinion, this phenomenon constitutes a new type of mass sociogenic illness (MSI) that is in contrast to all recent outbreaks spread solely via social media. In accordance with this hypothesis, we were able to identify the host of the German YouTube channel "Gewitter im Kopf" (“Thunderstorm in the brain”) as the initial virtual index case. The purpose of this paper is to present clinical characteristics of a sample of 32 patients diagnosed with MSMI-FTB compared to a large sample of patients with Tourette syndrome (TS) and other chronic tic disorders (CTD) (n = 1032) from the same center in Germany indicating clinical factors helpful to distinguish between tics in TS/CTD and MSMI-FTB. Our main findings were: in patients with MSMI-FTB compared to those with TS/CTD we found (i) a significantly higher age at onset, (ii) a significantly higher rate of females, (iii) a significantly higher rate of obscene and socially inappropriate symptoms, (iv) a significantly lower rate of comorbid ADHD, and (v) a significantly lower rate of OCD/OCB. In contrast, rates of comorbid anxiety and depression as well as reported frequencies of premonitory urges/sensations and suppressibility of symptoms did not differ between groups.

BackgroundMelbourne, Australia, recorded one of the longest and most stringent pandemic lockdowns in 2020, which was associated with an increase in preterm stillbirths among singleton pregnancies. Twin pregnancies may be particularly susceptible to the impacts of pandemic disruptions to maternity care due to their higher background risk of adverse perinatal outcomes.ObjectiveTo compare the rates of adverse perinatal outcomes in twin pregnancies exposed and unexposed to lockdown restrictions in Melbourne.Study DesignMulticenter retrospective cohort study of all twin pregnancies birthing in public maternity hospitals in Melbourne. We compared perinatal outcomes between a pre- pandemic group (‘unexposed’) and two lockdown-exposed groups: exposure 1 from 22 March 2020 to 21 March 2021 and exposure 2 from 22 March 2021 to 27 March 2022. We analyzed routinely-collected maternity data on all twin births≥20 weeks where outcomes were available for both infants. The primary outcomes were rates of preterm birth+0to 40+0of their pregnancy occurred entirely during each lockdown-exposure period. Perinatal outcomes were calculated per infant; maternal outcomes were calculated per pregnancy.ResultsWe included 2267 women birthing twins. Total preterm birthsrdcentile (5.7% vs 6.0%; aRR 1.00, 95%CI 0.98-1.02 p=0.74) or neonatal intensive care unit admissions in the exposure 1 group compared to the pre-pandemic group. In contrast, when comparing the pre-pandemic group with exposure 2 group, there was no significant difference in the rates of preterm birthConclusionsMelbourne’s first lockdown-exposure period was associated with fewer twin preterm births

To colonize a host, bacteria depend on an ensemble of signaling systems to convert information about the various environments encountered within the host into specific cellular activities. How these signaling systems coordinate transitions between cellular states in vivo remains poorly understood. To address this knowledge gap, we investigated how the bacterial symbiont Vibrio fischeri initially colonizes the light organ of the Hawaiian bobtail squid Euprymna scolopes. Previous work has shown that the small RNA Qrr1, which is a regulatory component of the quorum-sensing system in V. fischeri, promotes host colonization. Here, we report that transcriptional activation of Qrr1 is inhibited by the sensor kinase BinK, which suppresses cellular aggregation by V. fischeri prior to light organ entry. We show that Qrr1 expression depends on the alternative sigma factor σ54 and the transcription factors LuxO and SypG, which function similar to an OR logic gate, thereby ensuring Qrr1 is expressed during colonization. Finally, we provide evidence that this regulatory mechanism is widespread throughout the Vibrionaceae family. Together, our work reveals how coordination between the signaling pathways underlying aggregation and quorum-sensing promotes host colonization, which provides insight into how integration among signaling systems facilitates complex processes in bacteria.

Background: Pre-operative anxiety is prevalent and associated with adverse patient outcomes. Many anxiolytic techniques have been utilized in the pre-operative setting, with varying degrees of success. The Autonomous Sensory Meridian Response (ASMR) is an increasingly popular method of relaxation used for anxiety reduction in general society. It is a non-invasive, inexpensive intervention with no known adverse effects. It has not been researched in a pre-operative setting. We aimed to investigate the effects of ASMR in the pre-operative patient population. Methods: This prospective, double-blind trial randomly allocated 50 participants into either a placebo or ASMR group. Pre-operative anxiety was compared before and after viewing specially formatted educational video information in either an ASMR or non-ASMR format with validated anxiety scales-Visual Analogue Scale (VAAS), Amsterdam Pre-operative Anxiety and Information Scale (APAIS) and State-Trait Anxiety Inventory. The physiological characteristics of heart rate and blood pressure were measured as secondary outcomes. Results: The control group demonstrated a reduction in pre-operative VAAS of 6.6 (p = 0.01) and 1.1 (p = 0.02) on the APAIS. The ASMR group had a reduction of APAIS of 1.9 (p = 0.005) and no change in the VAAS. Changes in State-Trait Anxiety Inventory for state anxiety score were the same in both groups. Increased trait anxiety was correlated with increased post-intervention VAAS and APAIS scores. There was no effect of pre-existing trait anxiety and pre-interventional anxiety on the efficacy of ASMR. Post-intervention, there was a significant decrease in mean systolic blood pressure by 2.7mmHg in ASMR group. In multivariable analysis, ASMR group had a drop of 3.9mmHg in post-intervention systolic blood pressure compared to placebo (p

Objective In patients with Tourette syndrome and other primary tic disorders (PTDs), tics are typically preceded by premonitory urges (PUs). To date, only a few studies have investigated the location and frequency of PUs, and contrary to clinical experience, the results suggest that PUs are not located in the same anatomic region as the tics. This study aimed to further explore PU location and frequency in detail, differentiating the kind and complexity of the corresponding tics, in a large sample of patients with PTD.Methods A total of 291 adult (≥ 18 years) patients with a confirmed diagnosis of chronic PTD were included. The study was conducted online, assement included tics and the general characterization of PUs and a sophisticated body drawing for locating PUs.Results We found that PUs were located in the same body area as, or in direct proximity to, the corresponding tic. Most frequently, PUs were located in the face and at the head (62.1%). Compared with simple tics, complex (motor and vocal) tics were more often preceded by a PU; but there was no difference in PU frequency observed between motor tics and vocal tics. PUs were more often experienced at the front than at the back of the body (73% vs. 27%), while there was no difference between the right and left sides (41.6% vs. 41.3%).Conclusion The strong association between PU and tic location further supports the hypothesis that PUs represent the core of PTD. Accordingly, future therapies should focus on treating PUs to achieve greater tic reduction.

Background: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. Methods: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. Results: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. Conclusions: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Background The Coronavirus disease (COVID-19) pandemic has created unprecedented acute global health challenges. However, it also presents a set of unquantified and poorly understood risks in the medium to long term, specifically, risks to children whose mothers were infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Infections during pregnancy can increase the risk of atypical neurodevelopment in the offspring, but the long-term neurodevelopmental impact of in utero COVID-19 exposure is unknown. Prospective, longitudinal studies are needed to evaluate children exposed in utero to SARS-CoV2 to define this risk. Methods We have designed a prospective, case-controlled study to investigate the long-term impacts of SARS-CoV2 exposure on children exposed in utero. Women infected with SARS-CoV-2 during pregnancy will be recruited from Monash Health, the Royal Women’s Hospital and Western Health (Melbourne, Australia) and Londrina Municipal Maternity Hospital Lucilla Ballalai and PUCPR Medical Clinical (Londrina, Brazil). A control group in a 2:1 ratio (2 non-exposed: 1 exposed mother infant dyad) comprising women who gave birth in the same month of delivery, are of similar age but did not contract SARS-CoV-2 during their pregnancy will also be recruited. We aim to recruit 170 exposed and 340 non-exposed mother-infant dyads. Clinical and socio-demographic data will be collected directly from the mother and medical records. Biospecimens and clinical and epidemiological data will be collected from the mothers and offspring at multiple time points from birth through to 15 years of age using standardised sample collection, and neurological and behavioural measures. Discussion The mapped neurodevelopmental trajectories and comparisons between SARS-CoV-2 exposed and control children will indicate the potential for an increase in atypical neurodevelopment. This has significant implications for strategic planning in the mental health and paediatrics sectors and long-term monitoring of children globally.

The modification of lipopolysaccharide (LPS) inEscherichia coliandSalmonella spp. is primarily controlled by the two-component system PmrAB. LPS modification allows bacteria to avoid killing by positively charged antibiotics like polymyxin B. We previously demonstrated that in uropathogenicE. coli(UPEC), the sensor histidine kinase PmrB also activates a non-cognate transcription factor, QseB, and this activation somehow augments polymyxin B tolerance in UPEC. Here, we demonstrate – for the first time – that in the absence of the canonical LPS transcriptional regulator, PmrA, QseB can direct some modifications on the LPS. In agreement with this observation, transcriptional profiling analyses demonstrate regulatory overlaps between PmrA and QseB in terms of regulating LPS modification genes. However, both PmrA and QseB must be present for UPEC to mount robust tolerance to polymyxin B. Transcriptional and metabolomic analyses also reveal that QseB transcriptionally regulates the metabolism of glutamate and 2-oxoglutarate, which are consumed and produced during the modification of lipid A. We show that deletion ofqseBalters glutamate levels in the bacterial cells. TheqseBdeletion mutant, which is susceptible to positively charged antibiotics, is rescued by exogenous addition of 2-oxoglutarate. These findings uncover a previously unknown mechanism of metabolic control of antibiotic tolerance that may be contributing to antibiotic treatment failure in the clinic.IMPORTANCEAlthough antibiotic prescriptions are guided by well-established susceptibility testing methods, antibiotic treatments oftentimes fail. The presented work is significant, because it uncovers a mechanism by which bacteria transiently avoid killing by antibiotics. This mechanism involves two closely related transcription factors, PmrA and QseB, which are conserved across Enterobacteriaceae. We demonstrate that PmrA and QseB share regulatory targets in lipid A modification pathway and prove that QseB can orchestrate modifications of lipid A inE. coliin the absence of PmrA. Finally, we show that QseB controls glutamate metabolism during the antibiotic response. These results suggest that rewiring of QseB-mediated metabolic genes can lead to stable antibiotic resistance in subpopulations within the host, thereby contributing to antibiotic treatment failure.

Additional file 7: Fig. S7. Relative distributions of distinct cell types based on transcriptomic comparisons between day-150 (d150) human cortical spheroids (hCSs) generated with our protocol and d94 hCSs generated with the T3-induction protocol of Madhavan et al. (2018). This figure is related to figure 6. (A) Log10-converted fold change (FC) of GAPDH-normalized mRNA expression of cell-type-specific markers in d150 hCSs (batch-1) (present study) relative to that in d94 hCSs (Madhavan et al., 2018). (B) Log10-converted FC of GAPDH-normalized mRNA expression of cell-type-specific markers in d150 hCSs (batch-12) (present study) relative to that in d94 hCSs (Madhavan et al., 2018).

Additional file 6: Fig. S6. Robust presence of both neuroectoderm-derived and mesoderm-derived cell types in two independently grown day-150 (d150) human cortical spheroid (hCS) batches, with slightly different ratios in cell-type composition. (A) Log10-converted fold change (FC) of median GAPDH-normalized mRNA expression of markers for various brain cell types in batch-1 relative to batch-12 d150 hCSs. Each bar represents the median of the expression of all cell-type-specific markers for that brain cell type. (B) Log10-converted FC of median GAPDH-normalized mRNA expression of cell-type-specific markers for various brain cell types in batch-1 relative to batch-12 d150 hCSs. See Additional file 16 for markers used. SC: stem cell; NPC: neural progenitor cell; EXC: excitatory neuron; INH: inhibitory neuron; ASTR: astrocyte; OPC: oligodendrocyte precursor cell; pOL: pre-myelinating oligodendrocyte; MG: microglia; ENDO: endothelial cell.

Additional file 4: Fig. S4. Complete omission of SMAD inhibition (absence of dorsomorphin and SB43152 in the culture medium) results in mitigated growth of neuroectoderm-derived neurons and astrocytes. (A) Representative images of whole-spheroid signal scans of the neuronal marker MAP2, the astrocyte marker GFAP and the oligodendrocyte marker O1 in day-17 (d17), d33 and d73 human cortical spheroids (hCSs) (batch-11) grown with dorsomorphin and SB-431542 (+ SMAD inhibition) or without dorsomorphin and SB-431542 (- SMAD inhibition) in the culture medium. (B) Quantifications of the mean MAP2-, GFAP- and O1-signal intensities per field in d17, d33 and d73 hCSs (batch-11) grown with or without SMAD inhibition. One-way ANOVA per time point for -SMAD vs +SMAD: * p < 0.05. Each data point represents the level of mRNA expression in one spheroid. Error bars represent the standard error of the mean.

Additional file 16: Table S3. Median fold-change (FC) mRNA expression of brain cell-type markers. Markers were selected on the basis of extensive literature searches (for the full list of markers examined, see Additional file 11) and cell-specific mRNA expression levels (with a median FC larger than 3.5) in the single-cell human fetal brain RNA-sequencing dataset of Fan et al. (2018) [32]. We noticed that some of the previously reported cell-type-specific markers for the adult brain do not appear to be valid cell-type-specific markers for the fetal brain (Additional file 11). NPC: neural progenitor cell; OPC: oligodendrocyte precursor cell; (p)OL: (pre-myelinating) oligodendrocyte.

Additional file 1: Fig. S1. The protocol used to culture H9 human embryonic stem cells (ESCs) does not impair their pluripotency. Levels of mRNA expression of stem-cell-specific markers NANOG and OCT4, neural stem cell marker PAX6 and mature neuronal marker NEFL in H9 ESCs (six consecutive passage-numbers, P9-P14) and in day-150 (d150) batch-1 human cortical spheroids (hCSs-1). Error bars represent the standard error of the mean; ANOVA with Bonferroni post hoc comparisons: *** p < 0.001, ** p < 0.01 and * p < 0.05.

Additional file 2: Fig. S2. Ultrastructural transmission electron microscopy (TEM) analysis of early-stage (day-39, d39) and late-stage (d150) human cortical spheroids (hCSs) reveals multiple neuroectoderm-derived and mesoderm-derived cell types. (A) Left: Synapse formation in d39 hCS (yellow arrow head: synaptic vesicles). Right: Mature synapses (S) with vesicles (V) in d150 hCS (red arrow heads: dense core vesicles). (B) Overview images of d39 and d150 hCSs showing differences in cell density, length of outgrowths and number of cell contacts. Representative images of (C) astrocytes, (D) oligodendrocyte precursor cells (encircled in right image), (E) mature oligodendrocytes, (F) microglia cells and (G) endothelial cells in d150 hCSs. (H) Levels of mRNA expression of the T-cell/neuronal marker CRTAM, the B-cell markers CD80 and MS4A1, the natural killer cell marker FCGR3A, the leukocyte marker SELL and the dendritic cell marker CD209 in H9 human embryonic stem cells (ESCs) and d150 hCSs, as determined by quantitative PCR (qPCR) analysis. Independent samples T-test: * p < 0.05. Error bars represent the standard error of the mean. Each data point represents the level of mRNA expression in one spheroid. (I) Muscle tissue (‘Mus’) observed occasionally in d150 hCS. (J) Cartilage tissue (‘Cart’) observed occasionally in d150 hCS.

Additional file 5: Fig. S5. Modulation of BMP4 concentration tweaks the ratio between the extent of neuroectoderm- and mesoderm development. (A) Representative images of the morphologies and sizes of human cortical spheroids (hCSs) (batch-2), including neuroectoderm-layer formation/neural rosettes (blue arrow heads) at days 1, 12, 23 and 70 following culturing in the presence of 10 μM SB43152 and 0.1, 1, 2.5 or 10 μM dorsomorphin (DM). hCSs cultured in the presence of a high degree of SMAD inhibition (10 μM DM) and with a starting density of 1.25*104 H9 ESCs did not aggregate into spheres. (B) Quantifications of hCS (batch-2) circumferences during days 0 until 70 following culturing with 10 μM SB43152 and 0.1, 1 or 2.5 μM DM. (C) Representative immunocytochemistry whole-spheroid (batch-2) images and mean field-intensity quantifications of MAP2 (neuron) and GFAP (astrocyte) protein expression in day-13 (d13), d23 and d33 hCSs cultured in the presence of 0.1, 1 or 2.5 μM DM. ANOVA with Tukey post hoc comparisons: ** p < 0.01, * p < 0.05. (D) Levels of mRNA expression of the microglial marker TMEM119 in d13, d23 and d33 hCSs (batch-2) following culturing with 10 μM SB43152 and 0.1, 1 or 2.5 μM DM, as determined by qPCR analysis. ANOVA with Tukey post hoc comparisons: ** p < 0.01, * p < 0.05. Each data point in (C) and (D) represents one spheroid. Error bars represent the standard error of the mean.

Additional file 15: Table S2. Antibodies used for immunocytochemical analyses.

Additional file 3: Fig. S3. Low variability in the number of P2RY12-positive microglial cells among independent human cortical spheroid (hCS) batches and in hCSs grown with various start-cell densities. (A) Left: Representative immunocytochemistry (ICC) images of whole-spheroid signal scans of the microglia marker P2RY12 in five independently grown batches of day-150 (d150) hCSs. Microglia often developed in patch-like structures within the hCSs. Right: Quantifications of the mean P2RY12 signal intensities per field in five independently grown d150 hCS batches. ANOVA with Tukey post hoc comparisons: ** p < 0.01, * p < 0.05. (B) Left: Representative ICC images of whole-spheroid P2RY12 signal scans of d150 hCSs grown with various start H9 human embryonic stem cell (ESC) densities. Right: Quantifications of the mean P2RY12 signal intensities per field in d150 hCSs grown with 1.0*104, 2.0*104 or 4.0*104 start H9 ECSs. ANOVA with Tukey post hoc comparisons: ns, not significant. Each data point in (A) and (B) represents the level of mRNA expression in one spheroid. Error bars represent the standard error of the mean.

Research indicates that soluble fms-like tyrosine kinase 1 (sFLT-1) and placental growth factor (PLGF) have diagnostic and prognostic significance for women with preeclampsia. However, sparse research has studied these biomarkers in women with preexisting comorbidities such as chronic hypertension, diabetes mellitus, systemic lupus erythematosus and chronic kidney disease. We undertook a prospective longitudinal cohort study to compare the sFLT-1: PlGF ratio between women with and without comorbidities who did and did not go on to develop preeclampsia. We found that women with comorbidities may develop preeclampsia with a milder elevation in sFLT-1: PlGF than do women without comorbidities. This has clinical and research implications.

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.

Schoolwide Positive Behavioral Interventions and Supports (SWPBIS) is a framework intended to benefit all students in a school. However, recent research suggests that students with significant disabilities may not fully participate in SWPBIS. Given the complex reasons for varied involvement in SWPBIS (e.g., student educational placement), the purpose of this study was to investigate expert perspectives on the extent to which students with significant disabilities should be included in SWPBIS. Overall, experts agreed students with significant disabilities should be included in all tiers of SWPBIS, receive instruction in schoolwide rules and expectations, and have the opportunity to participate in schoolwide reward systems. Experts shared differing perspectives on the ways behavior violations of students with significant disabilities should be documented.

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.

This perspective aims to highlight aspects of the Early Hearing Detection and Intervention (EHDI) newborn hearing screening and follow-up processes that were impacted by the COVID-19 pandemic and considers factors that likely impacted follow-up after newborn hearing screening among infants born in the United States during 2020. Efforts to minimize the potential impact of missed or delayed identification of hearing loss in infants and young children will also be discussed to help guide future program improvement activities.

Age-specific reference values are important in medical science to evaluate the normal ranges of subjects and to help physicians signal potential disorders as early as possible. They are applied to ...

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.

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.

While there is a multitude of evidence supporting the efficacy of injury prevention training programmes, the literature investigating the implementation of these programmes is, in contrast, rather limited. This narrative review sought to describe the commonly reported barriers and facilitators of the implementation of injury prevention training programmes among athletes in organised sport. We also aimed to identify necessary steps to promote the uptake and sustainable use of these programmes in non-elite athletic communities. We identified 24 publications that discussed implementing evidence-based injury prevention training programmes. Frequently reported barriers to implementation include the perceived time and financial cost of the programme, coaches lacking confidence in their ability to implement it, and the programme including exercises that were difficult or confusing to follow. Frequently reported facilitators to implementation include the coach being aware of programme efficacy, shared motivation to complete the programme from both coaches and athletes, and the ability to easily integrate the programme into practice schedules. The current literature is focused on high-income, high-resource settings. We recommend that future studies focus on understanding the best practices of programme dissemination in culturally and economically diverse regions. Programmes ought to be of no financial burden to the user, be simply adaptable to different sports and individual athletes and be available for use in easily accessible forms, such as in a mobile smartphone application.