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Abstract Objective To compare specific perinatal outcomes in nulliparas with a singleton infant in cephalic presentation at term, with and without exposure to the COVID-19 pandemic during pregnancy. We hypothesised that the pandemic conditions in Melbourne may have been an independent contributor to trends in maternal Body Mass Index ≥ 25 kg/m2, macrosomia and caesarean section. Design Multi-centre retrospective cohort study and interrupted time-series analysis. Setting Metropolitan Melbourne, Victoria. Population Singleton infants ≥ 20 weeks gestational age born between 1 January 2019 and 31 March 2022. Main outcome measures Rates of maternal Body Mass Index ≥ 25 kg/m2, macrosomia (birthweight ≥ 4000 g) and caesarean section. Results 25 897 individuals gave birth for the first time to a singleton infant in cephalic presentation at term in the pre-pandemic cohort, and 25 298 in the pandemic-exposed cohort. Interrupted time-series analysis demonstrated no significant additional effect of the pandemic on pre-existing upward trends in maternal Body Mass Index ≥ 25 kg/m2, caesarean section or macrosomia. The rate of maternal Body Mass Index ≥ 25 kg/m2 was higher in the pandemic-exposed cohort compared with the pre-pandemic cohort, (45.82% vs. 44.58% respectively, p = 0.041) as was the overall rate of caesarean section (33.09% vs. 30.80%, p

Abstract Self-injurious behavior (SIB) is a well-known phenomenon in patients with chronic tic disorders (CTD). To investigate prospectively symptomatology of SIB in adults with CTD, we developed and validated the self-injurious behavior scale for tic disorders (SIBS-T). Patients completed the SIBS-T and a variety of assessments for tics and comorbidities. We investigated SIB frequency, internal consistency of the SIBS-T, and carried out an exploratory factor analysis (EFA). We enrolled n = 123 adult patients with CTD. SIB was reported by n = 103 patients (83.7%). The most frequently reported SIB were beating/pushing/throwing and were found in 79.6% of cases. Patients with SIB had significantly higher tic severity measured with the Adult Tic Questionnaire (ATQ) (p = 0.002) as well as higher severity of psychiatric comorbidities such as obsessive–compulsive symptoms (OCS) (p

Summary: Background: In response to the COVID-19 pandemic, Victoria’s largest maternity service provider implemented a telehealth-integrated antenatal care (ANC) schedule for high- and low-risk pregnancies. The program has been maintained since March 2020. Given ever-increasing healthcare costs, economic evaluation is crucial to ensure value and guide ongoing use. Methods: The aim of the study was to perform a cost-minimisation analysis of telehealth integrated ANC compared to conventional in-person ANC, from the hospital and patient perspectives. We hypothesised that the costs associated with telehealth integrated ANC would be less than in-person ANC. We generated propensity score matched pre- and post-telehealth cohorts from women with a singleton pregnancy who received ANC and birthed at Monash Health from 1 Jan 2018–22 Mar 2020 (pre-telehealth), and 20 Apr 2020–31 Dec 2021 (post-telehealth). Data were extracted from electronic medical and finance records. We assigned costs for all Monash Health outpatient, inpatient, and emergency department episodes to calculate mean cost per birth. Patient travel costs were estimated based on distance residing from hospital. Findings: Matched pre- and post-telehealth cohorts of n = 13,534 each were created. There were no significant differences in stillbirth, pre-eclampsia, severe maternal morbidity, or death. There was a AU$133 (0.98%, 95% CI [−0.17%, 2.16%]) increase in cost per birth in the post-telehealth cohort. This was driven by increased hospital costs (AU$340 or 2.64% increase, [1.44%, 3.86%]), due to a 4.78% increase in antenatal inpatient episodes and 3.51% increase in outpatient appointments post-telehealth. Increased care complexity was noted in the post-telehealth period with increased rates of gestational diabetes, caesarean birth, and specialty-led care (p-values all

Abstract This study presents new glyoxal (CHOCHO) products from the Ozone Monitoring Instrument (OMI) by utilizing updated level 1B irradiance/radiance data (Collection 4) and an updated glyoxal retrieval algorithm. The adoption of Collection 4 contributes to the reduction of artificial signals in differential glyoxal slant column densities (dSCDs) and improved fitting root mean square, and the updated retrieval settings result in fewer negative values of glyoxal dSCDs over oceans and less noisy dSCDs in the South Atlantic Anomaly. On‐line calculations of air mass factors consider interactive physical processes between input parameters. To address persistent trends in glyoxal SCDs over the Pacific Ocean that remain despite these updates, a trend correction is implemented. We evaluate the updated OMI glyoxal products using inter‐comparisons with GOME‐2A/2B glyoxal products. OMI glyoxal products exhibit good spatial and temporal agreement with GOME‐2A/2B, with correlation coefficients of 0.75–0.78 globally and 0.84–0.85 over source regions. Small biases are observed in OMI glyoxal vertical column densities, ranging from −0.2 ± 5.7% to 9 ± 3% in low and high glyoxal conditions, respectively, against GOME‐2A/2B. These advancements contribute to the reliability and accuracy of OMI glyoxal products, enhancing their utility for atmospheric studies and enabling a 20‐year‐long data record suitable for climate studies.

Abstract Transesophageal echocardiography (TEE) imaging is a vital tool used in the evaluation of complex cardiac pathology and the management of cardiac surgery patients. A key limitation to the application of deep learning strategies to intraoperative and intraprocedural TEE data is the complexity and unstructured nature of these images. In the present study, we developed a deep learning-based, multi-category TEE view classification model that can be used to add structure to intraoperative and intraprocedural TEE imaging data. More specifically, we trained a convolutional neural network (CNN) to predict standardized TEE views using labeled intraoperative and intraprocedural TEE videos from Cedars-Sinai Medical Center (CSMC). We externally validated our model on intraoperative TEE videos from Stanford University Medical Center (SUMC). Accuracy of our model was high across all labeled views. The highest performance was achieved for the Trans-Gastric Left Ventricular Short Axis View (area under the receiver operating curve [AUC] = 0.971 at CSMC, 0.957 at SUMC), the Mid-Esophageal Long Axis View (AUC = 0.954 at CSMC, 0.905 at SUMC), the Mid-Esophageal Aortic Valve Short Axis View (AUC = 0.946 at CSMC, 0.898 at SUMC), and the Mid-Esophageal 4-Chamber View (AUC = 0.939 at CSMC, 0.902 at SUMC). Ultimately, we demonstrate that our deep learning model can accurately classify standardized TEE views, which will facilitate further downstream deep learning analyses for intraoperative and intraprocedural TEE imaging.

Abstract Background Melbourne, 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. Methods Multicenter retrospective cohort study of all twin pregnancies birthing in public maternity hospitals in Melbourne. Multivariable log-binomial regression models were used to compare perinatal outcomes between a pre-pandemic group to women in whom weeks 20+0 to 40+0 of gestation occurred entirely during one of two lockdown-exposure periods: exposure 1 from 22 March 2020 to 21 March 2021 and exposure 2 from 22 March 2021 to 27 March 2022. Results Total preterm births

Abstract In clinical trials, Montgomery‐Åsberg Depression Rating Scale (MADRS) questionnaire data are added up to total scores before analysis, assuming equal contribution of each separate question. Item Response Theory (IRT)‐based analysis avoids this by using individual question responses to determine the latent variable (ψ), which represents a measure of depression severity. However, utilization of IRT in early phase trials remains difficult, because large datasets are needed to develop IRT models. Therefore, we aimed to evaluate the application and assumptions of a reference IRT model for analysis of an early phase trial. A cross‐over, placebo‐controlled study investigating the effect of intravenous racemic ketamine on MADRS scores in patients with treatment‐resistant major depressive disorder was used as a case study. One hundred forty‐seven MADRS responses were measured in 17 patients at five timepoints (predose to 2 weeks after dosing). Two reference IRT models based on different patient populations were selected from literature and used to determine ψ, while testing multiple approaches regarding assumed data distribution. Use of ψ versus total score to determine treatment effect was compared through linear mixed model analysis. Results showed that determined ψ values did not differ significantly between assumed distributions, but were significantly different when changing reference IRT model. Estimated treatment effect size was not significantly affected by chosen approach nor reference population. Finally, increased precision to determine treatment effect was achieved by using IRT versus total scores. This demonstrates the usefulness of reference IRT model application for analysis of questionnaire data in early phase clinical trials.

Introduction E-cigarette use is disparately high among sexual minoritized populations. As e-cigarette advertising may influence product appeal, this study tested sexual orientation- and gender-based differences in response to e-cigarette advertisement exposure on advertisement perceptions and product appeal. Methods We recruited 497 adults (mean age=31.9 years, 45.1% women, 54.3% heterosexual, 71.2% Non-Hispanic White) living in the United States via the crowdsourcing platform Prolific. Participants viewed two randomly selected e-cigarette advertisements (from n=173 advertisements). Post-exposure, participants rated the perceived advertisement effectiveness, relevance, and product use intention. Associations between sexual orientation and outcomes were estimated using multivariable linear mixed-effects models. We tested interaction effects between sexual orientation, gender, and advertisement feature (e.g. presence of humans, flavors, and product packaging), and ran Tukey post hoc tests for pairwise comparisons. Results Post-exposure, heterosexual women, sexual minoritized men, and sexual minoritized women (reference group: heterosexual men) rated perceived advertisement effectiveness and relevance lower after viewing advertisements featuring flavors (vs no flavors; all p

Introduction Preterm birth is a leading cause of perinatal morbidity and mortality. During the COVID-19 pandemic, reduction in rates of preterm birth in women exposed to viral mitigation measures was reported by multiple studies. In addition, others and we observed a more pronounced reduction of preterm birth in women who had previously experienced a preterm birth. The aim of this pilot study is to establish the feasibility of a lifestyle intervention based on viral mitigation measures in high-risk pregnancies, with the ultimate aim to reduce the incidence of preterm birth.Methods and analysis One hundred pregnant women, enrolled in antenatal clinics at two tertiary maternity centres in Melbourne, Australia, who have had a previous preterm birth between 22 and 34 weeks gestation will be recruited. This is a two-arm, parallel group, open-label randomised controlled feasibility trial: 50 women will be randomised to the intervention group, where they will be requested to comply with a set of lifestyle changes (similar to the viral mitigation measures observed during the pandemic). Another 50 women will be randomised to the control group, where they will undergo standard pregnancy care. The primary outcome of this trial is feasibility, which will be assessed by measuring patient eligibility rate, recruitment rate, compliance rate and data completion rate. Secondary outcomes include incidence of preterm birth, maternal satisfaction, maternal quality of life and other pregnancy outcomes. Standard methods in statistical analysis for randomised controlled trials on an intention to treat basis will be followed.Ethics and dissemination This trial has been approved by the Monash Human Research Ethics Committee; approval reference number RES-22-0000-122A. Study findings will be reported and submitted to peer-reviewed journals for publication, and presentation at conferences.Trial registration number ACTRN12622000753752; Pre-results.

The modification of lipopolysaccharide (LPS) in Escherichia coli and Salmonella spp. is primarily controlled by the two-component system PmrAB. LPS modification allows bacteria to avoid killing by positively charged antibiotics like polymyxin B (PMB). We previously demonstrated that in uropathogenic E. coli (UPEC), the sensor histidine kinase PmrB also activates a non-cognate transcription factor, QseB, and this activation somehow augments PMB 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 PMB. 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 of qseB alters glutamate levels in the bacterial cells. The qseB deletion 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. IMPORTANCE Although 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 Enterobacterales. We demonstrate that PmrA and QseB share regulatory targets in lipid A modification pathway and prove that QseB can orchestrate modifications of lipid A in Escherichia coli in 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 could lead to stable antibiotic resistance in subpopulations within the host, thereby contributing to antibiotic treatment failure.

Abstract 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.

Abstract Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

Abstract 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.

Background: Following the development of the Royal Australian College of Obstetricians and Gynaecologists Intrapartum Fetal Surveillance Guideline in 2003, an education program was developed to support guideline implementation and clinical practice. It was intended that improved clinician knowledge, particularly of cardiotocography, would reduce rates of intrapartum fetal morbidity and mortality. The program contains a multiple-choice assessment, designed to assess fetal surveillance knowledge and the application of that knowledge. We used the results of this assessment over time to evaluate the impact of the education program on clinicians’ fetal surveillance knowledge and interpretive skills, in the immediate and longer-term. Methods: We undertook a retrospective analysis of the assessment results for all participants in the Fetal Surveillance Education Program, between 2004 and 2018. Classical Test Theory and Rasch Item Response Theory analysis were used to evaluate the statistical reliability and quality of the assessment, and the measurement invariance or stability of the assessments over time. Clinicians’ assessment scores were then reviewed by craft group and previous exposure to the program. Results: The results from 64,430, broadly similar assessments, showed that participation in the education program was associated with an immediate improvement in clinician performance in the assessment. Performance improvement was sustained for up to 18 months following participation in the program and recurrent participation was associated with progressive improvements. These trends were observed for all craft groups (consultant obstetricians, doctors in training, general practitioners, midwives, student midwives). Conclusions: These findings suggest that the Fetal Surveillance Education Program has improved clinician knowledge and the associated cognitive skills over time. The stable difficulty of the assessment tool means any improvement in clinician’s results, with ongoing exposure to the program, can be reliably assessed and demonstrated. Importantly this holds true for all craft groups involved in intrapartum care and the interpretation of cardiotocography.

Fetal alcohol spectrum disorder (FASD) continues to be underdiagnosed in Australia, partly due to the lack of trained clinicians and diagnostic services. This project aimed to help increase FASD knowledge and diagnostic capacity across Australia. Six sites across Australia formed part of a national consortium, delivering training clinics, diagnostic clinics and community education sessions. The number of FASD diagnoses significantly increased across the project. Additionally, the number of community education sessions steadily increased across the project, with largely positive feedback. Participants attending the training clinics demonstrated increased knowledge of and confidence in FASD diagnosis. This evaluation showcases the benefits of a coordinated approach to prevention, assessment, diagnosis and training in FASD.

This self-reflective case study describes our project team’s efforts to promote equity in science professional learning (PL) by centering the voices of educators in the PL design process and within the course itself. We believe that educators’ experiences, priorities, and expertise are essential to developing professional learning that meets the needs of teachers and their students. We have a particular interest in amplifying the voices of those in historically underrepresented communities. Toward that end, we engaged science educators who work with Indigenous students and recent immigrants as collaborators in developing PL to support data-rich, place-based Earth Science instruction. In this case study, we share and critique the practices and tools that we have employed to center educator voices, rather than those of the PL designers and researchers. Our strategies for developing more equitable science professional learning include the use of: (a) equity-focused research methods, such as asset-based needs-sensing questions and peer-to-peer interviews; (b) a humanistic stance toward data-rich science learning, which emphasizes the typically unnamed sociocultural inputs and outputs that permeate all aspects of data; (c) a participatory design process that centers educators’ voices; and (d) a model of professional learning that uses representations of educator and student experiences as objects for reflection.

We present cosmological constraints from a gravitational lensing mass map covering 9400 deg ^2 reconstructed from measurements of the cosmic microwave background (CMB) made by the Atacama Cosmology Telescope (ACT) from 2017 to 2021. In combination with measurements of baryon acoustic oscillations and big bang nucleosynthesis, we obtain the clustering amplitude σ _8 = 0.819 ± 0.015 at 1.8% precision, ${S}_{8}\equiv {\sigma }_{8}{({{\rm{\Omega }}}_{{\rm{m}}}/0.3)}^{0.5}=0.840\pm 0.028$ , and the Hubble constant H _0 = (68.3 ± 1.1) km s ^−1 Mpc ^−1 at 1.6% precision. A joint constraint with Planck CMB lensing yields σ _8 = 0.812 ± 0.013, ${S}_{8}\equiv {\sigma }_{8}{({{\rm{\Omega }}}_{{\rm{m}}}/0.3)}^{0.5}=0.831\pm 0.023$ , and H _0 = (68.1 ± 1.0) km s ^−1 Mpc ^−1 . These measurements agree with ΛCDM extrapolations from the CMB anisotropies measured by Planck. We revisit constraints from the KiDS, DES, and HSC galaxy surveys with a uniform set of assumptions and find that S _8 from all three are lower than that from ACT+Planck lensing by levels ranging from 1.7 σ to 2.1 σ . This motivates further measurements and comparison, not just between the CMB anisotropies and galaxy lensing but also between CMB lensing probing z ∼ 0.5–5 on mostly linear scales and galaxy lensing at z ∼ 0.5 on smaller scales. We combine with CMB anisotropies to constrain extensions of ΛCDM, limiting neutrino masses to ∑ m _ν < 0.13 eV (95% c.l.), for example. We describe the mass map and related data products that will enable a wide array of cross-correlation science. Our results provide independent confirmation that the universe is spatially flat, conforms with general relativity, and is described remarkably well by the ΛCDM model, while paving a promising path for neutrino physics with lensing from upcoming ground-based CMB surveys.

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.

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.

Objectives Individuals with fetal alcohol spectrum disorder (FASD) are over-represented within the justice system and have significant employment challenges. The primary aim of this scoping review was to ascertain available employment resources for FASD individuals particularly those involved in the justice system. Secondary aims were to determine available evidence-based interventions for the justice workforce and employment providers.Methods Eligibility criteria: That the resource was (a) published between 1990 and 2021, (b) in English, (c) available electronically in full text, (d) focused on strategies for improving employment outcomes of individuals with FASD and (f) developed for those aged over 15. Sources of evidence: Electronic searches of the following databases were conducted: EMBASE, MEDLINE, PsycINFO, Scopus, Web of Science and Google Scholar. Grey literature was collected via the databases ProQuest Dissertations & Theses Global, OpenGrey, GreyNet International and Grey Matters. Charting methods: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews reporting guidelines, a five-stage methodological framework was employed. A quality appraisal of identified resources was conducted. Data were summarised qualitatively using a content analysis method that allowed for analysis of specific terms/themes/concepts/resource elements that resources covered, as well as a quantitative analysis of their frequency.Results An initial search identified 850 articles, 512 of which were obtained through online database searches, 321 through Google Scholar searches and 17 through google searches. Sixteen resources were identified as meeting inclusion criteria, including four peer-reviewed papers and 12 grey literature resources. Six of the resources extracted were deemed ‘good’ or ‘strong’ quality, with the remainder—all grey literature resources—being ‘adequate’ or ‘limited’. None of the resources identified were empirically evaluated or could be implemented synergistically. Content analysis revealed common themes addressing FASD-related employment challenges and required supports.Conclusions This review highlights the need for developing evidence-based employment-related resources for justice-involved people with FASD. Most of the 16 identified resources had a psychoeducational and advocacy component and described typical employment challenges with specific supports and accommodations to maximise workforce participation. However, none had been empirically evaluated, underscoring the importance of future research in this area to better inform more responsive and evidence-based employment-related programmes.Trial registration number doi:10.17605/OSF.IO/J5VMB.

Background: Infection during pregnancy can increase the risk of neurodevelopmental disorders in offspring. The impact of maternal SARS-CoV-2 infection on infant neurodevelopment is poorly understood. The maternal immune response to infection may be mimicked in rodent models of maternal immune activation which recapitulate altered neurodevelopment and behavioural disturbances in the offspring. In these models, epigenetic mechanisms, in particular DNA methylation, are one pathway through which this risk is conferred in utero to offspring. We hypothesised that in utero exposure to SARS-CoV-2 in humans may alter infant DNA methylation, particularly in genes associated with neurodevelopment. We aimed to test this hypothesis in a pilot sample of children in Victoria, Australia, who were exposed in utero to SARS-CoV-2. Methods: DNA was extracted from buccal swab specimens from (n = 4) SARS-CoV-2 in utero exposed and (n = 4) non-exposed infants and methylation status assessed across 850,000 methylation sites using an Illumina EPIC BeadChip. We also conducted an exploratory enrichment analysis using Gene Ontology annotations. Results: 1962 hypermethylated CpG sites were identified with an unadjusted p-value of 0.05, where 1133 CpGs mapped to 959 unique protein coding genes, and 716 hypomethylated CpG sites mapped to 559 unique protein coding genes in SARS-CoV-2 exposed infants compared to non-exposed. One differentially methylated position (cg06758191), located in the gene body of AFAP1 that was hypomethylated in the SARS-CoV-2 exposed cohort was significant after correction for multiple testing (FDR-adjusted p-value

Abstract 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

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.

Abstract Background Globally, medical cannabis legalization has increased in recent years and medical cannabis is commonly used to treat chronic pain. However, there are few randomized control trials studying medical cannabis indicating expert guidance on how to dose and administer medical cannabis safely and effectively is needed. Methods Using a multistage modified Delphi process, twenty global experts across nine countries developed consensus-based recommendations on how to dose and administer medical cannabis in patients with chronic pain. Results There was consensus that medical cannabis may be considered for patients experiencing neuropathic, inflammatory, nociplastic, and mixed pain. Three treatment protocols were developed. A routine protocol where the clinician initiates the patient on a CBD-predominant variety at a dose of 5 mg CBD twice daily and titrates the CBD-predominant dose by 10 mg every 2 to 3 days until the patient reaches their goals, or up to 40 mg/day. At a CBD-predominant dose of 40 mg/day, clinicians may consider adding THC at 2.5 mg and titrate by 2.5 mg every 2 to 7 days until a maximum daily dose of 40 mg/day of THC. A conservative protocol where the clinician initiates the patient on a CBD-predominant variety at a dose of 5 mg once daily and titrates the CBD-predominant dose by 10 mg every 2 to 3 days until the patient reaches their goals, or up to 40 mg/day. At a CBD-predominant dose of 40 mg/day, clinicians may consider adding THC at 1 mg/day and titrate by 1 mg every 7 days until a maximum daily dose of 40 mg/day of THC. A rapid protocol where the clinician initiates the patient on a balanced THC:CBD variety at 2.5–5 mg of each cannabinoid once or twice daily and titrates by 2.5–5 mg of each cannabinoid every 2 to 3 days until the patient reaches his/her goals or to a maximum THC dose of 40 mg/day. Conclusions In summary, using a modified Delphi process, expert consensus-based recommendations were developed on how to dose and administer medical cannabis for the treatment of patients with chronic pain.

Currently, we are facing a new manifestation of functional neurological disorder presenting with functional Tourette-like behavior (FTB). This study aimed to show characteristics of this phenotype presenting as an outbreak of “mass social media-induced illness” (MSMI) and to explore predisposing factors. Between 5–9/2021, we prospectively investigated 32 patients (mean/median age: 20.1/18 years, range: 11–53 years, n = 16 females) with MSMI-FTB using a neuro-psychiatric examination, a comprehensive semi-structured interview and aspects of the Operationalized Psychodynamic Diagnostic System. In contrast to tics, numbers of complex movements and vocalizations were nine times greater than of “simple” symptoms, and of vocalizations one and a half times greater than of movements. In line with our hypothesis of MSMI, symptoms largely overlapped with those presented by German YouTuber Jan Zimmermann justifying his role as “virtual” index case in current outbreak. Typically, symptoms started abruptly at a mean age of 19 years and deteriorated gradually with no differences between males and females. In all patients, we identified timely-related psychological stressors, unconscious intrapsychic conflicts, and/or structural deficits. Nearly all patients (94%) suffered from further psychiatric symptoms including abnormalities in social behavior (81%), obsessive-compulsive behavior (OCB) (47%), Tourette syndrome (TS) (47%), anxiety (41%), and depression (31%), about half (47%) had experienced bullying, and 75% suffered from coexisting somatic diseases. Our data suggest that pre-existing abnormalities in social behavior and psychiatric symptoms (OCB, anxiety, and depression), but also TS in combination with timely-related psychological stressors, unconscious intrapsychic conflicts, and structural deficits predispose to contagion with MSMI-FTB.

Randomized double-blind placebo-controlled trials (RCTs) are regarded as the gold standard for clinical trials. While there are established standards to avoid unblinding, in RCTs using tetrahydrocannabinol (THC) containing cannabinoids, however, accidental unblinding and intentional self-unbinding must be considered as a particular issue, since THC tests are widely available. To investigate unblinding rates in an RCT using a THC-containing cannabinoid, we re-contacted 54 out of 97 participants of the CANNA-TICS trial who had participated in our study center in Hannover. Of the 54 participants, 53 could be reached. Of these, one participant (2%) stated that she had unblinded herself intentionally during the treatment phase, and another three patients (6%) reported intentional unblinding after the end of the treatment. Noteworthy, two patients provided discrepant information and denied self-unblinding during the interview, although during study/clinic visits they had reported having done so. Thus, based on all available information, three participants (6%) unblinded themselves intentionally during the treatment phase and another three (6%) after the end of the treatment. Accidental unblinding during the treatment phase was reported by 4/54 participants (7%) (during study visits). Since one participant reported both intentional self-unblinding (during the interview) and accidental unblinding (during a study visit), the total unblinding rate was 17% (n = 9). Of these, seven participants (13%) reported unblinding during the treatment phase. When asked in the interview whether they knew that self-unblinding would have been possible, only 34% (n = 18/53) of participants stated that they had been aware of this possibility. Thus, altogether 33% (n = 6/18) of those being informed about the possibility of self-unblinding did so and half of them (3/18, 17 %) during the treatment phase. It can be expected that in parallel to increasing knowledge of medicinal and recreational use of cannabinoids, more and more people will also be informed about the availability of THC tests. Hence, in future RCTs using THC-containing cannabinoids, researchers have to take the possibility of accidental and intentional unblinding into consideration, when designing the study.

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.

Abstract Background Cardiac ventricular aneurysms affect 1 in 200,000 live births. To the best of our knowledge, no reported cases of a left ventricular pseudoaneurym and in utero rupture exist to guide optimal management. Case presentation We present a case of fetal left ventricular rupture with a large pericardial effusion, cardiac tamponade and subsequent pseudoaneurysm formation with concerns for a poor prognosis. Interventional drainage of the pericardial effusion led to resolution of tamponade and significant improvement in fetal condition. A multidisciplinary team was utilised to plan birth to minimise risk of pseudoaneurysmal rupture and a catastrophic bleed at birth. Conclusion For similar cases we recommend consideration of birth by caesarean section, delayed cord clamping and a prostaglandin E1 infusion, to reduce the systemic pressures on the left ventricle during transition from fetal to neonatal circulations, until definitive surgical repair. In this case, this resulted in a successful outcome.

Abstract Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.

Exercise mitigates obesity-associated pathologies; however, there is controversy regarding optimal exercise interventions. Autophagy, is known to decrease during obesity and is an important moderator for exercise adaptations. Purpose: To investigate individual and combined effects of different exercise interventions and autophagy inhibition on exercise adaptations during obesity. Methods: C57BL/6J mice initiated 45% high fat diet at 8 weeks of age. After 6 weeks of diet, animals were divided into moderate (MOD) or high intensity interval training interventions (HIIT), animals were further divided into autophagy inhibition or vehicle conditions (n = 10/group). Animals exercised and autophagy was inhibited 3X/week by NSC185058 injections, thereby blocking autophagosome formation. Interventions continued for 4 weeks. Results: High fat diet impaired glucose handling ∼17%; exercise interventions normalized glucoregulation to pre-high fat diet levels, without differences between any interventions. High fat diet induced ∼25% decrease in aerobic capacity, which returned to baseline after exercise interventions, with no differences between any interventions. No effects of autophagy inhibition were noted. Conclusions: HIIT and MOD training confer similar health-related adaptations. Keywords: Insulin resistance, Exercise capacity, Glucose tolerance, Obesity

Glucose tolerance tests (GTT) are commonly performed in beef cattle to evaluate the glucose-insulin signaling pathway. Blood samples are obtained via a catheter and then transferred back to the laboratory for further analysis. A hand-held glucometer used chute-side can make performing GTT's and quantifying blood glucose concentration much easier and faster for research purposes. The purpose of this study was to evaluate the agreement between a hand-held electronic glucometer (Precision Xtra; Abbott Diabetes Care Inc., Mississauga, ON, Canada) for chute-side use in beef cattle compared with a colorimetric assay in the laboratory (Stanbio Glucose LiquiColor; Stanbio Laboratory, Boerne, TX, USA). A GTT was performed on 13 Simmental × Angus steers during the growing phase. Blood samples were obtained via a jugular catheter. Glucometer readings were taken immediately after blood was sampled from the jugular with no preservative, and laboratory measurements were conducted on plasma preserved with sodium fluoride. A paired t-test (P = 0.40), Pearson's correlation (P < 0.001; r = 0.95), Bland-Altman plot, and Lin's concordance correlation coefficient (LCCC = 0.90) were completed to evaluate the performance of the glucometer relative to the results from the laboratory assay. Based on the results, we conclude that the glucometer is an acceptable method for measuring blood glucose concentration in beef cattle under field conditions.

Collagen is a highly versatile protein used in tissue engineering constructs and as a model piezoelectric biomaterial. The piezoelectricity of collagen can be enhanced through the alignment of collagen domains and fibres, although most fabrication techniques used to form dense collagenous constructs do not allow for significant collagen alignment. The use of aerosol jet printing (AJP) mitigates the limitations of using soluble collagen inks for bioprinting or extrusion-based 3D printing, particularly if microfibrillar collagen suspensions are used as a cost-effective and scalable ink source. In this work, Type I and Type II microfibrillar collagen from different anatomical sources were successfully deposited using AJP with two different atomisation methods, namely pneumatic-AJP (p-AJP) and ultrasonic-AJP (u-AJP). The printing parameters were optimised for their piezoelectric amplitude and surface potential. Fourier transform infrared spectra of the films revealed that ultrasonic atomisation did not cause notable denaturation of collagen, although the process resulted in the fractionation and preferential deposition of the oligomeric and gelatinous components within the slurry. The printed collagen samples displayed a piezoelectric response that was four times higher than the values obtained from drop-cast collagen films, and their surface potential was found to be positively correlated to the roughness of the films which can be controlled through the mode of atomisation. These results indicate the ability to enhance and control the piezoelectricity and surface potential using p-AJP and u-AJP, which offers a promising physical modulation technique to tailor cell adhesion, proliferation or differentiation for collagen-based tissue engineering constructs.

Background The 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.Methods Multicentre 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 dissemination Ethics 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 number ACTRN12620000878976; Pre-results.

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.

Abstract Background The purpose of this study was to assess the pharmacological treatment strategies of inpatients with borderline personality disorder between 2008 and 2012. Additionally, we compared pharmacotherapy during this period to a previous one (1996 to 2004). Methods Charts of 87 patients with the main diagnosis of borderline personality disorder receiving inpatient treatment in the University Medical Center of Goettingen, Germany, between 2008 and 2012 were evaluated retrospectively. For each inpatient treatment, psychotropic drug therapy including admission and discharge medication was documented. We compared the prescription rates of the interval 2008–2012 with the interval 1996–2004. Results 94% of all inpatients of the interval 2008–2012 were treated with at least one psychotropic drug at time of discharge. All classes of psychotropic drugs were applied. We found high prescription rates of naltrexone (35.6%), quetiapine (19.5%), mirtazapine (18.4%), sertraline (12.6%), and escitalopram (11.5%). Compared to 1996–2004, rates of low-potency antipsychotics, tri−/tetracyclic antidepressants and mood stabilizers significantly decreased while usage of naltrexone significantly increased. Conclusions In inpatient settings, pharmacotherapy is still highly prevalent in the management of BPD. Prescription strategies changed between 1996 and 2012. Quetiapine was preferred, older antidepressants and low-potency antipsychotics were avoided. Opioid antagonists are increasingly used and should be considered for further investigation.

Abstract Background The aim of this systematic review was to identify principles of exercise interventions associated with improved physical function, weight management or musculoskeletal pain relief among young and middle-aged adults with obesity and propose an evidence-based exercise prescription that could assist in secondary prevention of osteoarthritis. Methods A structured electronic review was conducted using MEDLINE, PubMed, and SPORTDiscus. The search string included 1) “obes*” AND “exercise” AND “interven*” AND “musculoskeletal pain OR knee pain OR hip pain”. Studies 1) were randomized controlled trials of humans, with a non-exercise control, 2) included participants aged 18–50 years, and 3) had outcomes that included physical function, musculoskeletal pain, and/or body composition. Studies were excluded if participants had peri-menopausal status, cancer, or obesity-related co-morbidities. A recommended exercise prescription was developed based on common principles used in the included exercise interventions with greatest change in function or pain. Results Seven studies were included. Similarities in exercise intensity (40–80% VO2max), frequency (three times per week), duration (30–60 min), and exercise mode (treadmill, cross-trainer, stationary bike, aquatic exercise) were observed in exercise interventions that resulted in improved physical function and/or pain, compared to non-exercise control groups. Conclusion Common principles in exercise prescription for improvements in weight management, physical function and pain relief among otherwise healthy people with obesity. Exercise prescription including moderate intensity exercise for 30–60 min, three times per week can be considered an effective treatment for weight management and obesity-related musculoskeletal symptoms. Exercise should be recommended to at-risk individuals as part of secondary prevention of osteoarthritis.

The development of resistance to endocrine therapy is a significant, clinical problem in breast cancer. Here, the authors identify a rare subpopulation of cells that drive resistance following transcriptional reprogramming.

Abstract The strict intake regimen of cysteamine bitartrate formulations, associated with side effects, is a concern for the treatment compliance in cystinosis therapy. Therefore, there is a need for a cysteamine formulation with an improved pharmacokinetic profile. This study investigated the pharmacokinetics, safety and tolerability of a new sustained‐release cysteamine dosage form, PO‐001, in healthy volunteers. This was a randomized, investigator‐blinded, three‐way cross‐over study to compare single doses (600 mg) of PO‐001 with Cystagon® (immediate‐release) and Procysbi® (delayed‐release). Collected blood samples were analyzed for plasma cysteamine concentrations and pharmacokinetic parameters were estimated by noncompartmental analysis. In addition, plasma cysteamine concentrations were analyzed using a population pharmacokinetic approach using NONMEM®. Pharmacokinetics showed clear sustained‐release characteristics of PO‐001 over time with a lower Cmax and longer Tmax compared to Cystagon® and Procysbi®. All treatment‐emergent adverse events were of mild severity, with the exception of two subjects who reported moderate severity gastrointestinal problems including vomiting and diarrhea, which were related to Cystagon® intake. Population PK simulations showed a favourable PK profile based on Cmax and Ctrough concentrations at steady state. In conclusion, a single dose of 600 mg PO‐001 was well tolerated with no findings of clinical concern. This new cysteamine bitartrate formulation showed pharmacokinetics of a sustained‐release formulation, which may be beneficial for the treatment of cystinosis patients. This study supports advancing this type of sustained‐release formulation into a subsequent study to confirm reduced dosing frequency with efficient control of white blood cells (WBCs) cystine levels. Netherlands Trial Registry (NTR) (NL67638.056.18).

The Yale Global Tic Severity Scale (YGTSS) is a clinician-rated instrument considered as the gold standard for assessing tics in patients with Tourette's Syndrome and other tic disorders. Previous psychometric investigations of the YGTSS exhibit different limitations such as small sample sizes and insufficient methods. To overcome these shortcomings, we used a subsample of the large-scale “European Multicentre Tics in Children Study” (EMTICS) including 706 children and adolescents with a chronic tic disorder and investigated convergent, discriminant and factorial validity, as well as internal consistency of the YGTSS. Our results confirm acceptable convergent and good to very good discriminant validity, respectively, indicated by a sufficiently high correlation of the YGTSS total tic score with the Clinical Global Impression Scale for tics (rs = 0.65) and only low to medium correlations with clinical severity ratings of attention deficit/hyperactivity symptoms (rs = 0.24), obsessive–compulsive symptoms (rs = 27) as well as internalizing symptoms (rs = 0.27). Internal consistency was found to be acceptable (Ω = 0.58 for YGTSS total tic score). A confirmatory factor analysis supports the concept of the two factors “motor tics” and “phonic tics,” but still demonstrated just a marginal model fit (root mean square error of approximation = 0.09 [0.08; 0.10], comparative fit index = 0.90, and Tucker Lewis index = 0.87). A subsequent analysis of local misspecifications revealed correlated measurement errors, suggesting opportunities for improvement regarding the item wording. In conclusion, our results indicate acceptable psychometric quality of the YGTSS. However, taking the wide use and importance of the YGTSS into account, our results suggest the need for further investigations and improvements of the YGTSS. In addition, our results show limitations of the global severity score as a sum score indicating that the separate use of the total tic score and the impairment rating is more beneficial.

Preterm birth is the leading cause of infant death worldwide, but the causes of preterm birth are largely unknown. During the early COVID-19 lockdowns, dramatic reductions in preterm birth were reported; however, these trends may be offset by increases in stillbirth rates. It is important to study these trends globally as the pandemic continues, and to understand the underlying cause(s). Lockdowns have dramatically impacted maternal workload, access to healthcare, hygiene practices, and air pollution - all of which could impact perinatal outcomes and might affect pregnant women differently in different regions of the world. In the international Perinatal Outcomes in the Pandemic (iPOP) Study, we will seize the unique opportunity offered by the COVID-19 pandemic to answer urgent questions about perinatal health. In the first two study phases, we will use population-based aggregate data and standardized outcome definitions to: 1) Determine rates of preterm birth, low birth weight, and stillbirth and describe changes during lockdowns; and assess if these changes are consistent globally, or differ by region and income setting, 2) Determine if the magnitude of changes in adverse perinatal outcomes during lockdown are modified by regional differences in COVID-19 infection rates, lockdown stringency, adherence to lockdown measures, air quality, or other social and economic markers, obtained from publicly available datasets. We will undertake an interrupted time series analysis covering births from January 2015 through July 2020. The iPOP Study will involve at least 121 researchers in 37 countries, including obstetricians, neonatologists, epidemiologists, public health researchers, environmental scientists, and policymakers. We will leverage the most disruptive and widespread “natural experiment” of our lifetime to make rapid discoveries about preterm birth. Whether the COVID-19 pandemic is worsening or unexpectedly improving perinatal outcomes, our research will provide critical new information to shape prenatal care strategies throughout (and well beyond) the pandemic.

OBJECTIVES/GOALS: MiaA is a highly conserved prenyl transferase that catalyzes synthesis of the i6A37 tRNA modification in E. coli. While transcriptional regulation of MiaA is well characterized, there is no information on the MiaA post-transcriptional regulation. The aim of this study is to characterize the post-transcriptional regulation of the MiaA gene in E. coli. METHODS/STUDY POPULATION: To characterize the post-transcriptional regulation of miaA, we executed a targeted genetic screen of an E. coli small RNA library on a miaA-lacZ translational reporter fusion strain to identify small RNAs (sRNAs) that modulate MiaA translation or transcription termination. We also measured MiaA mRNA levels and miaA-lacZ activity in the absence or over-expression of candidate sRNA regulators of MiaA. We also measured MiaA mRNA levels in the absence of RNaseE and PNPase, two enzymes involved in mRNA turnover. Finally, we measured the ability of purified recombinant CsrA to bind to the MiaA mRNA transcript in vitro. RESULTS/ANTICIPATED RESULTS: We identified the carbon sensing sRNA CsrB and its cognate protein interaction partner CsrA, as potential post-transcriptional regulators of MiaA. Over-expression of CsrB fully repressed miaA-lacZ activity and MiaA mRNA levels. The absence of CsrA resulted in a defective miaA-lacZ activity and a 10-fold decrease in MiaA mRNA levels. We also identified an increase in the MiaA mRNA half-life particularly in the absence of RNaseE. Our results demonstrate an additional layer of regulation for the miaA operon by the CsrA/CsrB protein-sRNA system. DISCUSSION/SIGNIFICANCE: MiaA is a highly conserved bacterial protein. Our data may represent phenomena in an array of bacteria that could be targeted by novel antibiotics. The human MiaA homologue, TRIT1, plays a role in mitochondrial disorders. We anticipate that information garnered from MiaA studies will elucidate TRIT1 function and its role in mitochondrial disorders.

Crucial in the pathogenesis of neurodegenerative diseases is the process of neuroinflammation that is often linked to the pro-inflammatory cytokines Tumor necrosis factor alpha (TNFα) and Interleukin-1beta (IL-1β). Human cortical spheroids (hCSs) constitute a valuable tool to study the molecular mechanisms underlying neurological diseases in a complex three-dimensional context. We recently designed a protocol to generate hCSs comprising all major brain cell types. Here we stimulate these hCSs for three time periods with TNFα and with IL-1β. Transcriptomic analysis reveals that the main process induced in the TNFα- as well as in the IL-1β-stimulated hCSs is neuroinflammation. Central in the neuroinflammatory response are endothelial cells, microglia and astrocytes, and dysregulated genes encoding cytokines, chemokines and their receptors, and downstream NFκB- and STAT-pathway components. Furthermore, we observe sets of neuroinflammation-related genes that are specifically modulated in the TNFα-stimulated and in the IL-1β-stimulated hCSs. Together, our results help to molecularly understand human neuroinflammation and thus a key mechanism of neurodegeneration.

Abstract Skeletal muscle atrophy is common across a variety of pathologies. Underlying mechanisms of atrophy differ between pathologies, and in many conditions, circulating factors are tied to muscle atrophy. Therefore, we sought to identify alterations to the plasma proteome across divergent forms of muscle atrophy, disuse and cancer cachexia, as potential mediators of atrophy. C57BL6/J mice were assigned to Lewis Lung Carcinoma (LLC)‐induced cachexia, disuse by hindlimb unloading (HU), or control (CON). Plasma samples were submitted for discovery proteomics and targets of interest confirmed by immunoblot. Considerably more peptides were altered in plasma from LLC (91) than HU (9) as compared to CON. Five total proteins were similarly modulated in HU and LLC compared to CON, none reached criteria for differential expression. Serum Amyloid A1 (SAA) was 4 and 6 Log2FC greater in LLC than CON or HU, respectively, confirmed by immunoblot. Recent reports suggest SAA is sufficient to induce atrophy via TLR. Therefore, we assessed TLR2,4, and IL‐6 mRNAs in hindlimb muscles. TLR mRNAs were not altered, suggesting SAA effects on atrophy during LLC are independent of TLR signaling. However, we noted > 6‐fold induction of IL‐6 in soleus of HU mice, despite minimal shift in the plasma proteome, indicating potential localized inflammation in atrophying muscle. Furthermore, paraoxonase 1 (PON1) was highly repressed in LLC mice and largely undetectable by immunoblot in this group. Our data suggest SAA and PON1 as potential novel atrokines for cancer cachexia and indicate localized inflammation in atrophying muscles independent of the plasma proteome.

Although several lines of evidence support the hypothesis of a dysregulation of serotoninergic neurotransmission in the pathophysiology of obsessive-compulsive disorder (OCD), there is also evidence for an involvement of other pathways such as the GABAergic, glutamatergic, and dopaminergic systems. Only recently, data obtained from a small number of animal studies alternatively suggested an involvement of the endocannabinoid system in the pathophysiology of OCD reporting beneficial effects in OCD-like behavior after use of substances that stimulate the endocannabinoid system. In humans, until today, only two case reports are available reporting successful treatment with dronabinol (tetrahydrocannabinol, THC), an agonist at central cannabinoid CB1 receptors, in patients with otherwise treatment refractory OCD. In addition, data obtained from a small open uncontrolled trial using the THC analogue nabilone suggest that the combination of nabilone plus exposure-based psychotherapy is more effective than each treatment alone. These reports are in line with data from a limited number of case studies and small controlled trials in patients with Tourette syndrome (TS), a chronic motor and vocal tic disorder often associated with comorbid obsessive compulsive behavior (OCB), reporting not only an improvement of tics, but also of comorbid OCB after use of different kinds of cannabis-based medicines including THC, cannabis extracts, and flowers. Here we present the case of a 22-year-old male patient, who suffered from severe OCD since childhood and significantly improved after treatment with medicinal cannabis with markedly reduced OCD and depression resulting in a considerable improvement of quality of life. In addition, we give a review of current literature on the effects of cannabinoids in animal models and patients with OCD and suggest a cannabinoid hypothesis of OCD.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by motor and vocal tics. There are several hypotheses as to the cause of the disease. One of which suggests that the immune system is involved in the pathophysiology of GTS. Here, we present a 40-year-old female patient with a typical history and clinical presentation of GTS with tics and psychiatric comorbidities, in whom positive oligoclonal bands (OCBs) type 2 in cerebral spinal fluid (CSF) were detected in an earlier study. At that time point, all other investigations were unremarkable (including neurological examination and cMRI), but 2 years later, she presented with further neurological symptoms including tetraparesis mostly affecting the left limbs, distal hypesthesia and paresthesia, and dyspnea. Since further examinations (including EMG, MRI, CSF, virological, and bacteriological tests, as well as autoimmune-encephalitis antibodies) revealed normal results, based on clinical presentation, the diagnosis of Guillain-Barré-like immune-mediated neuropathy was made and treatment with intravenous immunoglobulins (IVIg) (30 g/day for 5 days) was initiated resulting in complete remission of immune-mediated neuropathy. Based on the “immune hypothesis” of GTS, we were interested in whether in this patient positive CSF OCBs might serve as a biomarker for treatment response of tics and additional GTS-related psychiatric symptoms to IVIg, and therefore assessed tics, premonitory urges, and psychiatric comorbidities before and several times after the IVIg treatment. However, even though immune-mediated neuropathy resolved after treatment, tics, premonitory urges, and comorbidities remained unchanged. Thus, this case study suggests that treatment with IVIg is not effective in the treatment of GTS—even in a patient with intrathecal antibody synthesis as expressed by CSF isolated OCBs.

Abstract Introduction Gln‐1062 (MEMOGAIN) is an intranasally administered lipophilic prodrug of galantamine. Based on high brain‐to‐blood concentrations observed in pre‐clinical studies, Gln‐1062 is expected to have superior cognitive efficacy compared to oral galantamine. Methods Forty‐eight healthy elderly subjects were randomized 12:4 to Gln‐1062 (5.5, 11, or 22 mg, b.i.d., for 7 days) or placebo. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed repeatedly. Pharmacokinetics were compared with 16 mg oral galantamine. Results Gln‐1062 up to 22 mg, b.i.d., was well tolerated. Gln‐1062 plasma concentrations increased immediately following dosing (median Tmax of 0.5 hour [range 0.5‐1.0]). Cmax and AUC0‐last increased in a dose‐linear manner over all three dose levels. Gln‐1062 was rapidly cleaved into galantamine. Gln‐1062 significantly improved adaptive tracking (sustained attention) with 1.95% (95% confidence interval [CI] 0.630‐3.279, P = 0.0055) compared to placebo after correction for individual baseline performance. Discussion Gln‐1062 was considered to be safe and caused fewer gastrointestinal side effects than oral galantamine. Gln‐1062 behaved pharmacokinetically as expected and improved performance on cognitive tests.

IntroductionAlthough defined by the presence of tics, most patients with Gilles de la Tourette syndrome (TS) also suffer from different psychiatric disorders. While much is known about clinical characteristics of comorbidities such as attention deficit/hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), depression, and anxiety disorders, only very little is known about rage attacks. Most of this data is based on small studies in children. Until today no larger studies have been performed in adults with TS—most likely because of the lack of validated instruments. The aim of this study was to develop a new assessment and investigate rage attacks in a large sample of adults with TS and healthy individuals. Materials and MethodsBased on a parent questionnaire for children with TS, we generated 27 items for a revised version of a rage attack questionnaire (RAQ-R) and tested factor structure, internal consistency, as well as convergent and discriminant validity. We used an online survey and included 127 patients with TS and 645 control subjects. In addition to the RAQ-R, we used several other self-assessments to measure tic severity, quality of life, as well as several psychiatric symptoms including ADHD, OCD, depression, anxiety, and impulsivity.ResultsBased on expert option and statistical analyses [including item-total correlation, skewness, inter-item correlation, and principal component analysis (PCA)], we performed an item reduction resulting in a final, 22-items version of the RAQ-R (range, 0–66). Investigating internal consistency, discriminant validity, test reliability, and factor structure, the RAQ-R demonstrated good to excellent quality criteria. As assessed by RAQ-R, rage attacks were significantly more common in patients with TS compared to controls (p < 0.001). Rage attacks could be clearly differentiated from the phenomenon of impulsivity. Although rage attacks occurred more often in individuals with ADHD, they were also found in patients with “TS only”, independently from comorbid ADHD, impulsivity, and OCD. Rage attacks were found to significantly influence patients’ quality of life.ConclusionsThus, from our data based on a large sample it is suggested that rage attacks represent a discrete comorbidity in adults with TS.

Abstract Acetone monooxygenase (ACMO) is a unique member of the Baeyer–Villiger monooxygenase (BVMO) family based on its ability to act on small ketones, such as acetone. Herein, we performed a kinetic analysis of ACMO from the propane-utilizing bacterium Gordonia sp. strain TY-5 to assess its preference for smaller ketone substrates. Steady state kinetic analysis of ACMO with a range of linear (C3–C7) and cyclic ketones (C4–C6) reveals that the enzyme elicits the highest catalytic efficiency towards butanone and cyclobutanone. Stopped-flow and inhibition studies further revealed that ACMO has a relatively weak binding affinity for the coenzyme with a dissociation constant of 120 μM. We show through mutagenesis that sequence variation in the residue that coordinates to the 2′-phosphate of NADP(H) partially accounts for the weaker binding affinity observed. As for shown for related BVMOs, NADP+ stabilizes the C4a-peroxyflavin intermediate in ACMO; however, the rate of its formation is considerably slower in ACMO. The observed rate constant for NADPH-dependent flavin reduction was 60 s−1 at 25 °C, and experiments performed with 4(R)-[4-2H]NADPH confirm that the C4-pro-R-hydride from the nicotinamide ring is transferred to the FAD. The latter experimental result suggests that the nicotinamide ring rotates within the active site to carry out its two functional roles: reduction of the FAD cofactor and stabilization of the C4a-peroxyflavin adduct.

Background: Detection of defective deep brain stimulation (DBS) contacts/electrodes is sometimes challenging. Case Report: We report a patient with Tourette syndrome (TS), who presented with abrupt tic increase and mild generalized headache 9 years after DBS implantation. On the suspicion of a hardware defect, a fracture of the DBS electrode and extension lead was ruled out by radiography and standard implantable pulse generator readouts. Further investigation revealed position-dependent modifiable therapeutic impedances, suggesting an impaired contact of the extension lead/adaptor. After replacement normal impedances were recorded, and the patient fully recovered. Discussion: In DBS dysfunction with inconspicuous hardware check, position-dependent defects might be suspected.