A Modified Reach-to-Grasp Task in a Supine Position Shows Coordination Between Elbow and Hand Movements After Stroke

Objective: A modified reach-to-grasp task has been developed for the purpose of investigating arm-hand coordination in a supine position in the functional magnetic resonance imaging environment. The objective of this study was to investigate the kinematics of the reach-to-grasp task, in stroke and healthy participants.Design: Observational cohort study.Setting: Movement laboratory.Participants: Ten stroke participants and 10 age-matched healthy participants performed 10 repetitions of the modified reach-to-grasp task in two conditions—a natural condition and a standardized condition in a splint.Intervention: Not applicable.Main Outcome Measures: Kinematic variables of start time of transport, start time of aperture, movement duration, time of peak velocity (PV), percentage time of PV, peak deceleration (PD), percentage time of PD, peak aperture (PA), time of PA, and percentage time of PA were recorded. The correlation between key events in the grasp and transport trajectories were investigated. Performance between conditions and groups were compared.Results: Both groups demonstrated a significant correlation between the start time of aperture and the start time of transport and between the time of PA and PV in both conditions. A significant correlation was found between the time of PA and the PD in both conditions for the healthy group, but in neither condition for the stroke group. Movements by participants with stroke had a significantly longer movement duration, a smaller PV, and an earlier absolute time of PV and PD, and an earlier percentage time of PV and PD. They also had a smaller aperture than healthy participants. Wearing the splint resulted in a significantly higher PV, later absolute and percentage time of PV, PD, and PA, and a smaller PA compared to moving without the splint. The timing of transport variables time to peak velocity and time to peak deceleration, were strongest determinants of movement duration.Conclusion: The modified reach-to-grasp movement performed without the constraint of the splint, demonstrates similar motor control and coordination between the grasp and transport components of reach-to-grasp as in seated reach-to-grasp. This provides a new task that may be used to explore reach-to-grasp in the fMRI environment

Development of the PSYCHS: Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS

Aim: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS). Methods: The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR-P through an intensive series of joint videoconferences. Results: Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and modest harmonization for CHR-P criteria. The semi-structured interview, named Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS (PSYCHS), generates CHR-P criteria and severity scores for both CAARMS and SIPS. Conclusions: Using the PSYCHS for CHR-P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta-analyses

Monitoring quality and coverage of harm reduction services for people who use drugs: a consensus study.

BACKGROUND AND AIMS: Despite advances in our knowledge of effective services for people who use drugs over the last decades globally, coverage remains poor in most countries, while quality is often unknown. This paper aims to discuss the historical development of successful epidemiological indicators and to present a framework for extending them with additional indicators of coverage and quality of harm reduction services, for monitoring and evaluation at international, national or subnational levels. The ultimate aim is to improve these services in order to reduce health and social problems among people who use drugs, such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection, crime and legal problems, overdose (death) and other morbidity and mortality. METHODS AND RESULTS: The framework was developed collaboratively using consensus methods involving nominal group meetings, review of existing quality standards, repeated email commenting rounds and qualitative analysis of opinions/experiences from a broad range of professionals/experts, including members of civil society and organisations representing people who use drugs. Twelve priority candidate indicators are proposed for opioid agonist therapy (OAT), needle and syringe programmes (NSP) and generic cross-cutting aspects of harm reduction (and potentially other drug) services. Under the specific OAT indicators, priority indicators included 'coverage', 'waiting list time', 'dosage' and 'availability in prisons'. For the specific NSP indicators, the priority indicators included 'coverage', 'number of needles/syringes distributed/collected', 'provision of other drug use paraphernalia' and 'availability in prisons'. Among the generic or cross-cutting indicators the priority indicators were 'infectious diseases counselling and care', 'take away naloxone', 'information on safe use/sex' and 'condoms'. We discuss conditions for the successful development of the suggested indicators and constraints (e.g. funding, ideology). We propose conducting a pilot study to test the feasibility and applicability of the proposed indicators before their scaling up and routine implementation, to evaluate their effectiveness in comparing service coverage and quality across countries. CONCLUSIONS: The establishment of an improved set of validated and internationally agreed upon best practice indicators for monitoring harm reduction service will provide a structural basis for public health and epidemiological studies and support evidence and human rights-based health policies, services and interventions

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Describing speech abilities and trajectories of speech development in a heterogeneous group of children with autism

Children diagnosed with autism spectrum disorder (ASD) form a heterogeneous population. While the variation in language and social communication abilities are well documented, little is known about the speech of children on the spectrum. The small body of research to date reports three main findings: 1) differences in the prelinguistic speech of young children with ASD relative to typically developing children, 2) the presence of a small subgroup of minimally verbal children with a significant speech sound disorder (SSD), and 3) high rates of mild speech difficulties in older highly verbal children with ASD. The speech capacity and development of children across the entire autism spectrum remains largely undescribed. This thesis aimed to provide detailed descriptive speech data for a heterogeneous group of children with ASD, to explore the possibility of subgroups based on this speech data, and to examine the trajectories of speech development in these children. To address these aims, four main projects are reported in this thesis. Firstly, a systematic review was completed to provide a summary of speech assessment practices used in research with children with ASD. A systematic search of eight databases was used to find peer-reviewed research articles published between 1990 and 2014. The systematic review identified 21 articles that met the inclusion criteria. Assessment methods included connected speech samples, single-word naming tasks, speech imitation tasks, and analysis of the production of words and sentences. Given the large variation in participant characteristics and reporting standards in the studies included in the systematic review, it was difficult to draw comparisons. As part of the systematic review, a narrative review was completed to ascertain the core components of an evidence-based paediatric speech assessment which, together with the results of the systematic review, provide clinical and research guidelines for best practice. The results of this systematic review were used to guide assessment selection in the subsequent longitudinal study. The second project is a cross-sectional study reporting the results from the first data point of the longitudinal study and is included as a published paper. This study aimed to provide detailed descriptive baseline speech data and then use this data to explore whether subgroups exist within a heterogeneous cohort based on speech ability. Despite growing interest in the area of speech and autism, large gaps remain in the literature. There is limited information regarding the speech ability of young children with ASD across a range of functional levels, and few studies have reported detailed description of the speech skills of children with ASD. This study included 23 children aged 2;0-6;11 years with a diagnosis of ASD. Independent and relational speech analyses are reported from single-word naming tasks and spontaneous speech samples. Hierarchical cluster analysis identified three descriptive speech subgroups: A) children with high receptive and expressive vocabularies, high nonverbal communication, and high speech ability (n = 10), B) children with very low expressive vocabularies and low speech ability, but higher receptive vocabularies and nonverbal communication (n=3), and C) children with low vocabularies, low nonverbal communication, and low speech development (n=10). This is the first study to provide detailed descriptive speech data of a heterogeneous cohort of children with ASD and to use these data to explore the possibility of subgroups. Clustering suggests a small number of children may present with a unique communication profile which warrants further exploration. The third project presents the data from the longitudinal study for 22 of the same children described in the second project. This is the first longitudinal study detailing the speech development of children with ASD. The aims of this study were: 1) to describe changes in participant’s speech capacity over 12 months, 2) examine the stability of cluster membership over 12 months, and 3) describe what variables may explain changes in speech capacity over time. Four clusters emerged from clustering. Cluster membership remained stable for Cluster A and Cluster B children from Time 1 to Time 2. The Cluster C children from Time 1 had varied trajectories of speech development. One child made significant gains and joined Cluster A at Time 2 (n=11). Three children remained at the prelinguistic stage of language development and made very little speech gains over 12 months. These three children formed Time 2 Cluster C (n=3). Five children made gains across all areas of communication and formed Time 2 Cluster D (n=5). Findings of this study suggest that a child’s consonant repertoire and receptive vocabulary at Time 1 may be important variables to predict cluster membership at Time 2. Chapter 5 provides further detail regarding the three Cluster B children. These children presented with a consistent and unique communication profile of high receptive vocabularies and use of nonverbal communication, in the presence of low speech and low expressive vocabularies. This profile suggests a co-occurring speech sound disorder (SSD). The challenge of differentially diagnosing an SSD in minimally verbal children is discussed. Finally, an update of the original systematic review is presented in Chapter 6 to summarise the current state of evidence for the speech assessment of children with ASD. This update includes the results of a systematic search of the same eight databases using the same search terms, to find peer-reviewed research articles published between January 2015 and August 2021. Twenty-seven articles met inclusion criteria. There has been a significant increase in studies, particularly those investigating the speech of minimally verbal children with ASD. This research has seen a rise in studies using speech imitation tasks to assess the speech of less verbal children. Further, a number of studies adopted multiple assessment measures to describe the speech of children with ASD, in keeping with best practice speech guidelines. Together with the results from the longitudinal study, future research and clinical speech assessment guidelines are discussed. Collectively, the results from the four studies in this thesis highlight the value of describing the speech capacity of children with ASD across the heterogeneous spectrum. Children at all linguistic levels can complete a speech assessment, although some specific modifications for children with ASD should be considered. For example, we recommend including echolalia in a child’s speech sample, collecting speech samples whenever the child is most vocal - which may not be when interacting with others in play, and considering the whole communication profile of the child when interpreting their speech ability. Regarding the last point, many children with ASD have co-occurring language and social communication difficulties, and therefore, a score below normal limits on formal standardised assessments or poor speech ability during sampling, does not necessarily indicate a speech sound disorder. Some children may have low levels of speech, language and nonverbal communication. The results from the systematic reviews and longitudinal study suggest that a strengths-based speech assessment, focused on what the child can do, provides important descriptive information for differential diagnosis, baseline data collection, and intervention planning. Results from the longitudinal study suggest descriptive speech subgroups exist within the heterogeneous population of children with ASD. These subgroups emerged from the data even when the number or type of subgroups were not selected a priori. Children with low language, nonverbal communication, and speech at Time 1 had varied communication trajectories. Some children who initially presented as low verbal made significant gains and were verbal by Time 2. Further, a small subgroup of children with ASD present with a unique communication profile, with high levels of receptive vocabulary and nonverbal communication in the presence of very low expressive vocabulary and speech ability. These children do not develop speech along the same trajectory as children with comparable receptive vocabularies. Over 12 months, the speech capacity of children in this subgroup did not increase, despite improvements in receptive vocabulary and nonverbal communication. This profile suggests a co-occurring SSD, although more data is required to differentially diagnose a motor speech impairment from a phonological disorder. The combination of a child’s receptive vocabulary and consonant repertoire may predict the trajectory of speech development. Further research is required to explore these findings

Australian children with cleft palate achieve age-appropriate speech by 5 years of age

Introduction: Children with cleft palate demonstrate atypical speech sound development, which can influence their intelligibility, literacy and learning. There is limited documentation regarding how speech sound errors change over time in cleft palate speech and the effect that these errors have upon mono versus polysyllabic word production. The objective of this study was to examine the phonetic and phonological speech skills of children with cleft palate at ages 3 and 5. Methods: A cross-sectional observational design was used. Eligible participants were aged 3 or 5 years with a repaired cleft palate. The Diagnostic Evaluation of Articulation and Phonology (DEAP) Articulation subtest and a non-standardised list of mono and polysyllabic words were administered once for each child. The Profile of Phonology (PROPH) was used to analyse each child's speech. Results: N=51 children with cleft palate participated in the study. Three-year-old children with cleft palate produced significantly more speech errors than their typically-developing peers, but no difference was apparent at 5 years. The 5-year-olds demonstrated greater phonetic and phonological accuracy than the 3-year-old children. Polysyllabic words were more affected by errors than monosyllables in the 3-year-old group only. Conclusions: Children with cleft palate are prone to phonetic and phonological speech errors in their preschool years. Most of these speech errors approximate typically-developing children by 5 years. At 3 years, word shape has an influence upon phonological speech accuracy. Speech pathology intervention is indicated to support the intelligibility of these children from their earliest stages of development.The University of Sydney Douglas and Lola Douglas Speech Pathology Scholarshi

mTOR inhibition abrogates human mammary stem cells and early breast cancer progression markers

Abstract Background Mammary physiology is distinguished in containing adult stem/progenitor cells that are actively amending the breast tissue throughout the reproductive lifespan of women. Despite their importance in both mammary gland development, physiological maintenance, and reproduction, the exact role of mammary stem/progenitor cells in mammary tumorigenesis has not been fully elucidated in humans or animal models. The implications of modulating adult stem/progenitor cells in women could lead to a better understanding of not only their function, but also toward possible breast cancer prevention led us to evaluate the efficacy of rapamycin in reducing mammary stem/progenitor cell activity and malignant progression markers. Methods We analyzed a large number of human breast tissues for their basal and luminal cell composition with flow cytometry and their stem and progenitor cell function with sphere formation assay with respect to age and menopausal status in connection with a clinical study (NCT02642094) involving a low-dose (2 mg/day) and short-term (5–7 days) treatment of the mTOR inhibitor sirolimus. The expression of biomarkers in biopsies and surgical breast samples were measured with quantitative analysis of immunohistochemistry. Results Sirolimus treatment significantly abrogated mammary stem cell activity, particularly in postmenopausal patients. It did not affect the frequency of luminal progenitors but decreased their self-renewal capacity. While sirolimus had no effect on basal cell population, it decreased luminal cell population, particularly in postmenopausal patients. It also significantly diminished prognostic biomarkers associated with breast cancer progression from ductal carcinoma in situ to invasive breast cancer including p16INK4A, COX-2, and Ki67, as well as markers of the senescence-associated secretary phenotype, thereby possibly functioning in preventing early breast cancer progression. Conclusion Overall, these findings indicate a link from mTOR signaling to mammary stem and progenitor cell activity and cancer progression. Trial registration This study involves a clinical trial registered under the ClinicalTrials.gov identifier NCT02642094 registered December 30, 2015