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While extensive quantitative research has shed light on the cognitive mechanisms of dyslexia, few mixed-methods studies have been conducted to examine the perceptions of and attitudes towards learning in children with dyslexia, especially in Hong Kong, a bilingual context. In addition, the validity of the metaphor elicitation technique, which was adopted in previous interview studies, has not yet been examined in children. Therefore, 30 children with dyslexia (age range: 8-13; 10 females) in Hong Kong were interviewed for metaphors regarding six domains: Chinese reading, Chinese writing, having Chinese lessons, English reading, solving maths problems, and dyslexia. Word reading fluency and parent-rated learning interest and confidence were measured to validate the use of the metaphor elicitation method in assessing children's reading attitudes in both Chinese and English using correlation analyses. Perceptions were examined by way of qualitative analyses based on the metaphor entailments. Results showed that children who expressed more positive attitudes towards English reading performed better in English reading. Moreover, the attitudes also positively correlated with the corresponding parents' ratings. These findings suggested that the metaphor elicitation technique is a valid method for assessing attitudes towards English reading in children with dyslexia. Furthermore, their perceptions of dyslexia and learning generally corresponded to those from previous interview studies despite differences in languages and contexts. Importantly, descriptions related to multiple themes, including metalinguistic awareness, cognitive skills, coping strategies, and dyslexia, were well-aligned with scientific findings, demonstrating that children already have a good understanding of dyslexia and various learning domains.

Social-emotional deficits in school-aged children diagnosed with autism spectrum disorder (ASD) greatly hinder these children from fully participating in various school activities in the inclusive education setting. Previous studies have demonstrated evidence regarding the effectiveness of using virtual reality (VR) for enhancing the children's affective expression and social reciprocity. However, considering the technical and logistical complexity of the enabling hardware and software systems, how such approaches can be effectively and sustainably delivered in the school setting remains underexplored. This paper presents a study that utilised VR headsets to enhance affective expression and social reciprocity for children with ASD and explored how the approach could be effectively and sustainably delivered at schools. A total of eight VR learning scenarios were designed based on Kolb's experiential learning framework. 176 children aged 6-12 with a clinical diagnosis of ASD participated in the study. The statistical analyses showed that the participants who received the intervention significantly improved in affective expression and social reciprocity, compared to those who were in the control group. Moreover, the approaches to enhance long-term sustainability have also been presented and discussed in this paper.

Purpose: We examined the effect of character complexity on early Chinese literacy (word reading and writing). We also investigated whether cognitive skills (phonological awareness, morphological awareness, and rapid automatized naming [RAN]) could moderate the influence of character complexity on literacy outcomes. Method: Our pre-registered study included a sample of 342 Cantonese - speaking Hong Kong Chinese children (162 males, 180 females, mean age = 7.32, SD = 0.87) from Grade 1 to Grade 3. We used a generalized additive mixed model (GAMM) to estimate the main effect of complexity on word recognition and dictation as well as interaction effects with each of the three cognitive skills. Age and nonverbal IQ were also included as controls. Results: Character complexity had a slightly curvilinear but consistently negative association with word reading, with odds ratios ranging from 0.62 to 0.71 per 10% increase in complexity. RAN and morphological awareness buffered the negative influence of character complexity. For writing to dictation, character complexity was more curvilinear, but character complexity and the interactions between cognitive skills and character complexity were not significant. Conclusion: Complex visual input can be a barrier to early reading development in Chinese, and fostering morphological awareness may help mitigate this effect.

BackgroundEffective post-stroke mobility, recovery, performance, and participation are key goals for stroke survivors. However, these outcomes may be hindered by post-stroke fatigue (PSF), which can affect numerous aspects of post-stroke mobility, recovery, performance, functioning, community participation, and return to work. This review aimed to assess the scientific evidence on the relationship between PSF and mobility function, functional recovery, functional performance, and participation-related outcomes among stroke survivors.MethodA comprehensive search of Cochrane Central, PubMed, Embase, and Web of Science (WoS) databases was conducted from inception to December 2023. Observational, cross-sectional, and longitudinal studies were included. The methodological quality of the included studies was assessed using the National Institute of Health’s quality assessment tool, while the risk of bias was assessed using the Quality in Prognostic Studies tool. A total of 28 studies (n = 2,495 participants, 1,626 men, mean age ranging from 52.5 ± 9.5 to 71.1 ± 9.9 years) were included. The data analysis was conducted using narrative and quantitative synthesis. Fixed and random effects meta-analyses were conducted to explore the relationships between PSF and relevant outcomes.ResultsChronic PSF was found to have significant negative correlations with mobility (meta r = −0.106, p

ObjectiveTo investigate the psychometric properties of the Lift and Carry Test (LCT) time in people with stroke.DesignCross-sectional design.SettingUniversity based neurorehabilitation laboratory.ParticipantsTwenty-four people with stroke and 24 healthy controls.Outcome measuresLift and Carry Test (LCT), Fugl-Meyer Assessment of upper extremity and lower extremity, ankle dorsiflexor and plantarflexor muscle strength, Berg Balance Scale (BBS), Timed Up and Go (TUG) and Community Integration Measure.ResultsThe mean LCT time (29.70s) in people with stroke was more than double of that in healthy controls (13.70s). The LCT showed excellent intra-rater, inter-rater and test–retest reliability [intraclass correlation coefficient (ICC) = 0.943–1.000]. The LCT times demonstrated a significant negative correlation with the BBS score (rs = −0.771) and significant positive correlations with the TUG times (rs = 0.933). There was no significant correlation between LCT times and FMA score (p > 0.05). An optimal cut-off LCT time of 15.48 s (sensitivity = 95.8%, specificity = 87.5%) was identified to differentiate between people with stroke and healthy controls (area under the curve = 0.957).ConclusionLCT is an excellent clinical test for examining advanced functional ability in people with stroke and distinguishing people with stroke from healthy controls.

Abstract Digital ocular massage has been reported to temporarily lower intraocular pressure (IOP). This could be related to an enhanced aqueous humor outflow; however, the mechanism is not clearly understood. Using anterior segment optical coherence tomography, the Schlemm’s canal (SC) and trabecular meshwork (TM) can be imaged and measured. Here, 66 healthy adults underwent digital ocular massage for 10 min in their right eyes. The IOP and dimensions of the SC and TM were measured before and after ocular massage. All subjects demonstrated IOP reduction from 15.7 ± 2.5 mmHg at baseline to 9.6 ± 2.2 mmHg immediately after, and median of 11.6 mmHg 5-min after ocular massage (Friedman’s test, p

Background: The World Health Organization (WHO) has set hepatitis C (HCV) elimination targets for 2030. Understanding existing gaps in the “HCV care-cascade” is essential for meeting these targets. We aimed to identify the level of service scale-up needed along the “HCV care-cascade” to achieve the WHO’s HCV elimination targets in Ontario, Canada. Methods: By employing a decision analytic model, we projected the quality-adjusted life years (QALYs) and healthcare costs for individuals with HCV in Ontario. We increased RNA testing and treatment rates to 98%, followed by increasing antibody testing uptake until we achieved the WHO’s mortality target (i.e., a 65% reduction in liver-related mortality by 2030 vs. 2015). Results: Without scaling up by 2030, the expected QALYs and costs per person were 9.156 and CAD 48,996, respectively. Improved RNA testing and treatment rates reduced liver-related deaths to 3.3/100,000, a 57% reduction from 2015. Further doubling the antibody testing rates can achieve the WHO’s mortality target in 2035, but not in 2030. Compared to the status quo, such program would be cost-effective considering a 50,000 CAD/QALY gained threshold if annual implementation costs stayed under 2.3 M CAD/100,000 people. Conclusions: Doubling the antibody testing rates, along with increased RNA testing and treatment rates, showed promise in meeting the WHO’s goals by 2035.

Abstract Cancer is globally a disease of significant public health concern owing to its prevalence, and association with morbidity and mortality. Thus, cost‐effective treatments for cancer are important to help reduce its significant morbidity and mortality. However, the current therapeutic options for cancer such as chemotherapy, radiotherapy, and surgery may produce serious adverse events such as nausea, vomiting, fatigue, and peripheral neuropathy, especially in the long term. In addition, these therapeutic options may not be well tolerated by the elderly especially those who are frail. The current article is aimed at discussing an alternative therapeutic option, non‐invasive vagus nerve stimulation (VNS), and the roles it plays in cancer pathology and immunotherapy. The VNS does this by reducing oxidative stress via silent information regulator 1 (SIRT1); inhibiting inflammation via both hypothalamic–pituitary–axis (HPA) and the release of corticosteroid from the adrenal gland, and cholinergic anti‐inflammatory pathway (CAP), and increasing vagal activity which helps in the regulation of cell proliferation, differentiation, apoptosis, and metabolism, and increase chance of survival. Furthermore, it helps with reducing complications due to cancer or its treatments such as postoperative ileus and severity of peripheral neuropathy induced by chemotherapy, and improves cancer‐related fatigue, lymphopenia, and quality of life. These suggest that the importance of non‐invasive VNS in cancer pathology and immunotherapy cannot be overemphasized. Therefore, considering the safety of non‐invasive VNS and its cost‐effectiveness, it is a therapeutic option worth trying for these patients, especially in combination with other therapies.

Abstract Background Heart diseases are among the leading causes of death worldwide, many of which lead to pathological cardiomyocyte hypertrophy and capillary rarefaction in both patients and animal models, the quantification of which is both technically challenging and highly time-consuming. Here we developed a semiautomated pipeline for quantification of the size of cardiomyocytes and capillary density in cardiac histology, termed HeartJ, by generating macros in ImageJ, a broadly used, open-source, Java-based software. Methods We have used modified Gomori silver staining, which is easy to perform and digitize in high throughput, or Fluorescein-labeled lectin staining. The latter can be easily combined with other stainings, allowing additional quantitative analysis on the same section, e.g., the size of cardiomyocyte nuclei, capillary density, or single-cardiomyocyte protein expression. We validated the pipeline in a mouse model of cardiac hypertrophy induced by transverse aortic constriction, and in autopsy samples of patients with and without aortic stenosis. Results In both animals and humans, HeartJ-based histology quantification revealed significant hypertrophy of cardiomyocytes reflecting other parameters of hypertrophy and rarefaction of microvasculature and enabling the analysis of protein expression in individual cardiomyocytes. The analysis also revealed that murine and human cardiomyocytes had similar diameters in health and extent of hypertrophy in disease confirming the translatability of our murine cardiac hypertrophy model. HeartJ enables a rapid analysis that would not be feasible by manual methods. The pipeline has little hardware requirements and is freely available. Conclusions In summary, our analysis pipeline can facilitate effective and objective quantitative histological analyses in preclinical and clinical heart samples.

Abstract Vagus nerve stimulation (VNS) is used to deliver electric current to stimulate the vagus nerve. The aim of this study is to carry out a systematic review and meta-analysis to determine its effects on motor function in patients with stroke. PubMED, Embase, Web of Science (WoS), and Scopus were searched. Data on time since stroke, and mean scores and standard deviation on outcomes such as level of impairment and motor function were extracted. The results showed that invasive (MD 2.66, 95% CI 1.19–4.13, P = 0.0004) and non-invasive (MD 24.16, 95% CI 23.56–24.75, P = 0.00001) VNS are superior at improving level of motor impairment than the control post intervention and at follow-up respectively. Similarly, VNS improved motor function post intervention (MD 0.28, 95% CI 0.15–0.41, P

Abstract Managing chronic hepatitis C is challenging, as the majority of those infected are asymptomatic. Therefore, to ensure treatments are administered before the onset of severe complications, screening is important. In Canada, uncertainty regarding the cost-effectiveness and budget impact of screening has led to conflicting recommendations. The objective of this study is to estimate the cost-effectiveness and budget-impact of one-time HCV screening. A state-transition model was developed to evaluate the cost-effectiveness and budget-impact between a risk-based screening strategy (current-practice) and a one-time screening strategy on three different birth-cohorts. Cost and prevalence data were obtained from administrative data. Progression and utility data were based on recent systematic reviews. We used a provincial payer-perspective, life-time time-horizon and a 1.5% discount rate for the cost-effectiveness analysis, and used a 10-year time-horizon and no discounting for the budget-impact analysis. One-time screening strategy would cost more and provide more health benefits than the risk-based screening for all birth cohorts. For those born after 1964, the incremental-cost-effectiveness-ratio (ICER) per quality-adjusted-life-year (QALY) of screening versus current-practice varied from $27,422/QALY to $42,191/QALY across different provinces. One-time screening of the cohort would cost an additional $2 million to $236 million across different provinces. For those born 1945–1964, the ICER of screening versus current-practice varied from $35,217/QALY to $48,197/QALY across different provinces. For the cohort born before 1945, the ICER of screening versus current-practice was not cost-effective at a willingness-to-pay threshold of $50,000/QALY across all provinces. Our cost-effectiveness analysis suggests that a one-time HCV screening program for those born after 1945 is cost-effective. Considering the budget impact relative to other funded recommended health services and technologies, HCV screening could be considered affordable.

Background. Data on the economic burden of chronic hepatitis C (CHC) among immigrants are limited. Our objective was to estimate the CHC-attributable mortality and healthcare costs among immigrants in Ontario, Canada. Methods. We conducted a population-based matched cohort study among immigrants diagnosed with CHC between May 31, 2003, and December 31, 2018, using linked health administrative data. Immigrants with CHC (exposed) were matched 1 : 1 to immigrants without CHC (unexposed) using a combination of hard (index date, sex, and age) and propensity-score matching. Net costs (2020 Canadian dollars) collected from the healthcare payer perspective were calculated using a phase-of-care approach and used to estimate long-term costs adjusted for survival. Results. We matched 5,575 exposed individuals with unexposed controls, achieving a balanced match. The mean age was 47 years, and 52% was male. On average, 10.5% of exposed and 3.5% of unexposed individuals died 15 years postindex (relative risk = 2.9; 95% confidence interval (CI): 2.6–3.5). The net 30-day costs per person were $88 (95% CI: 55 to 122) for the prediagnosis, $324 (95% CI: 291 to 356) for the initial phase, $1,016 (95% CI: 900 to 1,132) for the late phase, and $975 (95% CI: −25 to 1,974) for the terminal phase. The mean net healthcare cost adjusted for survival at 15 years was $90,448. Conclusions. Compared to unexposed immigrants, immigrants infected with CHC have higher mortality rates and greater healthcare costs. These findings will support the planning of HCV elimination efforts among key risk groups in the province.

ABSTRACT: Objectives: The aim of this study was to estimate carbapenem resistance in Pseudomonas aeruginosa and Enterobacterales isolated from infected patients in intensive care unit (ICU) and non-ICU hospital wards in Hong Kong. Methods: Isolates of Pseudomonas aeruginosa (ICU, n = 35; non-ICU, n = 264) and Enterobacterales (ICU, n = 129; non-ICU, n = 1390) were collected in four Hong Kong hospitals in 2017–2020. Clinical and Laboratory Standards Institute broth microdilution minimum inhibitory concentrations (MICs) were interpreted according to Clinical and Laboratory Standards Institute 2021 M100 breakpoints. β-lactamase genes were identified in imipenem-, imipenem/relebactam-, and ceftolozane/tazobactam-nonsusceptible isolates. Results: Ceftolozane/tazobactam demonstrated potent in vitro activity against both P. aeruginosa (ICU, 88.6%; non-ICU, 98.5%) and Enterobacterales (96.1%; 97.1%). Percent susceptible values for P. aeruginosa isolates from ICU and non-ICU patients, respectively, were as follows: meropenem (ICU, 74.3%; non-ICU, 84.1%) and imipenem (68.6%; 73.1%). Only 1 of 77 isolates tested for β-lactamase genes carried a carbapenemase (VIM-2). Percent susceptible values for Enterobacterales isolates from ICU and non-ICU patients were as follows: meropenem (100%; 99.4%), ertapenem (100%; 98.0%), and imipenem (88.4%; 88.6%). A total of 62 Enterobacterales isolates were tested for β-lactamase genes. Only three isolates carried a carbapenemase gene; two (both Escherichia coli) were metallo-β-lactamase-positive (both NDM-5), and one (Klebsiella pneumoniae) was OXA-48-like-positive. Conclusions: Carbapenem-nonsusceptible isolates of P. aeruginosa were common (>15% of isolates). P. aeruginosa percent susceptible values for ceftolozane/tazobactam (97.3% susceptible overall) were ≥14% higher than those for carbapenems in both ICU and non-ICU isolates. Carbapenemases were rare among both P. aeruginosa (one isolate) and Enterobacterales (three isolates). Most Enterobacterales isolates tested from ICU and non-ICU patients in Hong Kong hospitals in 2017–2020 were susceptible to meropenem and ertapenem (≥98%); imipenem was less active (89% susceptible).

Autism spectrum disorder (ASD) significantly affects social and motor skills development in early, middle or even late childhood. To promote social and motor skills development among autistic children, an intervention consisting of Taekwondo and elements of music therapy was designed and implemented in Hong Kong. The objective of the current study is to investigate the effectiveness of this training, based on parents’ observations of their children who had completed the key stage of the training. Thirteen parents or caregivers (n = 13) whose children with autism participated in our Taekwondo training for two months were interviewed. Three major themes were identified by thematic analysis: (A) social skills-related change after the intervention, (B) motor skills-related change after the intervention, (C) characteristics of the intervention (i.e., session arrangement, tutor/coach attitude). Our findings show that our training was perceived by parents to have a significant impact on the promotion of physical ability and social communication in autistic children.

Abstract Social support has an important role in stroke rehabilitation. The Multidimensional Scale of Perceived Social Support (MSPSS) is an instrument examining the adequacy of perceived social support. However, the psychometric properties of the Chinese version of MSPSS (MSPSS-C) have not been examined in Chinese people with stroke. This study aimed at investigating the psychometric properties of the MSPSS-C, identifying the correlations between MSPSS-C scores and health-related measures of these people; and examining the differences in the levels of perceived social support between people with and without stroke in Hong Kong using a cohort of 57 community-dwelling people with stroke and 50 age-matched healthy controls. We found that the MSPSS-C subscales demonstrated excellent internal consistency, and a ceiling effect was observed for the family subscale of the MSPSS-C. The total MSPSS-C score had significant weak to moderate correlations with the scores of the concerned variables of interests. Exploratory factor analysis revealed a two-factor structure for the MSPSS-C. People with stroke had lower levels of perceived social support from friends and their significant other than those without stroke. The MSPSS-C is a valid tool for assessing perceived social support among chronic stroke survivors with moderate to very severe motor impairment.

BackgroundStroke results in impairment of motor function of both the upper and lower limbs. However, although it is debatable, motor function of the lower limb is believed to recover faster than that of the upper limb. The aim of this paper is to propose some hypotheses to explain the reasons for that, and discuss their implications for research and practice.MethodWe searched PubMED, Web of Science, Scopus, Embase and CENTRAL using the key words, stroke, cerebrovascular accident, upper extremity, lower extremity, and motor recovery for relevant literature.ResultThe search generated a total of 2,551 hits. However, out of this number, 51 duplicates were removed. Following review of the relevant literature, we proposed four hypotheses: natural instinct for walking hypothesis, bipedal locomotion hypothesis, central pattern generators (CPGs) hypothesis and role of spasticity hypothesis on the subject matter.ConclusionWe opine that, what may eventually account for the difference, is the frequency of use of the affected limb or intensity of the rehabilitation intervention. This is because, from the above hypotheses, the lower limb seems to be used more frequently. When limbs are used frequently, this will result in use-dependent plasticity and eventual recovery. Thus, rehabilitation techniques that involve high repetitive tasks practice such as robotic rehabilitation, Wii gaming and constraint induced movement therapy should be used during upper limb rehabilitation.

Soft wearable robotic hand can assist with hand function for the performance of activities of daily living (ADL). However, existing robotic hands lack a mathematical way to quantify the grip force generated for better controlling the grasp of objects during the performance of ADL. To address this issue, this article presents a soft wearable robotic hand with active control of finger flexion and extension through an elastomeric-based bi-directional soft actuator. This actuator bends and extends by pneumatic actuation at lower air pressure, and a flex sensor embedded inside the actuator measures the angles of the fingers in real-time. Analytical models are established to quantify the kinematic and tip force for gripping of the actuator in terms of the relationship between the input pressure and the bending angle, as well as the output force, and are validated experimentally and by the finite element method. Furthermore, the ability of the soft robotic hand to grasp objects is validated with and without being worn on a human hand. The robotic hand facilitates hand opening and closing by the wearer and successfully assists with grasping objects with sufficient force for ADL-related tasks, and the grip force provided by the actuator is further estimated by the analytical models on two healthy subjects. Results suggest the possibility of the soft robotic hand in providing controllable grip strength in rehabilitation and ADL assistance.

Some bispecific radiotracers have been developed to overcome the limitations of monospecific tracers and improve detection sensitivity for heterogeneous tumor lesions. Here, we aim to synthesize two bispecific tracers targeting prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP), which are key markers expressed in prostate cancer. A pyridine-based FAP-targeted ligand was synthesized through multi-step organic synthesis and then connected to the 2-Nal-containing PSMA-targeted motif. The Ki(PSMA) values of Ga-complexed bispecific ligands, Ga-AV01084 and Ga-AV01088, were 11.6 ± 3.25 and 28.7 ± 6.05 nM, respectively, and the IC50(FAP) values of Ga-AV01084 and Ga-AV01088 were 10.9 ± 0.67 and 16.7 ± 1.53 nM, respectively. Both [68Ga]Ga-AV01084 and [68Ga]Ga-AV01088 enabled the visualization of PSMA-expressing LNCaP tumor xenografts and FAP-expressing HEK293T:hFAP tumor xenografts in PET images acquired at 1 h post-injection. However, the tumor uptake values from the bispecific tracers were still lower than those obtained from the monospecific tracers, PSMA-targeted [68Ga]Ga-PSMA-617 and FAP-targeted [68Ga]Ga-AV02070. Further investigations are needed to optimize the selection of linkers and targeted pharmacophores to improve the tumor uptake of bispecific PSMA/FAP tracers for prostate cancer imaging.

Objectives To examine the cost-effectiveness of Multi-specialty INterprofessional Team (MINT) Memory Clinic care in comparison to the provision of usual care.Design Using a Markov-based state transition model, we performed a cost-utility (costs and quality-adjusted life years, QALY) analysis of MINT Memory Clinic care and usual care not involving MINT Memory Clinics.Setting A primary care-based Memory Clinic in Ontario, Canada.Participants The analysis included data from a sample of 229 patients assessed in the MINT Memory Clinic between January 2019 and January 2021.Primary outcome measures Effectiveness as measured in QALY, costs (in Canadian dollars) and the incremental cost-effectiveness ratio calculated as the incremental cost per QALY gained between MINT Memory Clinics versus usual care.Results MINT Memory Clinics were found to be less expensive ($C51 496 (95% Crl $C4806 to $C119 367) while slightly improving quality of life (+0.43 (95 Crl 0.01 to 1.24) QALY) compared with usual care. The probabilistic analysis showed that MINT Memory Clinics were the superior treatment compared with usual care 98% of the time. Variation in age was found to have the greatest impact on cost-effectiveness as patients may benefit from the MINT Memory Clinics more if they receive care beginning at a younger age.Conclusion Multispecialty interprofessional memory clinic care is less costly and more effective compared with usual care and early access to care significantly reduces care costs over time. The results of this economic evaluation can inform decision-making and improvements to health system design, resource allocation and care experience for persons living with dementia. Specifically, widespread scaling of MINT Memory Clinics into existing primary care systems may assist with improving quality and access to memory care services while decreasing the growing economic and social burden of dementia.

ObjectiveTo culturally adapt and examine the psychometric properties of the Chinese (Cantonese) version of the Upper Extremity Functional Index (C-UEFI) in people with chronic stroke.DesignCross-sectional study.SettingsUniversity-affiliated neurorehabilitation research laboratory.ParticipantsThe participants (N = 151) were people with chronic stroke (N = 101) and healthy controls (n = 50).Main outcome measuresWe assessed the C-UEFI, Fugl-Meyer Assessment for Upper Extremity (FMA-UE), Wolf Motor Function Test (WMFT), Six-Minute Walk Test (6MWT), Motor Activity Log (MAL), Activity-Specific Balance Confidence (ABC) scale, Lawton Instrumental Activities of Daily Living (IADL) scale, Survey of Activities and Fear of Falling in the Elderly (SAFFE), Stroke Impact Scale (SIS) and Community Integration Measure (CIM) as outcome measures.ResultsThe C-UEFI items demonstrated good test–retest reliability (intraclass correlation coefficient [ICC]3, 1 = 0.872) and excellent internal consistency (Cronbach's α = 0.922). People with chronic stroke had poorer C-UEFI scores than the healthy controls. The overall C-UEFI mean score of 101 people with stroke was significantly correlated with the mean scores of the FMA-UE, WMFT, MAL, ABC scale, IADL scale, SAFFE, SIS and CIM and the distance covered in the 6MWT. The C-UEFI cut-off score to distinguish between people with chronic stroke and healthy older adults according to upper extremity function was 57.5 out of 59 (sensitivity: 88.1%; specificity: 84%). The C-UEFI had good content validity, with an acceptable fit to the two-factor structure model.ConclusionsThe C-UEFI is reliable and valid for assessing functional recovery of upper extremity activity in Chinese people with chronic stroke.

IntroductionThe aim of our study was to assess the initial impact of COVID-19 on total publicly-funded direct healthcare costs and health services use in two Canadian provinces, Ontario and British Columbia (BC).MethodsThis retrospective repeated cross-sectional study used population-based administrative datasets, linked within each province, from January 1, 2018 to December 27, 2020. Interrupted time series analysis was used to estimate changes in the level and trends of weekly resource use and costs, with March 16-22, 2020 as the first pandemic week. Also, in each week of 2020, we identified cases with their first positive SARS-CoV-2 test and estimated their healthcare costs until death or December 27, 2020.ResultsThe resources with the largest level declines (95% confidence interval) in use in the first pandemic week compared to the previous week were physician services [Ontario: -43% (-49%,-37%); BC: -24% (-30%,-19%) (both pConclusionsReduced utilization of healthcare services in the overall population outweighed utilization by COVID-19 patients in 2020. Meeting the needs of all patients across all services is essential to maintain resilient healthcare systems.

Globally, there are about a billion people comprising of about 95 million children who experience disability. The number of people in Africa living with disability is about 80 million people; out of which 10%−15% are children of school age. The causes of disability among these children include epilepsy, vision loss, or hearing loss, cerebral palsy, poliomyelitis, tetanus, cerebrospinal meningitis and malaria. However, these causes of disability are preventable and can be managed with proper care. The aim of this article is to propose the establishment of childhood disability clinics in Africa in order to help prevent or reduce the incidence/ prevalence of disability among children. Some of the mandates of the clinics will be to carry out routine assessment of children for disability, to provide education on disability and strategies for disability prevention to parents and caregivers, to promptly prevent and manage disability or its causes. However, establishing these clinics requires shared commitment of all the stakeholders.

Advances in Next Generation Sequencing (NGS) technologies have enabled the accurate detection and quantification of circulating tumor-derived (ct)DNA in most gastrointestinal (GI) cancers. The prognostic and predictive utility of ctDNA in patiets with different stages of colorectal (CRC), gastro-esophageal (GEC) and pancreaticobiliary cancers (PBC) are currently under active investigation. The most mature clinical data to date are derived from studies in the prognostic utility of personalized ctDNA-based NGS assays in the detection of minimal residual disease (MRD) and early recurrence after surgery in CRC and other GI cancers. These findings are being validated in several prospective studies which are designed to test if ctDNA could outperform conventional approaches in guiding adjuvant chemotherapy, and in post-operative surveillance in some GI cancers. Several adaptive studies using ctDNA as a screening platform are also being used to identify patients with actionable genomic alterations for clinical trials of targeted therapies. In the palliative setting, ctDNA monitoring during treatment has shown promise in the detection and tracking of clonal variants associated with acquired resistance to targeted therapies and immune-checkpoint inhibitors (ICI). Moreover, ctDNA may help to guide the therapeutic re-challenge of targeted therapies in patients who have prior exposure to such treatment. This review will examine the most updated research findings on ctDNA as a biomarker in CRC, GEC and PBCs. It aims to provide insights into how the unique strengths of this biomarker could be optimally leveraged in improving the management of these GI cancers.

Fibroblast activation protein (FAP) is a membrane-tethered serine protease overexpressed in the reactive stromal fibroblasts of >90% human carcinomas, which makes it a promising target for developing radiopharmaceuticals for the imaging and therapy of carcinomas. Here, we synthesized two novel (R)-pyrrolidin-2-yl-boronic acid-based FAP-targeted ligands: SB02055 (DOTA-conjugated (R)-(1-((6-(3-(piperazin-1-yl)propoxy)quinoline-4-carbonyl)glycyl)pyrrolidin-2-yl)boronic acid) and SB04028 (DOTA-conjugated ((R)-1-((6-(3-(piperazin-1-yl)propoxy)quinoline-4-carbonyl)-D-alanyl)pyrrolidin-2-yl)boronic acid). natGa- and 68Ga-complexes of both ligands were evaluated in preclinical studies and compared to previously reported natGa/68Ga-complexed PNT6555. Enzymatic assays showed that FAP binding affinities (IC50) of natGa-SB02055, natGa-SB04028 and natGa-PNT6555 were 0.41 ± 0.06, 13.9 ± 1.29 and 78.1 ± 4.59 nM, respectively. PET imaging and biodistribution studies in HEK293T:hFAP tumor-bearing mice showed that while [68Ga]Ga-SB02055 presented with a nominal tumor uptake (1.08 ± 0.37 %ID/g), [68Ga]Ga-SB04028 demonstrated clear tumor visualization with ~1.5-fold higher tumor uptake (10.1 ± 0.42 %ID/g) compared to [68Ga]Ga-PNT6555 (6.38 ± 0.45 %ID/g). High accumulation in the bladder indicated renal excretion of all three tracers. [68Ga]Ga-SB04028 displayed a low background level uptake in most normal organs, and comparable to [68Ga]Ga-PNT6555. However, since its tumor uptake was considerably higher than [68Ga]Ga-PNT6555, the corresponding tumor-to-organ uptake ratios for [68Ga]Ga-SB04028 were also significantly greater than [68Ga]Ga-PNT6555. Our data demonstrate that (R)-(((quinoline-4-carbonyl)-d-alanyl)pyrrolidin-2-yl)boronic acid is a promising pharmacophore for the design of FAP-targeted radiopharmaceuticals for cancer imaging and radioligand therapy.

Fibroblast activation protein α (FAP-α) is a cell-surface protein overexpressed on cancer-associated fibroblasts that constitute a substantial component of tumor stroma and drive tumorigenesis. FAP is minimally expressed by most healthy tissues, including normal fibroblasts. This makes it a promising pan-cancer diagnostic and therapeutic target. In the present study, we synthesized two novel tracers, [68Ga]Ga-SB03045 and [68Ga]Ga-SB03058, bearing a (2S,4S)-4-fluoropyrrolidine-2-carbonitrile or a (4R)-thiazolidine-4-carbonitrile pharmacophore, respectively. [68Ga]Ga-SB03045 and [68Ga]Ga-SB03058 were evaluated for their FAP-targeting capabilities using substrate-based in vitro binding assays, and in PET/CT imaging and ex vivo biodistribution studies in an HEK293T:hFAP tumor xenograft mouse model. The IC50 values of natGa-SB03045 (1.59 ± 0.45 nM) and natGa-SB03058 (0.68 ± 0.09 nM) were found to be lower than those of the clinically validated natGa-FAPI-04 (4.11 ± 1.42 nM). Contrary to the results obtained in the FAP-binding assay, [68Ga]Ga-SB03058 demonstrated a ~1.5 fold lower tumor uptake than that of [68Ga]Ga-FAPI-04 (7.93 ± 1.33 vs. 11.90 ± 2.17 %ID/g), whereas [68Ga]Ga-SB03045 (11.8 ± 2.35 %ID/g) exhibited a tumor uptake comparable to that of [68Ga]Ga-FAPI-04. Thus, our data suggest that the (2S,4S)-4-fluoropyrrolidine-2-carbonitrile scaffold holds potential as a promising pharmacophore for the design of FAP-targeted radioligands for cancer diagnosis and therapy.

Compared to quinoline-based fibroblast activation protein (FAP)-targeted radiotracers, pyridine-based FAP-targeted tracers are expected to have faster pharmacokinetics due to their smaller molecular size and higher hydrophilicity, which we hypothesize would improve the tumor-to-background image contrast. We aim to develop 68Ga-labeled pyridine-based FAP-targeted tracers for cancer imaging with positron emission tomography (PET), and compare their imaging potential with the clinically validated [68Ga]Ga-FAPI-04. Two DOTA-conjugated pyridine-based AV02053 and AV02070 were synthesized through multi-step organic synthesis. IC50(FAP) values of Ga-AV02053 and Ga-AV02070 were determined by an enzymatic assay to be 187 ± 52.0 and 17.1 ± 4.60 nM, respectively. PET imaging and biodistribution studies were conducted in HEK293T:hFAP tumor-bearing mice at 1 h post-injection. The HEK293T:hFAP tumor xenografts were clearly visualized with good contrast on PET images by [68Ga]Ga-AV02053 and [68Ga]Ga-AV02070, and both tracers were excreted mainly through the renal pathway. The tumor uptake values of [68Ga]Ga-AV02070 (7.93 ± 1.88%ID/g) and [68Ga]Ga-AV02053 (5.6 ± 1.12%ID/g) were lower than that of previously reported [68Ga]Ga-FAPI-04 (12.5 ± 2.00%ID/g). However, both [68Ga]Ga-AV02070 and [68Ga]Ga-AV02053 showed higher tumor-to-background (blood, muscle, and bone) uptake ratios than [68Ga]Ga-FAPI-04. Our data suggests that pyridine-based pharmacophores are promising for the design of FAP-targeted tracers. Future optimization on the selection of a linker will be explored to increase tumor uptake while maintaining or even further improving the high tumor-to-background contrast.

Tumor heterogeneity limits the efficacy and reliability of monospecific radiopharmaceuticals in prostate cancer diagnosis and therapy. To overcome this limitation and improve lesion detection sensitivity, we developed and evaluated three bispecific radiotracers that can target both prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP), which are the two key proteins overexpressed in prostate cancer. Three FAP-targeting ligands with various linker lengths were synthesized through multistep organic synthesis, and then connected to the PSMA-targeting motif. IC50(PSMA) and IC50(FAP) values of Ga-complexed bispecific ligands, Ga-AV01017, Ga-AV01030, and Ga-AV01038 were 25.2–71.6 and 1.25–2.74 nM, respectively. The uptake values in PSMA-expressing LNCaP tumor xenografts were 4.38 ± 0.55, 5.17 ± 0.51, and 4.25 ± 0.86 %ID/g for [68Ga]Ga-AV01017, [68Ga]Ga-AV01030, and [68Ga]Ga-AV01038, respectively, which were lower than the monospecific PSMA-targeting tracer [68Ga]Ga-HTK03041 (23.1 ± 6.11 %ID/g). The uptake values in FAP-expressing HEK293T:hFAP tumor xenografts were 2.99 ± 0.37, 3.69 ± 0.81, 3.64 ± 0.83 %ID/g for [68Ga]Ga-AV01017, [68Ga]Ga-AV01030, and [68Ga]Ga-AV01038, respectively, which were also lower than the monospecific FAP-targeting tracer, [68Ga]Ga-FAPI-04 (12.5 ± 2.00 %ID/g). We observed that the bispecific tracers had prolonged blood retention, in which tracers with a longer linker tend to have a higher blood uptake and lower tumor uptake. Further investigations are needed to optimize the linker selection to generate promising bispecific PSMA/FAP-targeting tracers for prostate cancer imaging.

Abstract Background Chronic hepatitis B (CHB) infection poses a significant burden to public health worldwide. Most cases are clinically silent until late in the disease course. The main goal of current therapy is to improve survival and quality of life by preventing disease progression to cirrhosis and liver failure, and consequently hepatocellular carcinoma development. The objective of this review is to provide a contemporary and comprehensive evaluation of the effectiveness of treatment options. Methods We performed a systematic review of peer-reviewed literature for randomized controlled trials involving treatment-naïve CHB adult population who received antiviral therapy. The endpoints were virologic response (VR), normalization of alanine aminotransferase (ALT norm), HBeAg loss, HBeAg seroconversion, and HBsAg loss for the HBeAg-positive population; and VR and ALT norm for the HBeAg-negative population. Network meta-analysis (NMA) was performed to synthesize evidence on the efficacy of treatment. Results Forty-two publications were selected. Twenty-three evaluated HBeAg-positive population, 13 evaluated HBeAg-negative population, and six evaluated both. We applied NMA to the efficacy outcomes of the two populations separately. Treatment strategies were ranked by the probability of achieving outcomes, and pairwise comparisons calculated from NMA were reported in odds ratios (OR). For HBeAg-positive population, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) were the best for VR; OR vs adefovir = 14.29, 95% CI 7.69–25 and 12.5, 95% CI 4.35–33.33 respectively. TAF was the best for achieving ALT norm (OR vs placebo = 12.5, 95% CI 4.55–33.33), HBeAg loss, and seroconversion (OR vs entecavir/TDF combination = 3.03, 95% CI 1.04–8.84 and 3.33, 95% CI 1.16–10 respectively). In the HBeAg-negative population, TDF and TAF were the best for VR (OR vs adefovir = 9.79, 95% CI 2.38–42.7 and 11.71, 95% CI 1.03–150.48 respectively). Telbivudine and TAF were the best for ALT norm. Certain nucleos(t)ide combinations also had high probability of achieving positive outcomes. Conclusions Our results are consonant with current clinical guidelines and other evidence reviews. For both HBeAg-positive and HBeAg-negative populations, TDF and TAF are the most effective agents for virologic suppression, and TAF is effective across all outcomes.

Rehabilitation of severe impairment in motor function following stroke is very challenging. This is because one of the driving forces for recovery of motor function is tasks practice, something this category of patients cannot voluntarily perform. However, it has now been shown that tasks practice can equally be carried out cognitively and through observation of another person’s practice, using techniques known as mental practice and tasks observation, respectively. Mental practice and tasks observation are believed to activate networks of neurons in the brain known as mirror neurons and mentalizing systems to induce recovery. The effectiveness of these techniques has, however, limited evidence at the moment. One possible explanation for this could be the nature of the protocols of these techniques, especially as regards to the intensity of practice. This article proposes ways the potentials of the mirror neurons and mentalizing systems can be harnessed to optimize recovery of severe impairment in motor function using mental practice and tasks observation. The article suggests, among other ways, protocols where tasks observation or mirror therapy are carried out first, and are then followed by mental practice, increasing the number of times the tasks are observed or mentalized, observation of significant others performing the tasks and mental practice of very familiar tasks.

Objective: To examine the understanding of the concept peak oxygen uptake (peak VO2) among children and adolescents at different ages from a developmental perspective.Methods: A total of 549 children and adolescents aged 8 to 16 were recruited and instructed to fill in a 20-item Peak VO2Understanding Inventory developed with reference to the research literature on peak VO2. We presented the participants with twenty scenarios and asked them to indicate whether peak VO2 would “remain unchanged,” “increase,” or “decrease,” or that there was “insufficient information for a definite answer.” The cross-sectional data was analyzed by employing a series of ANOVA analyses and chi-square association tests. Additional statistical analyses were performed to examine the error patterns and if there were gender differences.Results: Except for the 8-year-old group, the overall accuracy rate did not improve with age. Age-related differences in the choice of answers (“increase,” “decrease,” “unchanged,” and “uncertain”) for determining the resulting peak VO2 after a change of antecedent were observed. Error analysis by item showed that prefactual thinking that is important to understand the concept was emerging rather than fully developed in our child and adolescent samples.Conclusion: The mastery of peak VO2 is not subject to age-related maturation but might demand the acquisition of specific logical reasoning skill such as perfactual thinking. Early introduction of peak VO2 and related concepts is advocated and should be emphasized on the reasoning rather than providing model answers in physical literacy education.

Connected speech produced by native speakers poses a challenge to second language learners. Video subtitles have been found to assist the decoding of English connected speech for learners of English as a foreign language (EFL). However, the presence of subtitles may divert the listeners’ attention to the visual cues while paying less attention to the speech signals. To test this proposal, we employed a bi-modal audio-visual listening test and examined whether EFL listeners were able to correctly identify the connected speech when misleading subtitles were present. We further tested whether connected speech with words of lower frequency further reduced the accuracy rate. Twenty-eight adolescent EFL learners, all with more than 10 years of experiences in learning English in schools, were tested with three major types of connected speech phonological processes, namely assimilation, elision, and juncture. The results of statistical analyses showed that matched and mismatched subtitles facilitated the comprehension of both familiar and unfamiliar connected speech. Error analyses revealed the degree of item-specific variations across the three types of connected speech processes as well as across the three subtitling conditions. This research provides insights on the immediate and long-term impact of subtitles on the decoding of English connected speech.

Inflammation and fibrosis play an important pathophysiological role in chronic kidney disease (CKD), with pro-inflammatory mediators and leukocytes promoting organ damage with subsequent fibrosis. Since chemokines are the main regulators of leukocyte chemotaxis and tissue inflammation, we performed systemic chemokine profiling in early CKD in mice. This revealed (C-C motif) ligands 6 and 9 (CCL6 and CCL9) as the most upregulated chemokines, with significantly higher levels of both chemokines in blood (CCL6: 3–4 fold; CCL9: 3–5 fold) as well as kidney as confirmed by Enzyme-linked Immunosorbent Assay (ELISA) in two additional CKD models. Chemokine treatment in a mouse model of early adenine-induced CKD almost completely abolished the CKD-induced infiltration of macrophages and myeloid cells in the kidney without impact on circulating leukocyte numbers. The other way around, especially CCL9-blockade aggravated monocyte and macrophage accumulation in kidney during CKD development, without impact on the ratio of M1-to-M2 macrophages. In parallel, CCL9-blockade raised serum creatinine and urea levels as readouts of kidney dysfunction. It also exacerbated CKD-induced expression of collagen (3.2-fold) and the pro-inflammatory chemokines CCL2 (1.8-fold) and CCL3 (2.1-fold) in kidney. Altogether, this study reveals for the first time that chemokines CCL6 and CCL9 are upregulated early in experimental CKD, with CCL9-blockade during CKD initiation enhancing kidney inflammation and fibrosis.

Abstract RASopathies are a group of heterogeneous conditions caused by germline mutations in RAS/MAPK signalling pathway genes. With next-generation sequencing (NGS), sequencing capacity is no longer a limitation to molecular diagnosis. Instead, the rising number of variants of unknown significance (VUSs) poses challenges to clinical interpretation and genetic counselling. We investigated the potential of an integrated pipeline combining NGS and the functional assessment of variants for the diagnosis of RASopathies. We included 63 Chinese patients with RASopathies that had previously tested negative for PTPN11 and HRAS mutations. In these patients, we performed a genetic analysis of genes associated with RASopathies using a multigene NGS panel and Sanger sequencing. For the VUSs, we evaluated evidence from genetic, bioinformatic and functional data. Twenty disease-causing mutations were identified in the 63 patients, providing a primary diagnostic yield of 31.7%. Four VUSs were identified in five patients. The functional assessment supported the pathogenicity of the RAF1 and RIT1 VUSs, while the significance of two VUSs in A2ML1 remained unclear. In summary, functional analysis improved the diagnostic yield from 31.7% to 36.5%. Although technically demanding and time-consuming, a functional genetic diagnostic analysis can ease the clinical translation of these findings to aid bedside interpretation.

Abstract Background Suboptimal physical activity levels and tolerance, poor motor skills and poor physical health are demonstrated in children with Autism Spectrum Disorder (ASD). We speculate that social interaction and communication deficits in children with ASD are two major factors that hinder these children from actively participating in group physical activities. While previous studies have demonstrated that exercise intervention improves motor skills and behavioral outcomes in children with ASD, these programs tend to focus only on a single sport, which may not cater to the interests of different children with ASD. In this protocol, a game-based exercise training program designed by a multi-disciplinary team (pediatrics, physical education and psychology) will be implemented by front-line healthcare providers trained following the train-the-trainer (TTT) model and subjected to validation. Method Using a randomized controlled trial design, the effectiveness of the game-based exercise program will be examined for 112 young children with ASD. These children were randomly assigned to two groups, which will be tested and trained in either one of the two arms of the waitlist conditions (control and intervention). The assessment of physical and psychological traits will be conducted at baseline (pre-test), at 16-weeks (post-treatment) and at 32-weeks (follow-up) of the program. Discussion Most of the interventions designed for ASD children target either their psychological traits or physical conditions, without bridging the two states. With the recognition of bidirectional relations between mental and physical health, the present game-based exercise program which includes multiple level of difficulties was developed to equip ASD children with the necessary skills for engaging in sustainable team sports or even professional sport training. The program, if effective, will provide an entertaining and engaging training for whole-person development among children with ASD. Trial registration This study is registered with the Chinese Clinical Trial Registry (ChiCTR-IOR-17011898). Registered 6th July 2017.

Multiorgan tropism of SARS-CoV-2 has previously been shown for several major organs. We have comprehensively analyzed 25 different formalin-fixed paraffin-embedded (FFPE) tissues/organs from autopsies of fatal COVID-19 cases (n = 8), using histopathological assessment, detection of SARS-CoV-2 RNA using polymerase chain reaction and RNA in situ hybridization, viral protein using immunohistochemistry, and virus particles using transmission electron microscopy. SARS-CoV-2 RNA was mainly localized in epithelial cells across all organs. Next to lung, trachea, kidney, heart, or liver, viral RNA was also found in tonsils, salivary glands, oropharynx, thyroid, adrenal gland, testicles, prostate, ovaries, small bowel, lymph nodes, skin and skeletal muscle. Viral RNA was predominantly found in cells expressing ACE2, TMPRSS2, or both. The SARS-CoV-2 replicating RNA was also detected in these organs. Immunohistochemistry and electron microscopy were not suitable for reliable and specific SARS-CoV-2 detection in autopsies. These findings were validated using in situ hybridization on external COVID-19 autopsy samples (n = 9). Apart from the lung, correlation of viral detection and histopathological assessment did not reveal any specific alterations that could be attributed to SARS-CoV-2. In summary, SARS-CoV-2 and its replication could be observed across all organ systems, which co-localizes with ACE2 and TMPRSS2 mainly in epithelial but also in mesenchymal and endothelial cells. Apart from the respiratory tract, no specific (histo-)morphologic alterations could be assigned to the SARS-CoV-2 infection.

Learning to read two scripts at a young age is a demanding task. This study aims to develop games for building fundamental code-related emergent literacy skills among biscriptal preschoolers. We developed five games and tested them on a sample of 102 Chinese kindergarteners. The participants were aged 4 to 5 years and were learning English as a second language. The children’s reading skills were measured with a battery of literacy tests as well as estimated by their teachers using a literacy-related behavior checklist. Correlational analysis revealed that the performances of the children in the tangram games were significantly correlated with teachers’ ratings and children’s Raven’s IQ. Further regression analysis confirmed that the tangram hand-copying game predicted unique variances for visual-orthographic skills and word identification abilities in Chinese and English. This study provides valuable evidence regarding the application of tangram games for assessing code-related emergent literacy skills in the visual domain.

Chronic hepatitis C (CHC) continues to be a highly burdensome disease worldwide. The often-asymptomatic nature of early-stage CHC means that the disease often remains undiagnosed, leaving its prevalence highly uncertain. This generates significant uncertainty in the planning of hepatitis C eradication programs to meet WHO targets. The aim of this work is to establish a mathematical framework for the estimation of a geographic locale's CHC prevalence and the proportion of its CHC population that remains undiagnosed. A Bayesian MCMC approach is taken to infer these populations from the observed occurrence of CHC-related events using a recently published natural history model of the disease. Using the Canadian context as a specific example, this study estimates that in 2013, the CHC prevalence rate in Canada was 0.63% (95% CI: 0.53% - 0.72%), with 27.1% (95% CI: 19.3% - 36.1%) of the infected population undiagnosed.

Research highlights the detrimental effect that directing too much conscious attention toward movement can have on postural control. While this concept has received support from many studies, recent evidence demonstrates that this principle does not always translate to aging clinical populations. Given the increasing clinical interest in this topic, the current study evaluated if the original notion (that an internal focus results in compromised balance performance) is upheld in young and older adults during a challenging balance task where we are able to objectively corroborate changes in attentional focus; using an electroencephalography (EEG) method previously identified as an objective indicator of conscious movement control. This method assesses the neural coherence, or “communication,” between T3 (verbal-analytical) and Fz (motor-planning) regions of the brain. Thirty-nine young and 40 older adults performed a challenging balance task while holding a 2-meter pole under two randomized conditions: Baseline and Internal focus of attention (directing attention internally toward movement production). Results showed that young adults demonstrated increased EEG T3-Fz coherence in conjunction with increased sway path during the Internal focus condition. However, no significant differences were observed in older adults between conditions for any measure. The current study provides supporting evidence for the detrimental effect that adopting an Internal focus can have on postural control—especially in populations able to govern these processes in a relatively “automatic” manner (e.g., young adults). However, this work illustrates that such observations may not readily translate between populations and are not robust to age-related changes. Further work is necessary to examine mechanisms underlying this clear translational issue.