Assessing aspects of early social communication in non-speaking children with bilateral cerebral palsy.

PURPOSE: Research suggests that rates for autism may be higher in cerebral palsy than in the general population. For those with severe bilateral physical impairment (GMFCS level IV and V) and little or no speech, describing a profile of social communication skills has been difficult because there are currently no assessments for early social communication specifically tailored for these children. Our aim was to explore the assessment of aspects of joint attention and social reciprocity in this group of children with CP. METHODS: We compared the performance of children with bilateral CP on carefully designed assessments of joint attention and social responsiveness with groups of children with Down syndrome and autism. All three groups were matched for chronological age and mental age. RESULTS: Approximately 30% of the children with bilateral CP had early social communication scores similar to the autistic children. The remaining 70% of children with CP had a range of early social communication scores similar to the children with Down syndrome. CONCLUSION: It is possible to assess key early social communication skills in non-speaking children with bilateral motor disability. This could provide insights to help clinicians and caregivers as they discuss abilities and explore potential areas for intervention.

With carefully designed activities, which do not rely on motor skills or verbal exchanges, it was possible to assess joint attention and social responsiveness skills in a group of non-speaking children with bilateral motor disability.We were able to identify a subgroup of non-speaking children with severe motor disability (approximately 30% of our cohort) whose scores on our assessments were similar to a group of autistic children.The ability to describe key early social communication skills should provide insights to help clinicians and caregivers as they discuss abilities and explore potential areas for intervention.

Discovery of GS-7682, a Novel 4'-Cyano-Modified C-Nucleoside Prodrug with Broad Activity against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys.

Acute respiratory viral infections, such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 (1), a novel phosphoramidate prodrug of a 4'-CN-4-aza-7,9-dideazaadenosine C-nucleoside GS-646089 (2) with broad antiviral activity against RSV (EC50 = 3-46 nM), human metapneumovirus (EC50 = 210 nM), human rhinovirus (EC50 = 54-61 nM), and enterovirus (EC50 = 83-90 nM). Prodrug optimization for cellular potency and lung cell metabolism identified 5'-methyl [(S)-hydroxy(phenoxy)phosphoryl]-l-alaninate in combination with 2',3'-diisobutyrate promoieties as being optimal for high levels of intracellular triphosphate formation in vitro and in vivo. 1 demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together, these findings support additional evaluation of 1 and its analogues as potential therapeutics for pneumo- and picornaviruses.

Progressive senescence programs induce intrinsic vulnerability to aging-related female breast cancer.

Cancer incidence escalates exponentially with advancing age; however, the underlying mechanism remains unclear. In this study, we build a chronological molecular clock at single-cell transcription level with a mammary stem cell-enriched population to depict physiological aging dynamics in female mice. We find that the mammary aging process is asynchronous and progressive, initiated by an early senescence program, succeeded by an entropic late senescence program with elevated cancer associated pathways, vulnerable to cancer predisposition. The transition towards senescence program is governed by a stem cell factor Bcl11b, loss of which accelerates mammary ageing with enhanced DMBA-induced tumor formation. We have identified a drug TPCA-1 that can rejuvenate mammary cells and significantly reduce aging-related cancer incidence. Our findings establish a molecular portrait of progressive mammary cell aging and elucidate the transcriptional regulatory network bridging mammary aging and cancer predisposition, which has potential implications for the management of cancer prevalence in the aged.

What relationships exist between nouns and verbs and the use of prepositions, adverbs, and adjectives in children and adolescents who use speech generating devices?

The relationships between the use of nouns and verbs, and other word classes have been well established in the typical language development literature. However, questions remain as to whether the same relationships are seen in the language use of individuals who use graphic symbol-based augmentative and alternative communication (AAC). The aim of the study was to examine relationships between the use of verbs and nouns, and the use of prepositions, adverbs, and adjectives through a secondary analysis of language transcripts taken from 12 children and adolescents who used aided AAC in conversation with an adult. A series of multiple linear mixed-effect regression analyses showed a positive predictive association between the use of verbs and the use of prepositions and adverbs, as well as a positive predictive relationship between the use of nouns and the use of adjectives. The theoretical and practical implications of these findings are discussed.

Characterisation of common hypothetical surface peptides between protozoan parasites (Perkinsus olseni) originating from different geographical locations.

Perkinsus olseni and P. marinus are classified as notifiable pathogens by the World Organisation for Animal Health and are known to cause perkinsosis in a variety of molluscs globally. Mass mortalities due to these parasites in farms and in the wild have been a recurrent issue. Diagnosis for these protozoans is currently done using Ray's fluid thioglycollate medium method followed by optical microscopy or molecular assays. Both require a high level of skill and are time-consuming. An immunoassay method would make the diagnosis of perkinsosis quicker and cheaper. The present study used mass spectrometry-based proteomics to investigate common hypothetical surface peptides between different geographical isolates of P. olseni, which could be used to develop immunoassays in the future. Two peptides were identified: POLS_08089, which is a 42.7 kDa peptide corresponding to the 60S ribosomal subunit protein L4; and POLS_15916, which is a conserved hypothetical protein of 55.6 kDa. The identification of peptides may allow the development of immunoassays through a more targeted approach.

The Functional Vision for Communication Questionnaire (FVC-Q): Exploring Parental Report of Non-Speaking Children's Fixation Skills Using a Structured History-Taking Approach.

This paper explores whether a structured history-taking tool yields useful descriptions of children's looking skills. Parents of 32 children referred to a specialist communication clinic reported their child's looking skills using the Functional Vision for Communication Questionnaire (FVC-Q), providing descriptions of single object fixation, fixation shifts between objects and fixation shifts from object to person. Descriptions were compared with clinical assessment. 24/32 children were reported to have some limitation in fixation. Limitation was subsequently seen in 30/32 children. Parental report and assessment agreed fully in 23/32 (72%). The largest area of discrepancy was object-person fixation shifts, with five children not observed to show this behavior despite its being reported. Findings indicate a structured questionnaire yields description of fixations, which correspond well with clinical assessment. Descriptions supported discussion between parents and clinicians. It is proposed that the FVC-Q is a valuable tool in supporting clinicians in eliciting information about fixation skills.

'They don't know what to do with our children': Experiences and views on feeding and swallowing from parents of children who use long-term ventilation.

Increasing use of paediatric long-term ventilation (LTV) has been reported around the world over the last two decades and it is anticipated that use of this medical intervention will continue to grow. Research has shown that children who use LTV have risk factors for feeding and swallowing difficulties which result in long-term reliance on non-oral feeding methods. This Patient and Public Involvement (PPI) activity explored experiences of parents of children with LTV on their children's feeding and swallowing journeys. Individual and group interviews with seven parents were conducted. Interview data was then analysed using content analysis. Families discussed a range of themes including impacts on their family, facilitators and barriers to feeding and swallowing journeys, speech and language therapy (SLT) support, their family's healthcare journey in relation to quality of life and future directions for research. This study highlighted potential key areas to explore when identifying ways to improve SLT care and research in feeding and swallowing for children who use LTV.

Porphyrin-fused graphene nanoribbons.

Graphene nanoribbons (GNRs), nanometre-wide strips of graphene, are promising materials for fabricating electronic devices. Many GNRs have been reported, yet no scalable strategies are known for synthesizing GNRs with metal atoms and heteroaromatic units at precisely defined positions in the conjugated backbone, which would be valuable for tuning their optical, electronic and magnetic properties. Here we report the solution-phase synthesis of a porphyrin-fused graphene nanoribbon (PGNR). This PGNR has metalloporphyrins fused into a twisted fjord-edged GNR backbone; it consists of long chains (>100 nm), with a narrow optical bandgap (~1.0 eV) and high local charge mobility (>400 cm2 V-1 s-1 by terahertz spectroscopy). We use this PGNR to fabricate ambipolar field-effect transistors with appealing switching behaviour, and single-electron transistors displaying multiple Coulomb diamonds. These results open an avenue to π-extended nanostructures with engineerable electrical and magnetic properties by transposing the coordination chemistry of porphyrins into graphene nanoribbons.

Feeding and swallowing outcomes of children receiving long-term ventilation: A scoping review protocol.

BACKGROUND: The last three decades have seen a growth in the number of children requiring long-term ventilation. Children with long-term ventilation present with underlying respiratory and neurological conditions that place them at risk of feeding and swallowing difficulties. To date, a scoping review or systematic review investigating the feeding and swallowing outcomes of children with long-term ventilation needs has not been conducted. AIMS: This paper describes a protocol for a scoping review of the feeding and swallowing outcomes of children receiving long-term ventilation. METHODS: This scoping review protocol will utilize the Joanna Briggs Institute scoping review methodology guideline. Our review will focus on the feeding and swallowing outcomes of children aged 0 to 18 years with long-term ventilation needs. A full search strategy initially created by the authors and a research librarian was conducted on the PubMed database. Following this, pilot testing took place to determine discrepancies in eligibility criteria. A full search strategy will be conducted across several databases. A data extraction form has been developed by the authors and will be used during the scoping review process. DISCUSSION: This protocol has been created to provide a rigorous and comprehensive basis for undertaking a scoping review. All necessary steps have been completed in order to commence the scoping review. REGISTRATION: This scoping review protocol was registered on Open Science Framework on the 26th November 2021 (Registration DOI 10.17605/OSF.IO/NQBPD).

Feeding and Swallowing Outcomes in Children Who Use Long-Term Ventilation: A Scoping Review.

The last two decades have seen increasing use of long-term ventilation (LTV) as an intervention in childhood. Children who use LTV have many risk factors for feeding and swallowing difficulties, including their underlying respiratory and/or neurological etiology, long hospitalizations, medical interventions, and limited exposure to oral feeding experiences. This review aimed to answer two questions: 1) 'What specific swallowing and feeding characteristics do these children experience?'; and 2) 'What impacts do these swallowing and feeding characteristics have on health status and quality of life?'. Texts were identified across bibliographic databases, reference lists, and grey literature. Studies were analyzed according to ventilation, feeding and swallowing, assessment and intervention, and quality of life parameters. Overall, 1919 papers were screened, with 31 papers included in the final data extraction process. A range of feeding and swallowing characteristics were observed, including oral secretion management difficulties, oral aversion, swallowing difficulties, and clinical signs of aspiration. Non-oral feeding was found to be the primary feeding method used. Little information on health status and quality of life was reported in scoping review texts. Children with LTV needs present with a range of feeding and swallowing concerns, and non-oral feeding is common. Further research is needed to understand the feeding and swallowing journey of this population. This will assist in future service planning and delivery, and in turn contribute to improving patient outcomes and quality of life.

Template-Directed Synthesis of Strained meso-meso-Linked Porphyrin Nanorings.

Strained macrocycles display interesting properties, such as conformational rigidity, often resulting in enhanced π-conjugation or enhanced affinity for non-covalent guest binding, yet they can be difficult to synthesize. Here we use computational modeling to design a template to direct the formation of an 18-porphyrin nanoring with direct meso-meso bonds between the porphyrin units. Coupling of a linear 18-porphyrin oligomer in the presence of this template gives the target nanoring, together with an unexpected 36-porphyrin ring by-product. Scanning tunneling microscopy (STM) revealed the elliptical conformations and flexibility of these nanorings on a Au(111) surface.

Vitamin D did not reduce multiple sclerosis disease activity after a clinically isolated syndrome.

Low serum levels of 25-hydroxyvitamin D [25(OH)D] and low sunlight exposure are known risk factors for the development of multiple sclerosis. Add-on vitamin D supplementation trials in established multiple sclerosis have been inconclusive. The effects of vitamin D supplementation to prevent multiple sclerosis is unknown. We aimed to test the hypothesis that oral vitamin D3 supplementation in high-risk clinically isolated syndrome (abnormal MRI, at least three T2 brain and/or spinal cord lesions), delays time to conversion to definite multiple sclerosis, that the therapeutic effect is dose-dependent, and that all doses are safe and well tolerated. We conducted a double-blind trial in Australia and New Zealand. Eligible participants were randomized 1:1:1:1 to placebo, 1000, 5000 or 10 000 international units (IU) of oral vitamin D3 daily within each study centre (n = 23) and followed for up to 48 weeks. Between 2013 and 2021, we enrolled 204 participants. Brain MRI scans were performed at baseline, 24 and 48 weeks. The main study outcome was conversion to clinically definite multiple sclerosis based on the 2010 McDonald criteria defined as either a clinical relapse or new brain MRI T2 lesion development. We included 199 cases in the intention-to-treat analysis based on assigned dose. Of these, 116 converted to multiple sclerosis by 48 weeks (58%). Compared to placebo, the hazard ratios (95% confidence interval) for conversion were 1000 IU 0.87 (0.50, 1.50); 5000 IU 1.37 (0.82, 2.29); and 10 000 IU 1.28 (0.76, 2.14). In an adjusted model including age, sex, latitude, study centre and baseline symptom number, clinically isolated syndrome onset site, presence of infratentorial lesions and use of steroids, the hazard ratios (versus placebo) were 1000 IU 0.80 (0.45, 1.44); 5000 IU 1.36 (0.78, 2.38); and 10 000 IU 1.07 (0.62, 1.85). Vitamin D3 supplementation was safe and well tolerated. We did not demonstrate reduction in multiple sclerosis disease activity by vitamin D3 supplementation after a high-risk clinically isolated syndrome.

Common ground in AAC: how children who use AAC and teaching staff shape interaction in the multimodal classroom.

Children who use augmentative and alternative communication (AAC) are multimodal communicators. However, in classroom interactions involving children and staff, achieving mutual understanding and accomplishing task-oriented goals by attending to the child's unaided AAC can be challenging. This study draws on excerpts of video recordings of interactions in a classroom for 6-9-year-old children who used AAC to explore how three child participants used the range of multimodal resources available to them - vocal, movement-based, and gestural, technological, temporal - to shape (and to some degree, co-control) classroom interactions. Our research was concerned with examining achievements and problems in establishing a sense of common ground and the realization of child agency. Through detailed multimodal analysis, this paper renders visible different types of practices rejecting a request for clarification, drawing new parties into a conversation, disrupting whole-class teacher talk-through which the children in the study voiced themselves in persuasive ways. It concludes by suggesting that multimodal accounts paint a more nuanced picture of children's resourcefulness and conversational asymmetry that highlights children's agency amidst material, semiotic, and institutional constraints.

The ability of typically developing 2-3 year olds to infer the control mechanism for eye-gaze technology and the impact of causal language instruction.

PURPOSE: Little is known about how children learn to control eye-gaze technology, and clinicians lack information to guide decision-making. This paper examines whether typically developing 2-3 year olds can infer for themselves the causal mechanisms by which eye-gaze technology is controlled, whether a teaching intervention based on causal language improves performance and how their performance compares to the same task accessed via a touchscreen.Methods and materials: Typically developing children's (n = 9, Mean Age 28.7 months) performance on a cause and effect game presented on eye-gaze and touchscreen devices was compared. The game was presented first with no specific instruction on how to control the devices. This was followed by a subsequent presentation with explicit instruction about how the access methods worked, using a causal language approach. A final presentation examined whether children had retained any learning. RESULTS: Performance in the eye-gaze condition without instruction (42.5% successful trials) was significantly below performance in the corresponding touchscreen condition (75%). However, when causal language instruction was added, performance with both access methods rose to comparable levels (90.7% eye-gaze and 94.6% touchscreen success). Performance gains were not retained post-intervention. CONCLUSIONS: Although 2-3 years in the study could make use of eye-gaze technology with support, this study found no evidence that these children could infer the causal mechanisms of control independently or intuitively. The lack of spatial contiguity and the comparative lack of feedback from eye-gaze devices are discussed as possible contributory factors.

There are challenges in young children inferring for themselves the causal link between eye movements and control of an eye-gaze device.Explicit instruction may improve children's performance in a specific task, but it is debatable whether this translates to the establishment of causal mechanisms for control of the device.Clinicians should be cautious of making assumptions about what children are learning from activities claiming to teach cause and effect or other foundational eye-gaze control skills.

Relationship between lexicon and grammar in children and youth who use augmentative and alternative communication.

The present study investigated the relationship between lexicon and grammar in individuals who use graphic symbol-based aided augmentative and alternative communication (AAC). Data came from 60 transcripts of generalization sessions that were part of two previous intervention studies, aimed at improving the expressive vocabulary and grammar of 12 children and youth who used graphic symbol-based AAC. The specific aims of the current study were to (a) describe vocabulary composition across different levels of expressive vocabulary and (b) analyze the relationship between global measures of expressive vocabulary and the use of grammar in individuals who use aided AAC. A series of multiple linear mixed effect regression analyses showed a positive predictive association between overall vocabulary size and the use of closed-class words, and a positive relationship between the use of verbs and the use of closed-class words. Additionally, the use of verbs had a significant positive association with the use of inflectional morphology, while the use of nouns did not. Theoretical and practical implications of these findings are discussed.

Respiratory benefit in preterm lambs is progressively lost when the concentration of fetal plasma betamethasone is titrated below two nanograms per milliliter.

Antenatal steroid therapy is the standard of care for women at imminent risk of preterm delivery. Current dosing regimens use suprapharmacological doses to achieve extended fetal steroid exposures. We aimed to determine the lowest fetal plasma betamethasone concentration sufficient to achieve functional preterm lung maturation. Ewes with single fetuses underwent surgery to install a fetal jugular catheter. Adopting a stepwise design, ewes were randomized to either a saline-only group (negative control group; n = 9) or one of four betamethasone treatment groups. Each betamethasone group fetus received a fetal intravenous infusion to target a constant plasma betamethasone level of either 1) 2 ng/mL (2 ng/mL positive control group, n = 9); 2) 1 ng/mL, (1 ng/mL group, n = 10); 3) 0.5 ng/mL (0.5 ng/mL group, n = 10); or 4) 0.25 ng/mL (0.25 ng/mL group, n = 10). Fetuses were infused for 48 h, delivered, and ventilated. The positive control group, negative control group, and mid-point 0.5 ng/mL group animals were tested first. An interim analysis informed the final betamethasone group tested. Positive control group animals had large, statistically significant improvements in respiratory function. Based on an interim analysis, the 1.0 ng/mL group was studied in favor of the 0.25 ng/mL group. Treatment efficacy was progressively lost at plasma betamethasone concentrations lower than 2 ng/mL. We demonstrated that the acute respiratory benefit conveyed by antenatal steroid exposure in the fetal sheep is progressively lost when constant fetal plasma betamethasone concentrations are reduced below a targeted value of 2 ng/mL.NEW & NOTEWORTHY Lung maturation benefits in preterm lambs were progressively lost when fetal plasma betamethasone concentrations fell below 2 ng/mL. The effective floor threshold for a robust, lung-maturing exposure likely lies between 1 and 2 ng betamethasone per milliliter of plasma. Hypothalamic pituitary adrenal axis signaling and immunocyte populations remained materially disrupted at subtherapeutic steroid concentrations. These data demonstrate the potential to improve antenatal steroid therapy using reduced dose regimens informed by glucocorticoid pharmacokinetics and pharmacodynamics.

TACH101, a first-in-class pan-inhibitor of KDM4 histone demethylase.

Histone lysine demethylase 4 (KDM4) is an epigenetic regulator that facilitates the transition between transcriptionally silent and active chromatin states by catalyzing the removal of methyl groups on histones H3K9, H3K36, and H1.4K26. KDM4 overamplification or dysregulation has been reported in various cancers and has been shown to drive key processes linked to tumorigenesis, such as replicative immortality, evasion of apoptosis, metastasis, DNA repair deficiency, and genomic instability. KDM4 also plays a role in epigenetic regulation of cancer stem cell renewal and has been linked to more aggressive disease and poorer clinical outcomes. The KDM4 family is composed of four main isoforms (KDM4A-D) that demonstrate functional redundancy and cross-activity; thus, selective inhibition of one isoform appears to be ineffective and pan-inhibition targeting multiple KDM4 isoforms is required. Here, we describe TACH101, a novel, small-molecule pan-inhibitor of KDM4 that selectively targets KDM4A-D with no effect on other KDM families. TACH101 demonstrated potent antiproliferative activity in cancer cell lines and organoid models derived from various histologies, including colorectal, esophageal, gastric, breast, pancreatic, and hematological malignancies. In vivo , potent inhibition of KDM4 led to efficient tumor growth inhibition and regression in several xenograft models. A reduction in the population of tumor-initiating cells was observed following TACH101 treatment. Overall, these observations demonstrate the broad applicability of TACH101 as a potential anticancer agent and support its advancement into clinical trials.

Covalent Template-Directed Synthesis of a Spoked 18-Porphyrin Nanoring.

Rings of porphyrins mimic natural light-harvesting chlorophyll arrays and offer insights into electronic delocalization, providing a motivation for creating larger nanorings with closely spaced porphyrin units. Here, we demonstrate the first synthesis of a macrocycle consisting entirely of 5,15-linked porphyrins. This porphyrin octadecamer was constructed using a covalent six-armed template, made by cobalt-catalyzed cyclotrimerization of an H-shaped tolan with porphyrin trimer ends. The porphyrins around the circumference of the nanoring were linked together by intramolecular oxidative meso-meso coupling and partial ß-ß fusion, to give a nanoring consisting of six edge-fused zinc(II) porphyrin dimer units and six un-fused nickel(II) porphyrins. STM imaging on a gold surface confirms the size and shape of the spoked 18-porphyrin nanoring (calculated diameter: 4.7 nm).

Index admission vs elective laparoscopic common bile duct exploration: a district general hospital experience over 6 years.

BACKGROUND: Laparoscopic common bile duct exploration (LCBDE) is relatively a new approach for clearing choledocholithiasis. The aim of this study is to assess the safety of this approach to clearing common bile duct (CBD) stones on an index admission including emergency setting. METHODS: Retrospective data collection and analysis were carried out for 207 consecutive cases of LCBDE performed in Royal Cornwall Hospital over 6 years (2015-2020). Patients were divided into two groups (Index admission vs elective) then both groups compared. RESULTS: A total of 207 cases of LCBDE were performed in our unit during the time period. One hundred twenty-two operations were performed on the index admission and 85 on a subsequent elective list. Mean operative time was 146 ± 64 min in the index admission group and 145 ± 65 min in the elective group (p = 0.913). Length of stay post-operatively was 3.3 ± 6.3 days in the index admission cases and 3.5 ± 4.6 days after elective cases. Successful clearance was achieved at the end of the operation in 116 patients in the index admission group, clearance failed in one case and negative exploration in 5 patients. In the elective group 83 patients had a successful clearance at the end of the operation, and 2 patients has had a negative exploration. Twelve patients (index admission group) and 8 patients of the elective cases required post-operative Endoscopic Retrograde Cholangiopancreatography (ERCP) to manage retained stones, recurrent stones and bile leak (p = 0.921). Three patients required re-operation for post-operative complications in each group. CONCLUSION: Common bile duct exploration in index admission is safe with high success rate if performed by well-trained surgeons with advanced laparoscopic skills.

Impact of rapid near-patient STI testing on service delivery outcomes in an integrated sexual health service in the United Kingdom: a controlled interrupted time series study.

OBJECTIVES: To evaluate the impact of a new clinic-based rapid sexually transmitted infection testing, diagnosis and treatment service on healthcare delivery and resource needs in an integrated sexual health service. DESIGN: Controlled interrupted time series study. SETTING: Two integrated sexual health services (SHS) in UK: Unity Sexual Health in Bristol, UK (intervention site) and Croydon Sexual Health in London (control site). PARTICIPANTS: Electronic patient records for all 58 418 attendances during the period 1 year before and 1 year after the intervention. INTERVENTION: Introduction of an in-clinic rapid testing system for gonorrhoea and chlamydia in combination with revised treatment pathways. OUTCOME MEASURES: Time-to-test notification, staff capacity, cost per episode of care and overall service costs. We also assessed rates of gonorrhoea culture swabs, follow-up attendances and examinations. RESULTS: Time-to-notification and the rate of gonorrhoea swabs significantly decreased following implementation of the new system. There was no evidence of change in follow-up visits or examination rates for patients seen in clinic related to the new system. Staff capacity in clinics appeared to be maintained across the study period. Overall, the number of episodes per week was unchanged in the intervention site, and the mean cost per episode decreased by 7.5% (95% CI 5.7% to 9.3%). CONCLUSIONS: The clear improvement in time-to-notification, while maintaining activity at a lower overall cost, suggests that the implementation of clinic-based testing had the intended impact, which bolsters the case for more widespread rollout in sexual health services.