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In fire-prone regions, the occurrence of some faunal species is contingent on the presence of resources that arise through post-fire plant succession. Through planned burning, managers can alter resource availability and aim to provide the conditions required to promote biodiversity. Understanding how species occurrence changes at different spatial and temporal scales after fire is essential to achieve this goal. However, many fire prescriptions are guided primarily by the responses of fire-sensitive plants when setting tolerable fire intervals. This approach assumes that maintaining floristic diversity will satisfy the requirements of fauna. We surveyed bird species in two semi-arid vegetation types across an environmental gradient in south-eastern Australia. We conducted four surveys at each of 253 sites across a 75-year chronosequence of time since fire and used generalized additive mixed models to examine changes in the occurrence of birds in response to time since fire. Model predictions were compared to plant-derived fire prescriptions currently guiding fire management in the region. Time since fire was a significant predictor for 18 of 28 species modeled, in at least one vegetation type, over a gradient of 1.3° of latitude. We detected considerable variation in the responses of some species, both between vegetation types and geographically within a vegetation type. Our evaluation of plant-derived fire prescriptions suggests that the intervals considered acceptable for maintaining floristic diversity may not be sustainable for populations of birds requiring longer unburnt vegetation, with 6 of the 12 species assessed attaining a mean occurrence probability of 20.3% by the minimum tolerable fire interval, and 57.3% by the maximum tolerable fire interval, in their respective vegetation types. Our findings highlight the potential vulnerability of fire-responsive bird species if fire prescriptions are applied in a manner that fails to account for the slow development of habitat resources needed by some species, and the variation detected within the responses of species. This highlights the need for species-specific data collected at an appropriate spatial scale to inform management plans., (© 2024 The Author(s). Ecological Applications published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

Population studies have suggested that viral infections may be contributing to risk of ischemic stroke, although the mechanisms for this are unclear. In this review, we examine the epidemiological evidence supporting the involvement of viral diseases, including influenza, COVID-19, chronic herpesvirus infections, and hepatitis C in current trends of stroke incidence. To support these associations, we highlight the virus-host interactions that are critical in the context of stroke, including direct effects of acute and persistent viral infections on vascular function, inflammation, and thrombosis. Additionally, we evaluate the systemic changes that occur during viral infection that can predispose individuals to ischemic stroke, including alterations in blood pressure regulation, coagulation, and lipid metabolism. Our review emphasizes the need to further elucidate precise mechanisms involved in viral infections and stroke risk. Future research will inform the development of targeted interventions for stroke prevention in the context of viral diseases.

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 (EC 50 = 3-46 nM), human metapneumovirus (EC 50 = 210 nM), human rhinovirus (EC 50 = 54-61 nM), and enterovirus (EC 50 = 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.

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., (© 2024. Crown.)

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.

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 cm 2  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., (© 2024. The Author(s).)

Objective: We examined the associations between 25-hydroxy vitamin D (25(OH)D 3 ) concentration and the diagnosis and growth of abdominal aortic aneurysm (AAA)., Methods: AAA cases and healthy controls were recruited from vascular centers or the community. A subset of participants with AAA were monitored by repeat ultrasound examination to assess AAA growth. Serum 25(OH)D 3 concentration was measured using a validated mass spectrometry method and categorized into guideline-recommended cut-points after deseasonalization. The associations between deseasonalized 25(OH)D 3 concentration and AAA diagnosis and growth were examined using logistic regression and linear mixed effects modeling., Results: A total of 4673 participants consisting of 873 (455 controls and 418 cases) from Queensland and 3800 (3588 controls and 212 cases) from Western Australia were recruited. For every 1 standard deviation increase in 25(OH)D 3 concentration, odds of AAA diagnosis was significantly reduced in both Queensland (adjusted odds ratio: 0.81; 95% confidence interval [CI]: 0.69-0.95; P  = .009) and Western Australia (adjusted odds ratio: 0.80; 95% CI: 0.68-0.94; P  = .005) cohorts. A subset of 310 eligible participants with small AAA from both regions were followed for a median of 4.2 (interquartile range: 2.0-5.8) years. Compared with vitamin D sufficient participants (50 to ˂75 nmol/L), annual mean AAA growth was significantly greater in those with higher vitamin D (≥75 nmol/L) (adjusted mean difference: 0.1 mm/y, 95% CI: 0.1-0.2; P  < .001)., Conclusions: High 25(OH)D 3 concentration was paradoxically associated with a lower likelihood of AAA diagnosis and faster AAA growth. Further research is needed to resolve these conflicting findings., Competing Interests: None., (© 2024 The Author(s).)

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., (© 2024. The Author(s).)

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.

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&#95;08089, which is a 42.7 kDa peptide corresponding to the 60S ribosomal subunit protein L4; and POLS&#95;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 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.

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., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

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)., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: The lead author (SL) was funded for this research work as part of a Health Education England (HEE) / National Institute of Health and Care Research (NIHR) Pre-doctoral Clinical Academic Fellowship completed between September 2021 to September 2022., (Copyright: © 2024 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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.

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.

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.

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.

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., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

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 β-β 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)., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: Guidelines on the management of acute pulmonary embolism (PE) recommend consideration of endovascular therapies (EVT) for patients at intermediate-high risk. However, long-term data on the outcomes of patients after EVT as compared to medical therapy is lacking. This study aimed to compare outcomes of patients receiving EVT as compared to medical therapy alone at 3 to 6 months., Methods: In this single-center, retrospective cohort study, 190 patients with PE underwent evaluation for presence of right ventricular (RV) dysfunction by transthoracic echocardiogram, residual perfusion defects on ventilation-perfusion scanning, and functional capacity by 6-minute walk distance (6MWD) at 3 to 6 month follow-up., Results: Fifty-eight (31%) patients received EVT for the management of their acute PE. At follow-up (median 120 [97-170] days), 71% of patients who received EVT had normalization of RV function compared with only 34% of patients who received medical therapy alone ( P < . 001). Patients who received EVT had a significantly greater increase in their estimated glomerular filtration rate ( P = . 001), decrease in N-terminal proB-type natriuretic peptide ( P = . 003), and decrease in hemoglobin values ( P = . 018). Patients with intermediate-high to high risk PE who received EVT had significantly greater distance achieved on their 6MWD as compared to those who received medical therapy alone ( P = . 025)., Conclusions: Patients with acute PE who received EVT plus medical therapy were more likely to achieve normalization of RV dysfunction at 3 to 6 month follow-up compared to patients who received medical therapy alone. These data suggest that EVT is an effective therapy option for acute PE in intermediate-high and high risk patients with potential durable long-term benefits., (© 2023 The Authors.)

microRNA (miRNA) are important regulators of gene expression. miRNA have the potential as a treatment to modulate genes, pathways and cells involved in ischemic stroke. In this review, we specifically present miRNA in stroke as a treatment to decrease thrombosis, reduce blood brain barrier (BBB) disruption and hemorrhagic transformation (HT), modulate inflammation, and modify angiogenesis. miRNA as a treatment for stroke is an emerging area with evidence from animal studies demonstrating its potential. While no miRNA is currently approved for human use, several have shown promise in clinical trials to treat medical conditions, such as miR-122 for hepatitis C. The role of miRNA as a treatment for specific applications in ischemic stroke is presented including a discussion of the benefits and barriers of miRNA as a treatment, and directions for future advancement., Competing Interests: Declaration of competing interest Authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: While the relationship between speech, language and communication needs (SLCN) and mental health difficulties has been recognized, speech and language therapists (SLTs), and mental health professionals face challenges in assessing and treating children with these co-occurring needs. There exists a gap in the evidence base for best practice for professionals working with children and young people (CYP) who experience difficulties in both areas., Aims: To explore the views of SLTs and mental health clinicians about their experiences of working with CYP exhibiting co-occurring SLCN and mental health difficulties., Methods & Procedures: Semi-structured interviews were conducted with eight SLTs and six mental health professionals, including psychotherapists, clinical psychologists, play therapists and counsellors, with experience working with CYP with SLCN. Interviews were analysed using reflexive thematic analysis and themes were identified from the data., Outcomes & Results: Participants felt that SLCN and mental health difficulties frequently co-occur. Participants described how CYP with SLCN and mental health issues commonly experience difficulties across and between the domains of language and cognition, emotional well-being and challenging behaviour. Findings suggest that there are organizational limitations in the fields of SLT and mental health that have implications for the efficacy of assessment and treatment of CYP with SLCN and mental health difficulties. Traditional talking therapies were perceived to be inaccessible and ineffective for CYP with SLCN and mental health difficulties. Interventions blending behaviour and emotion programmes with language and communication interventions were considered potentially beneficial., Conclusions & Implications: Future research should explore and evaluate current services and service set-up in SLT and mental health. The findings from this study have important implications for the efficacy of treatments provided to this population suggesting that more research needs to be done into effective diagnosis and interventions for this population., What This Paper Adds: What is already known on the subject Research suggests that CYP with SLCN, such as developmental language disorder (DLD), are likely to experience mental health difficulties including depression, anxiety and poor emotional well-being. CYP who experience difficulties with SLCN and poor mental health are not well understood and this area remains under-researched. This has implications for clinician knowledge and therefore the effective diagnosis and treatment of children and adolescents experiencing SLCN and mental health difficulties. In addition, little is known about the accessibility of talking therapies to CYP presenting with SLCN and mental health difficulties. What this paper adds to existing knowledge SLCN issues are understood by SLTs and mental health issues are understood by mental health professionals, but where these co-occur difficulties exist for the diagnostic process, with professionals perceiving that CYP in this category are often undiagnosed or misdiagnosed. Organizational boundaries between SLT and mental health were perceived to contribute to a lack of understanding of SLCN and mental health needs, which has implications for effective diagnosis and treatment. Traditional talking therapies were thought to be inaccessible for CYP with SLCN and mental health difficulties. Interventions used in both SLT and psychotherapy were perceived as clinically useful if combined. What are the potential or actual clinical implications of this work? This paper highlights implications for the accessibility and efficacy of the assessment and treatment provided to this population and to the organization of services currently treating this group of CYP. A direction for future research would be to undertake service evaluations and intervention-based studies., (© 2022 The Authors. International Journal of Language & Communication Disorders published by John Wiley & Sons Ltd on behalf of Royal College of Speech and Language Therapists.)

Natural light-harvesting systems absorb sunlight and transfer its energy to the reaction centre, where it is used for photosynthesis. Synthetic chromophore arrays provide useful models for understanding energy migration in these systems. Research has focused on mimicking rings of chlorophyll molecules found in purple bacteria, known as 'light-harvesting system 2'. Linear meso-meso linked porphyrin chains mediate rapid energy migration, but until now it has not been possible to bend them into rings. Here we show that oligo-pyridyl templates can be used to bend these rod-like photonic wires to create covalent nanorings that consist of 24 porphyrin units and a single butadiyne link. Their elliptical conformations have been probed by scanning tunnelling microscopy. This system exhibits two excited state energy transfer processes: one from a bound template to the peripheral porphyrins and one, in the template-free ring, from the exciton-coupled porphyrin array to the π-conjugated butadiyne-linked porphyrin dimer segment., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Metastasis is responsible for most breast cancer-related deaths; however, identifying the cellular determinants of metastasis has remained challenging. Here, we identified a minority population of immature THY1 + / VEGFA + tumor epithelial cells in human breast tumor biopsies that display angiogenic features and are marked by the expression of the oncogene, LMO2 . Higher abundance of LMO2 + basal cells correlated with tumor endothelial content and predicted poor distant recurrence-free survival in patients. Using MMTV-PyMT/Lmo2 CreERT2 mice, we demonstrated that Lmo2 lineage-traced cells integrate into the vasculature and have a higher propensity to metastasize. LMO2 knockdown in human breast tumors reduced lung metastasis by impairing intravasation, leading to a reduced frequency of circulating tumor cells. Mechanistically, we find that LMO2 binds to STAT3 and is required for STAT3 activation by tumor necrosis factor-α and interleukin-6. Collectively, our study identifies a population of metastasis-initiating cells with angiogenic features and establishes the LMO2-STAT3 signaling axis as a therapeutic target in breast cancer metastasis.

As precision medicine increases the response rate of treatment, tumors frequently bypass inhibition, and reoccur. In order for treatment to be effective long term, the mechanisms enabling treatment adaptation need to be understood. Here, we report a mouse model that, in the absence of p53 and the presence of oncogenic Kras G12D , develops breast tumors. Upon inactivation of Kras G12D , tumors initially regress and enter remission. Subsequently, the majority of tumors adapt to the withdrawal of Kras G12D expression and return. Kras G12D -independent tumor cells show a strong mesenchymal profile with active RAS-RAF-MEK-ERK (MAPK/ERK) signaling. Both Kras G12D -dependent and Kras G12D -independent tumors display a high level of genomic instability, and Kras G12D -independent tumors harbor numerous amplified genes that can activate the MAPK/ERK signaling pathway. Our study identifies both epithelial-mesenchymal transition (EMT) and active MAPK/ERK signaling in tumors that adapt to oncogenic Kras G12D withdrawal in a novel Trp53 -/- breast cancer mouse model. To achieve long-lasting responses in the clinic to RAS-fueled cancer, treatment will need to focus in parallel on obstructing tumors from adapting to oncogene inhibition., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Objective: To determine whether silastic ring laparoscopic Roux-en-Y gastric bypass (SR-LRYGB) or laparoscopic sleeve gastrectomy (LSG) produces superior diabetes remission at 5 years., Research Design and Methods: In a single-center, double-blind trial, 114 adults with type 2 diabetes and BMI 35-65 kg/m2 were randomly assigned to SR-LRYGB or LSG (1:1; stratified by age-group, BMI group, ethnicity, diabetes duration, and insulin therapy) using a web-based service. Diabetes and other metabolic medications were adjusted according to a prespecified protocol. The primary outcome was diabetes remission assessed at 5 years, defined by HbA1c <6% (42 mmol/mol) without glucose-lowering medications. Secondary outcomes included changes in weight, cardiometabolic risk factors, quality of life, and adverse events., Results: Diabetes remission after SR-LRYGB versus LSG occurred in 25 (47%) of 53 vs. 18 (33%) of 55 patients (adjusted odds ratios 4.5 [95% CI 1.6, 15.5; P = 0.009] and 4.2 [1.3, 13.4; P = 0.015] in the intention-to-treat analysis). Percent body weight loss was greater after SR-LRYGB than after LSG (absolute difference 10.7%; 95% CI 7.3, 14.0; P < 0.001). Improvements in cardiometabolic risk factors were similar, but HDL cholesterol increased more after SR-LRYGB. Early and late complications were similar in both groups. General health and physical functioning improved after both types of surgery, with greater improvement in physical functioning after SR-LRYGB. People of Māori or Pacific ethnicity (26%) had lower incidence of diabetes remission than those of New Zealand European or other ethnicities (2 of 25 vs. 41 of 83; P < 0.001)., Conclusions: SR-LRYGB provided superior diabetes remission and weight loss compared with LSG at 5 years, with similar low risks of complications., (© 2022 by the American Diabetes Association.)

Background: Recent evidence suggests that pre-school children with co-occurring phonological speech sound disorder (SSD) and expressive language difficulties are at a higher risk of ongoing communication and literacy needs in comparison with children with these difficulties in isolation. However, to date there has been no systematic or scoping review of the literature specific to interventions for children with this dual profile., Aims: To explore the evidence regarding interventions for pre-school children with co-occurring phonological SSD and expressive language difficulties, including the content/delivery of such interventions, areas of speech and language targeted, and a broad overview of study quality., Methods & Procedures: A scoping review methodology was used in accordance with the guidance from the Joanna Briggs Institute. Following a systematic search of Ovid Medline, Ovid Emcare, OVID Embase, CINAHL, Psychinfo and ERIC, 11 studies were included in the review. A researcher-developed data extraction form was used to extract specific information about each intervention, with the JBI appraisal tools used to provide a broad overview of the quality of each study., Main Contribution: Included papers consisted of six randomized controlled trials (RCTs), two cohort studies, two case studies and one case series. Interventions fell into two main categories: (1) integrated interventions that combined content for both speech and language targets and/or explicitly used the same type of technique to improve both domains; and (2) single-domain interventions that explicitly included content to target speech or language only, but also aimed to improve the other domain indirectly. Study quality varied, with detail on the content, context and delivery of interventions often underspecified, hampering the replication and clinical applicability of findings., Conclusions & Implications: Early emerging evidence was identified to support both integrated speech and language interventions as well as single-domain interventions. However, caution should be exercised due to the variation in the quality and level of detail reported for the interventions. Future intervention studies may seek to address this by reporting in accordance with Template for Intervention Description and Replication (TIDieR) reporting guidelines. This approach would enable clinicians to consider the applicability of the intervention to individual children within differing settings., What This Paper Adds: What is already known on the subject Pre-school children with co-occurring phonological SSD and expressive language difficulties frequently present within speech and language therapy services. These children are at a higher risk of long-term communication and literacy difficulties compared with children with these needs in isolation. Some emerging evidence suggests that interventions for children with this co-occurring profile may exist within the literature; however, this evidence may not be known to clinicians in everyday practice. What this paper adds to existing knowledge This review is the first to systematically examine evidence of interventions for pre-school children with co-occurring phonological SSD and expressive language difficulties. The review identified a small number of intervention studies that varied in research quality and level of detail provided regarding the content and delivery of interventions. What are the potential or actual clinical implications of this work? The findings of this study highlight published evidence for interventions for pre-school children with co-occurring phonological SSD and expressive language difficulties. These may take the form of integrating techniques for speech/language into a single intervention, or the explicit targeting of one domain with the aim of also influencing the other. However, there is a need for further high-quality research in this area. Such studies should provide sufficient detail to enable replication. This would enable clinicians to understand the relevance and applicability of such intervention findings to the individual children they see within their clinical practice., (© 2022 Royal College of Speech and Language Therapists.)

Antenatal steroids (ANSs) are routinely administered to women judged to be at imminent risk of preterm delivery. Their principal benefit is precocious functional maturation of the preterm fetal lung. Current dosing regimens expose the mother and fetus to high steroid levels that may be unnecessary, increasing the potential risks of disruption to the maternal and fetal hypothalamic-pituitary-adrenal (HPA) axis and glucose regulation, alterations in placental function, and reduced fetal growth. Using a sheep model of pregnancy, we tested the hypothesis that direct fetal administration of an ultra-low dose course of betamethasone phosphate (∼0.33 mg) would be sufficient to elicit functional maturation of the fetal lung. A jugular catheter was installed in singleton ovine fetuses at 122-day gestation under general anesthesia. Animals were randomized to receive either: 1 ) fetal intravenous betamethasone phosphate to target fetal plasma betamethasone mean levels of 2 ng/mL for 26 h (fetal treatment group; n = 16); 2 ) fetal intravenous saline for 26 h and two maternal intramuscular injections of 0.25 mg/kg betamethasone phosphate + betamethasone acetate, simulating a standard clinical treatment (maternal treatment group; n = 12); or 3 ) fetal intravenous saline only for 26 h (negative control group; n = 10). Fetuses were delivered 48 h after surgery, ventilated for 30 min to allow the collection of lung function and physiological data, and euthanized. Quantitative PCR and Western blots were used to assess markers of lung maturation. The average total betamethasone phosphate dose for the fetal treatment group was 1% (0.3 mg) of the maternal treatment group (31-mg betamethasone phosphate + betamethasone acetate). At 30 min of ventilation, arterial [Formula: see text], pH, heart rate, and ventilation efficacy index (VEI) were significantly ( P < 0.05) and equivalently improved in both the fetal treatment group and maternal treatment group, relative to the negative control group. Similarly, SP-A, SP-C, and AQ-5 mRNA expression was significantly higher in both the fetal treatment group and maternal treatment group, relative to negative control. Maternal steroid administration was not required to generate preterm fetal lung maturation in sheep. Using a low dose and targeting steroid treatments directly to the fetus has the potential to significantly reduce maternal exposures, while simultaneously reducing the potential risk of adverse outcomes associated with current clinical dosing regimens.

Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.

Purpose: The aim of this study was to develop and test a new classification scale to describe looking behaviours (gaze fixations and gaze shifts) in relation to eye-pointing., Methods: The Eye-pointing Classification Scale (EpCS) was developed and tested following established procedures for the construction and evaluation of equivalent scales, and involved 2 phases: Drawing on research literature, Phase 1 involved initial drafting of the scale through a series of multi-disciplinary group discussions; evaluation of the scale through a survey procedure, and subsequent expert group evaluation. Phase 2, was an examination of scale reliability and relationships between child characteristics and level of EpCS classification., Results: In Phase 1, an initial draft of the scale was developed and then evaluated by 52 participants in 10 countries, leading to its refinement. Subsequent expert evaluation of content, style and structure indicated that no further refinement was required. In Phase 2, the scale achieved excellent levels of reliability in clinical testing. A significant relationship was identified between level of child motor ability and EpCS classification, and level of child language understanding and EpCS classification.Implications for rehabilitationNon-speaking children with severe bilateral cerebral palsy who have limited upper limb movement may communicate by using controlled looking behaviours to point to objects and people, referred to as eye-pointing.However, there is little consensus as to which looking behaviours represent eye-pointing and which do not.The Eye-pointing Classification Scale (EpCS) was developed to describe looking behaviours related to eye-pointing in this population of childrenThe EpCS provides a new robust tool for clinical management and research with children with cerebral palsy.

Low 25-hydroxyvitamin D (25(OH)D) concentration is a recognised risk factor for multiple sclerosis (MS). Associations with vitamin D metabolites and vitamin D binding globulin (VDBG) have not been widely studied. We assessed the association between vitamin D metabolites (25(OH)D 2 , 25(OH)D 3 , c3-epimer 25(OH)D 3 , 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), and 24,25-dihydroxyvitamin D 3 (24,25(OH) 2 D 3 )) measured by liquid chromatography-tandem mass spectrometry assays, VDBG measured using a polyclonal immunoassay, and calculated free and bioavailable 25(OH)D, free 1,25(OH) 2 D 3 , and the 24,25(OH) 2 D 3 : total 25(OH)D and total 1,25(OH) 2 D: total 25(OH)D ratios with risk of a first clinical diagnosis of CNS demyelination (FCD) in an Australian case-control study (n = 196 cases, n = 241 controls, matched on age, sex and study region). Higher 25(OH)D (adjusted odds ratio (AOR) = 0.94 (95 % confidence interval (CI) 0.85-1.03) per 10 nmol/L increment) and 24,25(OH) 2 D 3 (AOR = 0.81 (95 %CI 0.65-1.00) per 1 nmol/L increment) concentrations were associated with reduced FCD risk. Our results were compatible with no association for the other vitamin D metabolites, ratios, or VDBG with FCD risk. Thus, using standardised assays, and a comprehensive range of vitamin D metabolites, we confirmed the association of higher 25(OH)D and reduced FCD risk, and describe a similar effect for 24,25(OH) 2 D 3 ; free or bioavailable 25(OH)D were not associated with FCD risk., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the Bone Morphogenetic Signaling (BMP) pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling., Competing Interests: FR, EC, JA, RJ, MC filer of a provisional patent: U.S.Provisional Application No. 63/124,644 titled "Modulating BMP signaling in the treatment of Alzheimer's disease", BN, MA is the co-founder of Dorian Therapeutics. Dorian therapeutics was incorporated in June 2018 and it is an early stage anti-aging company that focuses on the process of cellular senescence. Most of the experiments were performed before the company was formed, BC, NG, KL, WH, SK, DQ, KP, AA, MM, HH, SQ No competing interests declared, (© 2022, Reinitz et al.)

Background: The COVID-19 pandemic has led to an avalanche of scientific studies, drawing on many different types of data. However, studies addressing the effectiveness of government actions against COVID-19, especially non-pharmaceutical interventions, often exhibit data problems that threaten the validity of their results. This review is thus intended to help epidemiologists and other researchers identify a set of data issues that, in our view, must be addressed in order for their work to be credible. We further intend to help journal editors and peer reviewers when evaluating studies, to apprise policy-makers, journalists, and other research consumers about the strengths and weaknesses of published studies, and to inform the wider debate about the scientific quality of COVID-19 research., Results: To this end, we describe common challenges in the collection, reporting, and use of epidemiologic, policy, and other data, including completeness and representativeness of outcomes data; their comparability over time and among jurisdictions; the adequacy of policy variables and data on intermediate outcomes such as mobility and mask use; and a mismatch between level of intervention and outcome variables. We urge researchers to think critically about potential problems with the COVID-19 data sources over the specific time periods and particular locations they have chosen to analyze, and to choose not only appropriate study designs but also to conduct appropriate checks and sensitivity analyses to investigate the impact(s) of potential threats on study findings., Conclusions: In an effort to encourage high quality research, we provide recommendations on how to address the issues we identify. Our first recommendation is for researchers to choose an appropriate design (and the data it requires). This review describes considerations and issues in order to identify the strongest analytical designs and demonstrates how interrupted time-series and comparative longitudinal studies can be particularly useful. Furthermore, we recommend that researchers conduct checks or sensitivity analyses of the results to data source and design choices, which we illustrate. Regardless of the approaches taken, researchers should be explicit about the kind of data problems or other biases that the design choice and sensitivity analyses are addressing., (© 2022. The Author(s).)

An interlaboratory comparison study was conducted by the Vitamin D Standardization Program (VDSP) to assess the performance of liquid chromatography - tandem mass spectrometry (LC-MS/MS) assays used for the determination of serum total 25-hydroxyvitamin D (25(OH)D), which is the sum of 25-hydroxyvitamin D 2 (25(OH)D 2 ) and 25-hydroxyvitamin D 3 (25(OH)D 3 ). A set of 50 single-donor samples was assigned target values for concentrations of 25(OH)D 2 , 25(OH)D 3 , 3-epi-25-hydroxyvitamin D 3 (3-epi-25(OH)D 3 ), and 24R,25-dihydroxyvitamin D 3 (24R,25(OH) 2 D 3 ) using isotope dilution liquid chromatography - tandem mass spectrometry (ID LC-MS/MS). VDSP Intercomparison Study 2 Part 1 includes results from 14 laboratories using 14 custom LC-MS/MS assays. Assay performance was evaluated using mean % bias compared to the assigned target values and using linear regression analysis of the test assay mean results and the target values. Only 53% of the LC-MS/MS assays met the VDSP criterion of mean % bias ≤ |±5%|. For the LC-MS/MS assays not meeting the ≤ |±5%| criterion, four assays had mean % bias of between 12 and 21%. Based on multivariable regression analysis using the concentrations of the four individual vitamin D metabolites in the 50 single-donor samples, the performance of several LC-MS/MS assays was found to be influenced by the presence of 3-epi-25(OH)D 3 . The results of this interlaboratory study represent the most comprehensive comparison of LC-MS/MS assay performance for serum total 25(OH)D and document the significant impact of the lack of separation of 3-epi-25(OH)D 3 and 25(OH)D 3 on assay performance, particularly with regard to mean % bias., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Twitter is one of the most popular social networking platforms today with nearly 238 million active daily users. While the platform is used by a myriad of individuals for various purposes, businesses both large and small have begun to adopt Twitter into their business strategy to better connect with consumers. Considering the growing emphasis on social media engagement in the business sector, the present study examines some of the fastest-growing American small businesses from the perspective of media events theory. According to media events theory, certain large-scale events will attract excess viewership and attention from the public, both on traditional and digital platforms. We examine how small businesses leveraged media events of 2020, including COVID-19 and the 2020 US presidential election, so as to increase engagement and foster the growth of their businesses via Twitter. Using 35000 tweets based on media event-related hashtags collected throughout 2020, we investigated Twitter engagement among 100 of the fastest-growing small businesses in the USA. Through the use of network analysis metrics, we illustrate that businesses that tweeted about media events often received greater levels of user engagement and exerted greater influence over their respective networks., Competing Interests: Conflict of interestThe authors declare no conflict of interests., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The Vitamin D External Quality Assessment Scheme (DEQAS) distributes human serum samples four times per year to over 1000 participants worldwide for the determination of total serum 25-hydroxyvitamin D [25(OH)D)]. These samples are stored at -40 °C prior to distribution and the participants are instructed to store the samples frozen at -20 °C or lower after receipt; however, the samples are shipped to participants at ambient conditions (i.e., no temperature control). To address the question of whether shipment at ambient conditions is sufficient for reliable performance of various 25(OH)D assays, the equivalence of DEQAS human serum samples shipped under frozen and ambient conditions was assessed. As part of a Vitamin D Standardization Program (VDSP) commutability study, two sets of the same nine DEQAS samples were shipped to participants at ambient temperature and frozen on dry ice. Twenty-eight laboratories participated in this study and provided 34 sets of results for the measurement of 25(OH)D using 20 ligand binding assays and 14 liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Equivalence of the assay response for the frozen versus ambient DEQAS samples for each assay was evaluated using multi-level modeling, paired t-tests including a false discovery rate (FDR) approach, and ordinary least squares linear regression analysis of frozen versus ambient results. Using the paired t-test and confirmed by FDR testing, differences in the results for the ambient and frozen samples were found to be statistically significant at p < 0.05 for four assays (DiaSorin, DIAsource, Siemens, and SNIBE prototype). For all 14 LC-MS/MS assays, the differences in the results for the ambient- and frozen-shipped samples were not found to be significant at p < 0.05 indicating that these analytes were stable during shipment at ambient conditions. Even though assay results have been shown to vary considerably among different 25(OH)D assays in other studies, the results of this study also indicate that sample handling/transport conditions may influence 25(OH)D assay response for several assays., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Conversational repair has been found to play a fundamental role in the acquisition of language. This paper describes existing research on conversational repair and its relationship to language learning, whether a first language or a second language, as well as its relevance to augmentative and alternative communication (AAC). A case is made for incorporating prompts to repair in conversation-based language interventions with children learning to use AAC. We argue that interventions targeting linguistic complexity should encourage self-repair in conversation in order to develop linguistic and operational competency as well as increase automaticity when using AAC. Clinical implications and directions for future research are discussed.

Objectives: To investigate experiences of implementing a new rapid sexual health testing, diagnosis and treatment service., Design: A theory-based qualitative evaluation with a focused ethnographic approach using non-participant observations and interviews with patient and clinic staff. Normalisation process theory was used to structure interview questions and thematic analysis., Setting: A sexual health centre in Bristol, UK., Participants: 26 patients and 21 staff involved in the rapid sexually transmitted infection (STI) service were interviewed. Purposive sampling was aimed for a range of views and experiences and sociodemographics and STI results for patients, job grades and roles for staff. 40 hours of observations were conducted., Results: Implementation of the new service required co-ordinated changes in practice across multiple staff teams. Patients also needed to make changes to how they accessed the service. Multiple small 'pilots' of process changes were necessary to find workable options. For example, the service was introduced in phases beginning with male patients. This responsive operating mode created challenges for delivering comprehensive training and communication in advance to all staff. However, staff worked together to adjust and improve the new service, and morale was buoyed through observing positive impacts on patient care. Patients valued faster results and avoiding unnecessary treatment. Patients reported that they were willing to drop-off self-samples and return for a follow-up appointment, enabling infection-specific treatment in accordance with test results, thus improving antimicrobial stewardship., Conclusions: The new service was acceptable to staff and patients. Implementation of service changes to improve access and delivery of care in the context of stretched resources can pose challenges for staff at all levels. Early evaluation of pilots of process changes played an important role in the success of the service by rapidly feeding back issues for adjustment. Visibility to staff of positive impacts on patient care is important in maintaining morale., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Prosthetic joint infection (PJI) causes significant morbidity and mortality following knee replacement surgery. Identifying causative organisms and antibiotic sensitivities is critical in increasing the chance of infection eradication. This study investigated whether biopsy alone was superior to aspiration alone for serological diagnosis in PJI following knee replacement. Secondly, we investigated whether biopsy identifies the same or new/different microbiological flora as aspiration., Methods: Since December 2014, the Exeter Knee Reconstruction Unit (EKRU) has prospectively collated data regarding all PJIs referred from our local/regional network which have been reviewed via our Multi-Disciplinary Team (MDT). We identified and included consecutive patients from this MDT from Dec.2014-Mar.2020 and analysed their electronic records. Statistical analysis was performed using Stata., Results: 65/100 patients studied had both pre-operative aspiration and biopsy. 31/65 (48%) had positive aspiration and biopsies. No aspirate samples were positive with corresponding biopsies negative. In 19/65 (29%) of infection positive patients, biopsy identified new (7) or additional (12) organisms not identified by aspiration. Aspiration had a sensitivity of 70%, specificity of 88%, positive predictive value of 90.3% and negative predictive value of 64.7%. Biopsy had a sensitivity of 97.5%, specificity of 88%, positive predictive value of 92.9% and negative predictive value of 95.7%., Conclusion: In 29% of confirmed PJI cases, arthroscopic biopsy identified either additional organisms in a polymicrobial PJI when compared to aspiration, or new positive results when aspiration alone was negative. This study demonstrates the benefits of arthroscopic biopsy for serological diagnosis in cases of knee PJI and aids treatment planning., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Limb-threatening sarcomas invading major vessels present an oncological and reconstructive challenge. Curative resection involves either performing an amputation or an immediate reconstruction of the invaded vessels. We present our 15-year experience of these cases at the North of England Bone and Soft Tissue Tumour Service., Materials and Methods: A Strengthening the Reporting of Observational studies in Epidemiology (STROBE) compliant retrospective review of our prospective database was performed including patients who required major vessel reconstruction following sarcoma excision from 2003 until 2018. Patient demographic data along with tumour and histological subtypes, treatment modality, complications and outcomes were inquired. Autologous and prosthetic vessel reconstruction approaches were compared., Results: Nineteen patients were identified with the most common tumour locations being the thigh and groin areas. Five cases involved recurrent tumours. Clear resection margins were obtained in 15 cases. Autologous vein grafts were preferred over polytetrafluoroethylene (PTFE) prosthesis in 17 cases. A pedicled flap or free flap was required to achieve adequate soft tissue cover in six patients, while the rest underwent primary closure. Five patients lost the patency of the reconstructed vessels with one of these requiring an amputation. The estimated disease-specific survival at 5 years was 58%., Discussion: Limb-preservation surgery in the context of vessel compromise is not only safe, but also a functionally and psychosocially beneficial means of avoiding an amputation. We believe that careful pre-operative planning and discussion in a multidisciplinary setting is key for obtaining positive outcomes., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

An interlaboratory study was conducted through the Vitamin D Standardization Program (VDSP) to assess commutability of Standard Reference Materials® (SRMs) and proficiency testing/external quality assessment (PT/EQA) samples for determination of serum total 25-hydroxyvitamin D [25(OH)D] using ligand binding assays and liquid chromatography-tandem mass spectrometry (LC-MS/MS). A set of 50 single-donor serum samples were assigned target values for 25-hydroxyvitamin D 2 [25(OH)D 2 ] and 25-hydroxyvitamin D 3 [25(OH)D 3 ] using reference measurement procedures (RMPs). SRM and PT/EQA samples evaluated included SRM 972a (four levels), SRM 2973, six College of American Pathologists (CAP) Accuracy-Based Vitamin D (ABVD) samples, and nine Vitamin D External Quality Assessment Scheme (DEQAS) samples. Results were received from 28 different laboratories using 20 ligand binding assays and 14 LC-MS/MS methods. Using the test assay results for total serum 25(OH)D (i.e., the sum of 25(OH)D 2 and 25(OH)D 3 ) determined for the single-donor samples and the RMP target values, the linear regression and 95% prediction intervals (PIs) were calculated. Using a subset of 42 samples that had concentrations of 25(OH)D 2 below 30 nmol/L, one or more of the SRM and PT/EQA samples with high concentrations of 25(OH)D 2 were deemed non-commutable using 5 of 11 unique ligand binding assays. SRM 972a (level 4), which has high exogenous concentration of 3-epi-25(OH)D 3 , was deemed non-commutable for 50% of the LC-MS/MS assays., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Objective: To determine the prevalence of vitamin D deficiency in Indonesian children hospitalized with pneumonia and evaluate the association between vitamin D status and severity of pneumonia., Methods: A hospital-based cross-sectional study was conducted from February 2016 to July 2017 in two district hospitals in Yogyakarta province, Indonesia. Infants and young children aged 2-59 months hospitalized with pneumonia were recruited. Serum blood samples were collected on admission and analyzed for total serum 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2 concentrations using liquid chromatography-tandem mass spectrometry. Vitamin D deficiency was defined as a level of serum vitamin D <50 nmol/L. The association between vitamin D deficiency and severity of hospitalized pneumonia according to WHO criteria, including the presence of danger signs, hypoxemia (SpO2 in air below 90%), duration of hospitalization, and admission to Intensive Care Unit (ICU), was analyzed using logistic regression., Results: 133 children with WHO-defined pneumonia were enrolled in the study and 127 (96%) had their vitamin D status determined. The mean vitamin D concentration was 67 (± 24 SD) nmol/L and 19% of participants were vitamin D deficient. Age younger than 6 months was associated with prolonged hospitalization (> 5 days) and low birth weight and poor nutritional status on admission were risk factors for hypoxemia. However, vitamin D status was not associated with the presence of danger signs, duration of hospitalization, or hypoxemia., Conclusions: One in every five children hospitalized with pneumonia was vitamin D deficient. Vitamin D status was not associated with the severity of pneumonia., Competing Interests: The authors have declared that no competing interests exist.