Clinical Implications of a Formulary Conversion From Budesonide/formoterol to Fluticasone/salmeterol at a VA Medical Center.

Background: Chronic obstructive pulmonary disease (COPD) is a respiratory disorder associated with chronic and slowly progressive systemic inflammation. The Global Initiative for Chronic Obstructive Lung Disease recommends a combination inhaler of a long-acting ß-2 agonist and inhaled corticosteroid for patients with a history of frequent exacerbations. In 2021, the US Department of Veterans Affairs transitioned patients who were prescribed budesonide/formoterol inhaler to a fluticasone/salmeterol inhaler. Methods: The primary objective of this study was to compare clinical outcomes including COPD exacerbations and hospitalizations 6 months before vs 6 months after the inhaler transition. Secondary outcomes included adverse effects, treatment failure, tobacco use, and antimicrobial/systemic corticosteroid use. A retrospective chart review was conducted on patients with a prescription for a budesonide/formoterol or fluticasone/salmeterol inhalers between February 1, 2021, and May 30, 2022, at the Hershel "Woody" Williams Veterans Affairs Medical Center, Huntington, West Virginia. Results: In a convenience sample of 100 patients who transitioned from the budesonide/formoterol inhaler to the fluticasone/salmeterol inhaler, exacerbations increased from 24 before the transition to 29 after the transition, which was not a statistically significant change (P = .56). There were no statistically significant differences in the secondary endpoints including active tobacco use. Three patients had adverse reactions to fluticasone/salmeterol, while 18 patients experienced a therapeutic failure to fluticasone/salmeterol. Conclusions: Patients with COPD that transitioned from budesonide/formoterol to fluticasone/salmeterol during the formulary conversion yield no clinical or statistically significant change in their clinical outcomes. Switching between these inhalers in the same therapeutic class may not impact clinical efficacy of the therapy for veterans with COPD but some intolerances and treatment failures should be expected.

Irritability in young people with copy number variants associated with neurodevelopmental disorders (ND-CNVs).

A range of rare mutations involving micro-deletion or -duplication of genetic material (copy number variants (CNVs)) have been associated with high neurodevelopmental and psychiatric risk (ND-CNVs). Irritability is frequently observed in childhood neurodevelopmental conditions, yet its aetiology is largely unknown. Genetic variation may play a role, but there is a sparsity of studies investigating the presentation of irritability in young people with ND-CNVs. This study aimed to investigate whether there is a difference in irritability in young people with rare ND-CNVs compared to those without ND-CNVs, and to what extent irritability is associated with psychiatric diagnoses and cognitive ability (IQ). Irritability and broader psychopathology were assessed in 485 young people with ND-CNVs and 164 sibling controls, using the child and adolescent psychiatric assessment. Autism was assessed using the social communication questionnaire, and intelligence quotient (IQ) by the Wechsler abbreviated scale of intelligence. Fifty four percent of young people with ND-CNVs met the threshold for irritability; significantly more than controls (OR = 3.77, CI = 3.07-7.90, p = 5.31 × 10-11). When controlling for the presence of other psychiatric comorbidities, ND-CNV status was still associated with irritability. There was no evidence for a relationship between irritability and IQ. Irritability is an important aspect of the clinical picture in young people with ND-CNVs. This work shows that genetic variation is associated with irritability in young people with ND-CNVs, independent of psychiatric comorbidities or IQ impairment. Clinicians should be aware of this increased risk to inform management and interventions.

Experiences and concerns of parents of children with a 16p11.2 deletion or duplication diagnosis: a reflexive thematic analysis.

BACKGROUND: 16p11.2 proximal deletion and duplication syndromes (Break points 4-5) (593KB, Chr16; 29.6-30.2mb - HG38) are observed to have highly varied phenotypes, with a known propensity for lifelong psychiatric problems. This study aimed to contribute to a research gap by qualitatively exploring the challenges families with 16p11.2 deletion and duplication face by answering three research questions: (1) What are parents' perceptions of the ongoing support needs of families with children who have 16p11.2 living in the UK?; (2) What are their experiences in trying to access support?; (3) In these regards, do the experiences of parents of children with duplication converge or vary from those of parents of children with 16p11.2 deletion? METHODS: 33 parents with children (aged 7-17 years) with 16p11.2 deletion or duplication participated in structured interviews, including the Autism Diagnostic Interview- Revised (ADI-R). Their answers to the ADI-R question 'what are your current concerns' were transcribed and subsequently analysed using Braun and Clarke's six step reflexive thematic analysis framework. RESULTS: Three themes were identified: (1) Child is Behind Peers (subthemes: developmentally; academically; socially; emotionally); (2) Metabolism and Eating Patterns and; (3) Support (subthemes: insufficient support available; parent has to fight to access support; COVID-19 was a barrier to accessing support; 16p11.2 diagnosis can be a barrier to support, child is well-supported). CONCLUSIONS: Parents of children with either 16p11.2 deletion or duplication shared similar experiences. However, metabolism concerns were specific to parents of children with 16p11.2 deletion. The theme Child is Behind Peers echoed concerns raised in previous Neurodevelopmental Copy Number Variant research. However, there were some key subthemes relating to research question (2) which were specific to this study. This included parents' descriptions of diagnostic overshadowing and the impact of a lack of eponymous name and scant awareness of 16p11.2.

Less Versus More: The Effect of Recast Length in Treatment of Grammatical Errors.

PURPOSE: Although conversational recast treatment is generally efficacious, there are many ways in which the individual components of the treatment can be delivered. Some of these are known to enhance treatment, others appear to interfere with learning, and still others appear to have no impact at all. This study tests the potential effect of clinicians' recast length on child learning during a recast treatment. METHOD: Twenty-six preschool children were treated for grammatical errors using Enhanced Conversational Recast Treatment. Half heard recasts of four or fewer words (Short Recast condition), and half heard recasts of five or more words (Extended Recast condition). Outcome measures included generalization of the treated grammatical form, spontaneous use of these forms, change in mean length of utterances in words, and the number of children in each condition who showed a clinically meaningful response. RESULTS: There was strong evidence of improvements in the use of grammatical forms targeted by the treatment compared with forms that were tracked but not treated. Twenty children (11 in the Short Recast condition and nine in the Extended Recast condition) showed a clinically meaningful response. There was minimal support for the hypothesis that the length of clinician utterance influenced either progress on a grammatical form targeted by the treatment or on the child's mean length of utterance in words. CONCLUSIONS: The study adds to the evidence for the efficacy of Enhanced Conversational Recast Treatment. However, there is little evidence that clinicians need to regulate the length of the recast they provide to children. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24653613.

Irritability in young people with copy number variants associated with neurodevelopmental disorders (ND-CNVs).

Background: A range of rare mutations involving micro-deletion or -duplication of genetic material (copy number variants (CNVs)) have been associated with high neurodevelopmental and psychiatric risk (ND-CNVs). Irritability is frequently observed in childhood neurodevelopmental conditions, yet its aetiology is largely unknown. Genetic variation may play a role, but there is a sparsity of studies investigating presentation of irritability in young people with ND-CNVs. Aims: This study aimed to investigate whether there is a difference in irritability in young people with rare ND-CNVs compared to those without ND-CNVs, and to what extent irritability is associated with psychiatric diagnoses and cognitive ability (IQ). Methods: Irritability and broader psychopathology was assessed in 485 young people with ND-CNVs and 164 sibling controls, using the child and adolescent psychiatric assessment (CAPA). Autism was assessed using the Social Communication Questionnaire (SCQ), and Intelligence Quotient (IQ) by the Wechsler Abbreviated Scale of Intelligence (WASI). Results: 54% of young people with ND-CNVs met the threshold for irritability; significantly more than controls (OR = 3.77, CI = 3.07-7.90, p= 5.31 × 10-11). When controlling for the presence of other psychiatric comorbidities, ND-CNV status was still associated with irritability. There was no evidence for a relationship between irritability and IQ. Conclusions: Irritability is an important aspect of the clinical picture in young people with ND-CNVs. This work shows that genetic variation is associated with irritability in young people with ND-CNVs, independent of psychiatric comorbidities or IQ impairment. Clinicians should be aware of this increased risk to inform management and interventions.

Ancient diversity in host-parasite interaction genes in a model parasitic nematode.

Host-parasite interactions exert strong selection pressures on the genomes of both host and parasite. These interactions can lead to negative frequency-dependent selection, a form of balancing selection that is hypothesised to explain the high levels of polymorphism seen in many host immune and parasite antigen loci. Here, we sequence the genomes of several individuals of Heligmosomoides bakeri, a model parasite of house mice, and Heligmosomoides polygyrus, a closely related parasite of wood mice. Although H. bakeri is commonly referred to as H. polygyrus in the literature, their genomes show levels of divergence that are consistent with at least a million years of independent evolution. The genomes of both species contain hyper-divergent haplotypes that are enriched for proteins that interact with the host immune response. Many of these haplotypes originated prior to the divergence between H. bakeri and H. polygyrus, suggesting that they have been maintained by long-term balancing selection. Together, our results suggest that the selection pressures exerted by the host immune response have played a key role in shaping patterns of genetic diversity in the genomes of parasitic nematodes.

Borrelia bavariensis in Questing Ixodes ricinus Ticks, United Kingdom.

We detected Borrelia bavariensis in Ixodes ricinus ticks collected near 2 towns in the United Kingdom. Human B. bavariensis infections have not been reported previously in the country, underscoring the value of tick surveillance to warn of emerging human disease. B. bavariensis should be considered in patients with suspected neuroborreliosis.

In vivo evidence of microstructural hypo-connectivity of brain white matter in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome, or 22q11.2DS, is a genetic syndrome associated with high rates of schizophrenia and autism spectrum disorders, in addition to widespread structural and functional abnormalities throughout the brain. Experimental animal models have identified neuronal connectivity deficits, e.g., decreased axonal length and complexity of axonal branching, as a primary mechanism underlying atypical brain development in 22q11.2DS. However, it is still unclear whether deficits in axonal morphology can also be observed in people with 22q11.2DS. Here, we provide an unparalleled in vivo characterization of white matter microstructure in participants with 22q11.2DS (12-15 years) and those undergoing typical development (8-18 years) using a customized magnetic resonance imaging scanner which is sensitive to axonal morphology. A rich array of diffusion MRI metrics are extracted to present microstructural profiles of typical and atypical white matter development, and provide new evidence of connectivity differences in individuals with 22q11.2DS. A recent, large-scale consortium study of 22q11.2DS identified higher diffusion anisotropy and reduced overall diffusion mobility of water as hallmark microstructural alterations of white matter in individuals across a wide age range (6-52 years). We observed similar findings across the white matter tracts included in this study, in addition to identifying deficits in axonal morphology. This, in combination with reduced tract volume measurements, supports the hypothesis that abnormal microstructural connectivity in 22q11.2DS may be mediated by densely packed axons with disproportionately small diameters. Our findings provide insight into the in vivo white matter phenotype of 22q11.2DS, and promote the continued investigation of shared features in neurodevelopmental and psychiatric disorders.

Practice patterns in the management of pediatric iliofemoral arterial thrombosis.

BACKGROUND: Acute arterial thrombosis can be life- and limb-threatening. Most pediatric patients with iliofemoral arterial thrombosis are treated successfully with medical therapy; however, expert consensus is limited, and many recommendations are based on the extrapolation of adult data. We aim to understand treatment patterns and long-term outcomes after pediatric acute iliofemoral arterial thrombosis, from which management recommendations can be informed. METHODS: A single-institution retrospective study of pediatric patients diagnosed with iliofemoral arterial thrombosis from 2009 to 2018 was performed. Multiple parameters of management and follow-up were evaluated. Children anticoagulated for ≤28 days versus >28 days were compared. Data analysis used Fisher exact and Mann-Whitney U tests. RESULTS: Two hundred thirty-six children were included. Median age at diagnosis was 65 days (interquartile range 17-163), with 207 diagnosed as infants, 15 diagnosed between 1 to 2 years, and 14 diagnosed between 2 to 16 years. The median treatment duration was 28 days (interquartile range 13-42); patients treated for >28 days had a longer time for thrombus resolution, and more follow-up ultrasounds were performed. Limb length discrepancy did not differ between the groups (1.0% vs 6.3%, P = .06), and no patients were documented to have developed peripheral arterial disease over a median 6.5-year follow-up. Multiple treatment strategies were employed, the most common being heparin bridged to enoxaparin (25.0%) and enoxaparin monotherapy (21.6%). Eight patients (3.4%) underwent surgical intervention. CONCLUSION: Pediatric iliofemoral arterial thrombosis is primarily a disease of infants treated adequately with heparin or enoxaparin, infrequently requires surgical intervention, and is rarely associated with long-term complications. When guided by thrombus resolution on ultrasound, a four-week or shorter course of anticoagulation does not increase the need for surgical intervention or long-term complications.

Complex working memory in adults with and without stuttering disorders: Performance patterns and predictive relationships.

PURPOSE: Available studies of working memory (WM) in speakers who stutter tend to rely on parent report, focus on phonological WM, or measure WM in combination with other processes. The present research aimed to: (1) compare complex WM in adults who stutter (AWS) and adults who do not stutter (AWNS); (2) characterize group performance patterns; and (2) determine whether WM predicts stuttering severity. METHODS: Eighteen AWS and 20 AWNS completed parallel verbal and spatial span tasks in which to-be-remembered items were interleaved with a distracting task across varying set sizes. Dependent variables included the number of correctly recalled items, accuracy on distraction tasks, and detailed analyses of item-level responses. We further examined whether span scores predicted subjective and objective measures of stuttering severity. RESULTS: Relative to AWNS, AWS showed poorer recall, specifically on short set sizes in the spatial task. Groups performed similarly on distraction tasks and showed comparable error patterns. Predictive relationships differed by span task and severity measure. Lower verbal span scores predicted greater stuttering impact and more overt stuttering behaviors; lower spatial span scores predicted lower impact and was unrelated to overt behaviors. CONCLUSIONS: Findings suggest that AWS differ subtly from AWNS in WM performance. Group differences became more apparent under certain task conditions but could not be attributed to specific underlying processes. Data further indicated a complex relationship between WM and stuttering severity. Overall, results corroborate previous studies linking stuttering to domain-general weaknesses, but highlight the need for additional research to clarify the nature of this relationship.

Semantic Aspects of Verb Production in Various Discourse Tasks in People With Nonfluent Aphasia.

PURPOSE: The purpose of this study was to investigate how people with nonfluent aphasia produce semantically weighted verbs compared to people without aphasia, as well as how a discourse elicitation task affects verb production in people with nonfluent aphasia and people without aphasia. METHOD: This study included 30 people with nonfluent aphasia and 32 age-matched people without aphasia from AphasiaBank. Language samples of five different discourse tasks were obtained and coded for heavy, light, and be-copular verbs. The number of verbs per utterance and the proportion of heavy, light, and be-copular verbs were compared between groups and between tasks. RESULTS: People with nonfluent aphasia showed a similar proportion of heavy verbs but reduced verbs per utterance and proportion of light verbs compared to people without aphasia. With regard to discourse task effects, we found a trend for a higher proportion of heavy verbs in sequential picture descriptions, and a higher proportion of be-copular verbs and lower proportion of heavy verbs for a recount compared to other tasks in people without aphasia. The discourse task effects were minimally found in people with nonfluent aphasia. CONCLUSIONS: Our results suggest that people with nonfluent aphasia present with relatively preserved heavy verb production but with impaired production of light verbs in discourse. In addition, it appears that discourse tasks do not significantly influence the type of verbs produced by people with nonfluent aphasia possibly due to the floor effects and wide range of individual variability. This study is a preliminary effort to evaluate methodological factors that impact verb production; future studies are needed to develop a framework for clinical decision making when selecting a discourse elicitation task for people with aphasia.

Neurocognitive Profiles of 22q11.2 and 16p11.2 Deletions and Duplications.

Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are among the most common rare genetic disorders associated with significant risk for neuropsychiatric disorders across the lifespan. Microdeletions and duplications in these loci are associated with neurocognitive deficits, yet there are few studies comparing these groups using the same measures. We address this gap in a prospective international collaboration applying the same computerized neurocognitive assessment. The Penn Computerized Neurocognitive Battery (CNB) was administered in a multi-site study on rare genomic disorders: 22q11.2 deletion (n = 397); 22q11.2 duplication (n = 77); 16p11.2 deletion (n = 94); and 16p11.2 duplication (n = 26). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and sensori-motor speed. Accuracy and speed for each neurocognitive domain were included as dependent measures in a mixed-model repeated measures analysis, with locus (22q11.2, 16p11.2) and copy number (deletion/duplication) as grouping factors and neurocognitive domain as a repeated measures factor, with age and sex as covariates. We also examined correlation with IQ and site effects. We found that 22q11.2 deletions were associated with greater deficits in overall performance accuracy than 22q11.2 duplications, while 16p11.2 duplications were associated with greater deficits than 16p11.2 deletions. Duplications at both loci were associated with reduced speed. Performance profiles differed among the groups with particularly poor performance of 16p11.2 duplication on non-verbal reasoning and social cognition. Average accuracy on the CNB was moderately correlated with Full Scale IQ. No site effects were observed. Deletions and duplications of 22q11.2 and 16p11.2 have varied effects on neurocognition indicating locus specificity, with performance profiles differing among the groups. These profile differences can help inform mechanistic substrates to heterogeneity in presentation and outcome. Future studies could aim to link performance profiles to clinical features and brain function.

Sleep EEG in young people with 22q11.2 deletion syndrome: A cross-sectional study of slow-waves, spindles and correlations with memory and neurodevelopmental symptoms.

Background: Young people living with 22q11.2 Deletion Syndrome (22q11.2DS) are at increased risk of schizophrenia, intellectual disability, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In common with these conditions, 22q11.2DS is also associated with sleep problems. We investigated whether abnormal sleep or sleep-dependent network activity in 22q11.2DS reflects convergent, early signatures of neural circuit disruption also evident in associated neurodevelopmental conditions. Methods: In a cross-sectional design, we recorded high-density sleep EEG in young people (6-20 years) with 22q11.2DS (n=28) and their unaffected siblings (n=17), quantifying associations between sleep architecture, EEG oscillations (spindles and slow waves) and psychiatric symptoms. We also measured performance on a memory task before and after sleep. Results: 22q11.2DS was associated with significant alterations in sleep architecture, including a greater proportion of N3 sleep and lower proportions of N1 and REM sleep than in siblings. During sleep, deletion carriers showed broadband increases in EEG power with increased slow-wave and spindle amplitudes, increased spindle frequency and density, and stronger coupling between spindles and slow-waves. Spindle and slow-wave amplitudes correlated positively with overnight memory in controls, but negatively in 22q11.2DS. Mediation analyses indicated that genotype effects on anxiety, ADHD and ASD were partially mediated by sleep EEG measures. Conclusions: This study provides a detailed description of sleep neurophysiology in 22q11.2DS, highlighting alterations in EEG signatures of sleep which have been previously linked to neurodevelopment, some of which were associated with psychiatric symptoms. Sleep EEG features may therefore reflect delayed or compromised neurodevelopmental processes in 22q11.2DS, which could inform our understanding of the neurobiology of this condition and be biomarkers for neuropsychiatric disorders. Funding: This research was funded by a Lilly Innovation Fellowship Award (UB), the National Institute of Mental Health (NIMH 5UO1MH101724; MvdB), a Wellcome Trust Institutional Strategic Support Fund (ISSF) award (MvdB), the Waterloo Foundation (918-1234; MvdB), the Baily Thomas Charitable Fund (2315/1; MvdB), MRC grant Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment (IMAGINE) (MR/L011166/1; JH, MvdB and MO), MRC grant Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment 2 (IMAGINE-2) (MR/T033045/1; MvdB, JH and MO); Wellcome Trust Strategic Award 'Defining Endophenotypes From Integrated Neurosciences' Wellcome Trust (100202/Z/12/Z MO, JH). NAD was supported by a National Institute for Health Research Academic Clinical Fellowship in Mental Health and MWJ by a Wellcome Trust Senior Research Fellowship in Basic Biomedical Science (202810/Z/16/Z). CE and HAM were supported by Medical Research Council Doctoral Training Grants (C.B.E. 1644194, H.A.M MR/K501347/1). HMM and UB were employed by Eli Lilly & Co during the study; HMM is currently an employee of Boehringer Ingelheim Pharma GmbH & Co KG. The views and opinions expressed are those of the author(s), and not necessarily those of the NHS, the NIHR or the Department of Health funders.

Ticks on wild boar in the metropolitan area of Barcelona (Spain) are infected with spotted fever group rickettsiae.

Tick-borne pathogens (TBPs) constitute an emerging public health concern favoured by multidimensional global changes. Amongst these, increase and spread of wild boar (Sus scrofa) populations are of special concern since this species can act as a reservoir of zoonotic pathogens and promote tick abundance. Thus, we aimed to make a first assessment of the risk by TBPs resulting from wild boar and ticks in the vicinity of a highly populated area. Between 2014 and 2016, we collected spleen samples and 2256 ticks from 261 wild boars (out of 438 inspected) in the metropolitan area of Barcelona (MAB; northeast Spain). We morphologically identified four tick species: Hyalomma lusitanicum (infestation prevalence: 33.6%), Dermacentor marginatus (26.9%), Rhipicephalus sanguineus sensu lato (18.9%) and R. bursa (0.2%). Ticks were pooled according to species and individual host. A total of 180 tick pools and 167 spleen samples were screened by real-time PCR and/or reverse line blot hybridization assay for Ehrlichia sp., Anaplasma sp., Babesia sp., Rickettsia sp., Borrelia burgdorferi sensu lato and Coxiella burnetii. Seventy-two out of the 180 tick pools were positive to Rickettsia spp. (minimum prevalence of 8.7%), including Rickettsia massiliae, R. slovaca and R. raoultii. We did not detect Rickettsia spp. in wild boar spleens nor other TBPs in ticks or wild boars. Since the ticks identified can bite humans, and the recorded spotted fever group (SFG) rickettsiae are zoonotic pathogens, there is a risk of SFG rickettsiae transmission for MAB inhabitants. Our results suggest a broader distribution of H. lusitanicum, competent vector for the Crimean-Congo haemorrhagic fever virus than previously known. Wild boar is not a Rickettsia spp. reservoir according to the spleen negative results. However, its abundance could favour tick life cycle and abundance, and its proximity to humans could promote the infection risk by Rickettsia spp.

Increasing compliance with alcohol service laws in community sporting clubs in Australia.

INTRODUCTION: Many community sporting clubs in Australia sell alcohol, but many do not comply with laws that require verification of age and forbid underage alcohol sales. This study aimed to assess the effectiveness of an intervention that incorporated sales monitoring and community awareness raising to improve compliance with alcohol service regulations in community sporting clubs. METHODS: Non-randomised community trial in 'matched' intervention and comparison communities. A total of 50 sporting clubs from two metropolitan and two regional areas in Victoria, Australia, were selected, and baseline and follow-up purchase observations completed during 2018. Youth who looked underage were monitored as they attempted to purchase alcohol. Intervention clubs received feedback letters regarding staff sales behaviour. Other intervention actions included building awareness of underage supply of alcohol and media coverage of baseline observations. RESULTS: Observations were completed at 46 clubs (intervention = 24; comparison = 22) at baseline and 39 (intervention = 24; comparison = 15) at follow up. Compliance was low but improved at follow up for both groups for age verification (intervention +12.5%; comparison +8.5%) and non-supply of alcohol (intervention +12.5%; comparison +10.6%); but no significant intervention effects were found. DISCUSSION AND CONCLUSIONS: Findings indicated low compliance with age verification checks and underage alcohol sales laws at baseline. Promising improvements in compliance were observed at follow up; however, 'spillover' of intervention activities may have compromised ability to detect significant intervention effects. Further intervention effort and evaluation is recommended to encourage alcohol sales compliance in community sporting clubs.

A qualitative study of sedentary behaviours in stroke survivors: non-participant observations and interviews with stroke service staff in stroke units and community services.

PURPOSE: Sedentary behaviour (SB) is associated with negative health outcomes and is prevalent post-stroke. This study explored SB after stroke from the perspective of stroke service staff. METHODS: Qualitative mixed-methods study. Non-participant observations in two stroke services (England/Scotland) and semi-structured interviews with staff underpinned by the COM-B model of behaviour change. Observations were analysed thematically; interviews were analysed using the Framework approach. RESULTS: One hundred and thirty-two observation hours (October - December 2017), and 31 staff interviewed (January -June 2018). Four themes were identified: (1) Opportunities for staff to support stroke survivors to reduce SB; (2) Physical and psychological capability of staff to support stroke survivors to reduce SB; (3) Motivating factors influencing staff behaviour to support stroke survivors to reduce SB; (4) Staff suggestions for a future intervention to support stroke survivors to reduce SB. CONCLUSIONS: Staff are aware of the consequences of prolonged sitting but did not relate to SB. Explicit knowledge of SB was limited. Staff need training to support stroke survivors to reduce SB. Sedentary behaviour in the community was not reported to change markedly, highlighting the need to engage stroke survivors in movement from when capable in hospital, following through to home.Implications for rehabilitationStroke survivor sedentary behaviour is influenced, directly and indirectly, by the actions and instructions of stroke service staff in the inpatient and community setting.The built and social environment, both in the inpatient and community settings, may limit opportunities for safe movement and can result in stroke survivors spending more time sedentary.Stroke service staff appreciate the benefit of encouraging stroke survivors to stand and move more, if it is safe for them to do so.Staff would be amenable to encourage stroke survivors to reduce sedentary behaviour, provided they have the knowledge and resources to equip them to support this.

Triple Targeting of Breast Tumors Driven by Hormonal Receptors and HER2.

Breast cancers that express hormonal receptors (HR) and HER2 display resistance to targeted therapy. Tumor-promotional signaling from the HER2 and estrogen receptor (ER) pathways converges at the cyclin D1 and cyclin-dependent kinases (CDK) 4 and 6 complex, which drives cell-cycle progression and development of therapeutic resistance. Therefore, we hypothesized that co-targeting of ER, HER2, and CDK4/6 may result in improved tumoricidal activity and suppress drug-resistant subclones that arise on therapy. We tested the activity of the triple targeted combination therapy with tucatinib (HER2 small-molecule inhibitor), palbociclib (CKD4/6 inhibitor), and fulvestrant (selective ER degrader) in HR+/HER2+ human breast tumor cell lines and xenograft models. In addition, we evaluated whether triple targeted combination prevents growth of tucatinib or palbociclib-resistant subclones in vitro and in vivo Triple targeted combination significantly reduced HR+/HER2+ tumor cell viability, clonogenic survival, and in vivo growth. Moreover, survival of HR+/HER2+ cells that were resistant to the third drug in the regimen was reduced by the other two drugs in combination. We propose that a targeted triple combination approach will be clinically effective in the treatment of otherwise drug-resistant tumors, inducing robust responses in patients.

Differential reward in "male" versus "female" pollen of functionally dioecious Solanum.

PREMISE: Five to six percent of angiosperm species exhibit a dioecious sexual system, with unisexual "male" or "female" flowers borne on separate plants. The consequent need for inter-individual pollen exchange is a special challenge for taxa where pollen is the sole pollinator reward. Dioecious Australian Solanum assure visits from pollen-foraging bees via production of inaperturate pollen in functionally female (morphologically bisexual) flowers. Biochemical composition of pollen from Australian Solanum has not been assessed nor compared to porate pollen from staminate flowers to reveal whether these flowers differ in their pollinator reward potential. METHODS: Porate pollen from male flowers and inaperturate pollen from functionally female flowers of two functionally dioecious Australian species were compared for protein and amino acid content. We also assessed pollen from bisexual and staminate flowers of a closely related andromonoecious species, in which all pollen is porate, as a comparison across co-occurring sexual systems. RESULTS: In both functionally dioecious species, porate pollen grains from staminate flowers had significantly higher levels of proteins and amino acids than inaperturate pollen grains from functionally female flowers. Levels of proteins and amino acids were highest in bisexual and staminate flowers of the andromonoecious species. CONCLUSIONS: Higher levels of proteins and amino acids in porate pollen of "male" flowers in our functionally dioecious Solanum species suggests a greater nutritive reward for bees foraging on "male" plants than for those foraging on functionally "female" plants. Greater reward in porate pollen (including andromonoecious species) may be connected to the potential to generate a pollen tube.