"It helps and it doesn't help": maternal perspectives on how the use of smartphones and tablet computers influences parent-infant attachment.

As families increase their use of mobile touch screen devices (smartphones and tablet computers), there is potential for this use to influence parent-child interactions required to form a secure attachment during infancy, and thus future child developmental outcomes. Thirty families of infants (aged 9-15 months) were interviewed to explore how parents and infants use these devices, and how device use influenced parents' thoughts, feelings and behaviours towards their infant and other family interactions. Two-thirds of infants were routinely involved in family video calls and one-third used devices for other purposes. Parent and/or child device use served to both enhance connection and increase distraction between parents and infants and between other family members. Mechanisms for these influences are discussed. The findings highlight a new opportunity for how hardware and software should be designed and used to maximise benefits and reduce detriments of device use to optimise parent-infant attachment and child development.Practitioner Summary: Many families with infants regularly use smartphones and tablet computers. This qualitative study found that how devices were used either enhanced or disrupted feelings of parent-infant attachment. Practitioners should be aware of the potential beneficial and detrimental impacts of device use among families given implications for attachment and future child development.

Leakage beyond the primary lesion: A temporal analysis of cerebrovascular dysregulation at sites of hippocampal secondary neurodegeneration following cortical photothrombotic stroke.

We have previously demonstrated that a cortical stroke causes persistent impairment of hippocampal-dependent cognitive tasks concomitant with secondary neurodegenerative processes such as amyloid-ß accumulation in the hippocampus, a region remote from the primary infarct. Interestingly, there is emerging evidence suggesting that deposition of amyloid-ß around cerebral vessels may lead to cerebrovascular structural changes, neurovascular dysfunction, and disruption of blood-brain barrier integrity. However, there is limited knowledge about the temporal changes of hippocampal cerebrovasculature after cortical stroke. In the current study, we aimed to characterise the spatiotemporal cerebrovascular changes after cortical stroke. This was done using the photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Cerebrovascular morphology as well as the co-localisation of amyloid-ß with vasculature and blood-brain barrier integrity were assessed in the cortex and hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed transient cerebrovascular remodelling in the peri-infarct area up to 28 days post-stroke. Importantly, the cerebrovascular changes were extended beyond the peri-infarct region to the ipsilateral hippocampus and were sustained out to 84 days post-stroke. When investigating vessel diameter, we showed a decrease at 84 days in the peri-infarct and CA1 regions that were exacerbated in vessels with amyloid-ß deposition. Lastly, we showed sustained vascular leakage in the peri-infarct and ipsilateral hippocampus, indicative of a compromised blood-brain-barrier. Our findings indicate that hippocampal vasculature may represent an important therapeutic target to mitigate the progression of post-stroke cognitive impairment.

Blood pressure variability is associated with Infarct Growth in Acute Ischemic Stroke.

Introduction Evidence based blood pressure (BP) targets in acute ischemic stroke are lacking. Previous observational studies have focused on single baseline BP and clinical outcomes, without consideration for dynamic changes. We aim to determine the association between BP parameters including variability, peak, nadir, median and mean during stroke and infarct growth (primary outcome), risk of haemorrhagic transformation and functional outcome (secondary outcomes). Methods Suspected stroke patients were prospectively recruited from a single comprehensive stroke centre. Multimodal computed tomography imaging was used to define infarct core. BP was recorded as per national stroke guidelines during the initial 24-hours. Infarct growth and evidence of parenchymal haemorrhage were determined by follow-up magnetic resonance imaging at 24 hours. Functional outcome at 3-months was assessed using the modified Rankin Scale. Subgroup analysis was performed according to stroke etiology and treatment for the association between BP, infarct volume growth and risk of hemorrhagic transformation. The association between BP parameters and outcomes were determined using regression modelling. Results A total of 229 patients were included in this study. The median age was 67.4, 64.4% were male and the baseline National Institutes of Health Stroke Scale was 8. Blood pressure variability (BPV) was independently associated with increased infarct growth (multivariate coefficient 1.60, 95% CI 0.27-2.94, P=0.019) and an increased odds of parenchymal haemorrhage (adjusted OR 1.21, 95% CI 1.02-1.44, P= 0.028). The odds of a favourable outcome at 90 days were inversely associated with BPV on simple, but not adjusted logistic regression. On subgroup analysis, only in patients with large vessel occlusions undergoing endovascular clot retrieval was BPV associated with infarct growth (multivariate adjusted coefficient 2.62, 95% CI 0.53-4.70, P=0.014) and an increased odds of hemorrhagic transformation (adjusted OR 1.26, 95% CI 1.01-1.57, P=0.045). Conclusions: An increase in BPV was associated with infarct expansion, increased risk of haemorrhagic transformation, and was negatively associated with favourable functional outcomes at 3-months.

Clopidogrel Administration Impairs Post-Stroke Learning and Memory Recovery in Mice.

Clopidogrel, which is one of the most prescribed antiplatelet medications in the world, is given to stroke survivors for the prevention of secondary cardiovascular events. Clopidogrel exerts its antiplatelet activity via antagonism of the P2Y12 receptor (P2RY12). Although not widely known or considered during the initial clinical trials for clopidogrel, P2RY12 is also expressed on microglia, which are the brain's immune cells, where the receptor facilitates chemotactic migration toward sites of cellular damage. If microglial P2RY12 is blocked, microglia lose the ability to migrate to damaged sites and carry out essential repair processes. We aimed to investigate whether administering clopidogrel to mice post-stroke was associated with (i) impaired motor skills and cognitive recovery; (ii) physiological changes, such as survival rate and body weight; (iii) changes in the neurovascular unit, including blood vessels, microglia, and neurons; and (iv) changes in immune cells. Photothrombotic stroke (or sham surgery) was induced in adult male mice. From 24 h post-stroke, mice were treated daily for 14 days with either clopidogrel or a control. Cognitive performance (memory and learning) was assessed using a mouse touchscreen platform (paired associated learning task), while motor impairment was assessed using the cylinder task for paw asymmetry. On day 15, the mice were euthanized and their brains were collected for immunohistochemistry analysis. Clopidogrel administration significantly impaired learning and memory recovery, reduced mouse survival rates, and reduced body weight post-stroke. Furthermore, clopidogrel significantly increased vascular leakage, significantly increased the number and appearance of microglia, and significantly reduced the number of T cells within the peri-infarct region post-stroke. These data suggest that clopidogrel hampers cognitive performance post-stroke. This effect is potentially mediated by an increase in vascular permeability post-stroke, providing a pathway for clopidogrel to access the central nervous system, and thus, interfere in repair and recovery processes.

Growth Hormone Increases BDNF and mTOR Expression in Specific Brain Regions after Photothrombotic Stroke in Mice.

Aims: We have shown that growth hormone (GH) treatment poststroke increases neuroplasticity in peri-infarct areas and the hippocampus, improving motor and cognitive outcomes. We aimed to explore the mechanisms of GH treatment by investigating how GH modulates pathways known to induce neuroplasticity, focusing on association between brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) in the peri-infarct area, hippocampus, and thalamus. Methods: Recombinant human growth hormone (r-hGH) or saline was delivered (0.25 µl/hr, 0.04 mg/day) to mice for 28 days, commencing 48 hours after photothrombotic stroke. Protein levels of pro-BDNF, total-mTOR, phosphorylated-mTOR, total-p70S6K, and phosporylated-p70S6K within the peri-infarct area, hippocampus, and thalamus were evaluated by western blotting at 30 days poststroke. Results: r-hGH treatment significantly increased pro-BDNF in peri-infarct area, hippocampus, and thalamus (p < 0.01). r-hGH treatment significantly increased expression levels of total-mTOR in the peri-infarct area and thalamus (p < 0.05). r-hGH treatment significantly increased expression of total-p70S6K in the hippocampus (p < 0.05). Conclusion: r-hGH increases pro-BDNF within the peri-infarct area and regions that are known to experience secondary neurodegeneration after stroke. Upregulation of total-mTOR protein expression in the peri-infarct and thalamus suggests that this might be a pathway that is involved in the neurorestorative effects previously reported in these animals and warrants further investigation. These findings suggest region-specific mechanisms of action of GH treatment and provide further understanding for how GH treatment promotes neurorestorative effects after stroke.

'There's good and bad': parent perspectives on the influence of mobile touch screen device use on prenatal attachment.

The potential for human-computer interaction to have a substantial impact on adults is well documented. However, its potential importance prior to birth has rarely been reported. Parental use of smartphones and tablet computers could influence the relationship between parent and baby during pregnancy (prenatal attachment) and thus child development. Twenty-seven families were interviewed to explore how parents used these devices during pregnancy, and how device use influenced parents' thoughts, feelings and behaviours towards their baby while in utero. All used devices for a variety of purposes, and all described good levels of prenatal attachment. Parents described both disrupted and enhanced connectedness as a result of device use, and increased parental stress. The findings highlight a new opportunity for how device design and use guidelines could support families to maximise benefits and reduce detriments of device use to optimise prenatal attachment, and thus future parent-child attachment and child development. Practitioner summary: Many parents regularly use smartphones and tablet computers while pregnant. This qualitative study found that how devices were used either enhanced or disrupted feelings of prenatal attachment. Practitioners should be aware of potential beneficial and detrimental impacts of device use during pregnancy given implications for future attachment and child development.

Genomic DNA Methylation Signatures Enable Concurrent Diagnosis and Clinical Genetic Variant Classification in Neurodevelopmental Syndromes.

Pediatric developmental syndromes present with systemic, complex, and often overlapping clinical features that are not infrequently a consequence of Mendelian inheritance of mutations in genes involved in DNA methylation, establishment of histone modifications, and chromatin remodeling (the "epigenetic machinery"). The mechanistic cross-talk between histone modification and DNA methylation suggests that these syndromes might be expected to display specific DNA methylation signatures that are a reflection of those primary errors associated with chromatin dysregulation. Given the interrelated functions of these chromatin regulatory proteins, we sought to identify DNA methylation epi-signatures that could provide syndrome-specific biomarkers to complement standard clinical diagnostics. In the present study, we examined peripheral blood samples from a large cohort of individuals encompassing 14 Mendelian disorders displaying mutations in the genes encoding proteins of the epigenetic machinery. We demonstrated that specific but partially overlapping DNA methylation signatures are associated with many of these conditions. The degree of overlap among these epi-signatures is minimal, further suggesting that, consistent with the initial event, the downstream changes are unique to every syndrome. In addition, by combining these epi-signatures, we have demonstrated that a machine learning tool can be built to concurrently screen for multiple syndromes with high sensitivity and specificity, and we highlight the utility of this tool in solving ambiguous case subjects presenting with variants of unknown significance, along with its ability to generate accurate predictions for subjects presenting with the overlapping clinical and molecular features associated with the disruption of the epigenetic machinery.

Corticosterone Administration Alters White Matter Tract Structure and Reduces Gliosis in the Sub-Acute Phase of Experimental Stroke.

White matter tract (WMT) degeneration has been reported to occur following a stroke, and it is associated with post-stroke functional disturbances. White matter pathology has been suggested to be an independent predictor of post-stroke recovery. However, the factors that influence WMT remodeling are poorly understood. Cortisol is a steroid hormone released in response to prolonged stress, and elevated levels of cortisol have been reported to interfere with brain recovery. The objective of this study was to investigate the influence of corticosterone (CORT; the rodent equivalent of cortisol) on WMT structure post-stroke. Photothrombotic stroke (or sham surgery) was induced in 8-week-old male C57BL/6 mice. At 72 h, mice were exposed to standard drinking water ± CORT (100 µg/mL). After two weeks of CORT administration, mice were euthanised and brain tissue collected for histological and biochemical analysis of WMT (particularly the corpus callosum and corticospinal tract). CORT administration was associated with increased tissue loss within the ipsilateral hemisphere, and modest and inconsistent WMT reorganization. Further, a structural and molecular analysis of the WMT components suggested that CORT exerted effects over axons and glial cells. Our findings highlight that CORT at stress-like levels can moderately influence the reorganization and microstructure of WMT post-stroke.

The association of mobile touch screen device use with parent-child attachment: a systematic review.

Mobile touch screen devices (smartphones and tablet computers) have become an integral part of many parents' and children's lives, with this interaction linked to physical, mental and social outcomes. Despite the known importance of parent-child attachment, evidence on the association between device use and attachment was yet to be reviewed. Following protocol pre-registration, databases were searched, papers screened, and methodological quality assessed. Three papers met the inclusion criteria, and reported some negative associations between duration of parent/child smartphone use and attachment outcomes. A narrative synthesis on two groups of related papers found child time using any screen technology (including television viewing), and child 'problematic' internet, mobile phone, gaming and social media use, was negatively associated with attachment outcomes. Currently there is limited direct evidence on any association between time parents or children spend using these devices and parent-child attachment to support time guidelines for families and professionals working with families. Practitioner summary: Many parents and children regularly spend time using smartphones and tablet computers. This systematic review found limited evidence evaluating associations between child/adolescent or parent time using devices and parent-child attachment. Until quality evidence exists, practitioners should be alert to potential impacts of device use on family relationships and child outcomes.

Mutations in EZH2 cause Weaver syndrome.

We used trio-based whole-exome sequencing to analyze two families affected by Weaver syndrome, including one of the original families reported in 1974. Filtering of rare variants in the affected probands against the parental variants identified two different de novo mutations in the enhancer of zeste homolog 2 (EZH2). Sanger sequencing of EZH2 in a third classically-affected proband identified a third de novo mutation in this gene. These data show that mutations in EZH2 cause Weaver syndrome.

Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome.

Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delayed osseous maturation, expressive-language deficits, and a distinctive facial appearance. Occurrence is generally sporadic, although parent-to-child transmission has been reported on occasion. Employing whole-exome sequencing, we identified heterozygous truncating mutations in SRCAP in five unrelated individuals with sporadic FHS. Sanger sequencing identified mutations in SRCAP in eight more affected persons. Mutations were de novo in all six instances in which parental DNA was available. SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein (CREBBP, better known as CBP, the major cause of Rubinstein-Taybi syndrome [RTS]). Five SRCAP mutations, two of which are recurrent, were identified; all are tightly clustered within a small (111 codon) region of the final exon. These mutations are predicted to abolish three C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact. Our findings show that SRCAP mutations are the major cause of FHS and offer an explanation for the clinical overlap between FHS and RTS.

Executive function deficits and glutamatergic protein alterations in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.

Changes in executive function are at the root of most cognitive problems associated with Parkinson's disease. Because dopaminergic treatment does not necessarily alleviate deficits in executive function, it has been hypothesized that dysfunction of neurotransmitters/systems other than dopamine (DA) may be associated with this decrease in cognitive function. We have reported decreases in motor function and dopaminergic/glutamatergic biomarkers in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinson's mouse model. Assessment of executive function and dopaminergic/glutamatergic biomarkers within the limbic circuit has not previously been explored in our model. Our results show progressive behavioral decline in a cued response task (a rodent model for frontal cortex cognitive function) with increasing weekly doses of MPTP. Although within the dorsolateral (DL) striatum mice that had been given MPTP showed a 63% and 83% loss of tyrosine hydroxylase and dopamine transporter expression, respectively, there were no changes in the nucleus accumbens or medial prefrontal cortex (mPFC). Furthermore, dopamine-1 receptor and vesicular glutamate transporter (VGLUT)-1 expression increased in the mPFC following DA loss. There were significant MPTP-induced decreases and increases in VGLUT-1 and VGLUT-2 expression, respectively, within the DL striatum. We propose that the behavioral decline following MPTP treatment may be associated with a change not only in cortical-cortical (VGLUT-1) glutamate function but also in striatal DA and glutamate (VGLUT-1/VGLUT-2) input.

Clinical Assessment of a Lateral Epicondylar Anatomical Plate for the Stabilization of Humeral Condylar Fractures in Dogs.

OBJECTIVE: To report the use of a Lateral Epicondylar Anatomical Plate for the management of humeral condylar fractures (HCF) in dogs. STUDY DESIGN: Medical records of dogs with HCF stabilized using the Lateral Epicondylar Anatomical Plate at six UK veterinary referral centres between April 2018 and February 2021 were reviewed. Long-term follow-up (>6 months) was obtained via owner questionnaire, which incorporated the Liverpool Osteoarthritis in Dogs clinical metrology instrument. RESULTS: Sixty-two HCF were treated in 61 dogs (44 lateral condylar fractures [LCF] and 18 intracondylar (T/Y) fractures [ICF]). Fifty-one dogs were Spaniels or Spaniel crossbreeds. Intraoperative contouring of the plate was required for one dog-a French Bulldog. Postoperative complications occurred in 14/42 LCF and 6/18 ICF; overall there were 14 minor, 8 major, and 2 catastrophic complications. On final follow-up imaging, there was evidence of partial or complete osseous continuity of the condylar part of the fracture 32/53 HCF (24/39 LCF and 8/14 ICF) and lateral epicondylar part of the fracture in 53/53 HCF (39/39 LCF and 14/14 ICF). At final reexamination, 20/28 dogs with LCF and 5/13 dogs with ICF were not lame and the remaining dogs demonstrated mild lameness. According to the owner questionnaire, 17/17 dogs with LCF and 8/10 dogs with ICF returned to full limb use and median Liverpool Osteoarthritis in Dogs scores were 2/52 for LCF and 6.5/52 for ICF. CONCLUSION: The Lateral Epicondylar Anatomical Plate can be used successfully for the surgical stabilization of HCF in dogs.

NK1 tachykinin receptor antagonist treatment reduces cerebral edema and intracranial pressure in an ovine model of ischemic stroke.

Following ischemic stroke, substance P (SP)-mediated neurogenic inflammation is associated with profound blood-brain barrier (BBB) dysfunction, cerebral edema, and elevated intracranial pressure (ICP). SP elicits its effects by binding the neurokinin 1 tachykinin receptor (NK1-R), with administration of an NK1-R antagonist shown to ameliorate BBB dysfunction and cerebral edema in rodent and permanent ovine stroke models. Given the importance of reperfusion in clinical stroke, this study examined the efficacy of NK1-R antagonist treatment in reducing cerebral edema and ICP in an ovine model of transient middle cerebral artery occlusion (tMCAo). Anesthetized sheep (n = 24) were subject to 2-hours tMCAo and randomized (n = 6/group) to receive early NK1-R treatment (days 1-3 post-stroke), delayed NK1-R treatment (day 5 post-stroke), or saline vehicle. At 6-days post-stroke animals were re-anaesthetized and ICP measured, followed by MRI to evaluate infarction, edema and BBB dysfunction. Following both early and delayed NK1-R antagonist administration, ICP was significantly reduced on day 6 compared to vehicle animals (p < 0.05), accompanied by a reduction in cerebral edema, midline shift and BBB dysfunction (p < 0.05). This study demonstrates that NK1-R antagonist treatment is an effective novel therapy for cerebral edema and elevated ICP following stroke in an ovine model, warranting future clinical evaluation.

Hydrogen sulfide preconditions the db/db diabetic mouse heart against ischemia-reperfusion injury by activating Nrf2 signaling in an Erk-dependent manner.

Hydrogen sulfide (H2S) therapy protects nondiabetic animals in various models of myocardial injury, including acute myocardial infarction and heart failure. Here, we sought to examine whether H2S therapy provides cardioprotection in the setting of type 2 diabetes. H2S therapy in the form of sodium sulfide (Na2S) beginning 24 h or 7 days before myocardial ischemia significantly decreased myocardial injury in db/db diabetic mice (12 wk of age). In an effort to evaluate the signaling mechanism responsible for the observed cardioprotection, we focused on the role of nuclear factor E2-related factor (Nrf2) signaling. Our results indicate that diabetes does not alter the ability of H2S to increase the nuclear localization of Nrf2, but does impair aspects of Nrf2 signaling. Specifically, the expression of NADPH quinine oxidoreductase 1 was increased after the acute treatment, whereas the expression of heme-oxygenase-1 (HO-1) was only increased after 7 days of treatment. This discrepancy was found to be the result of an increased nuclear expression of Bach1, a known repressor of HO-1 transcription, which blocked the binding of Nrf2 to the HO-1 promoter. Further analysis revealed that 7 days of Na2S treatment overcame this impairment by removing Bach1 from the nucleus in an Erk1/2-dependent manner. Our findings demonstrate for the first time that exogenous administration of Na2S attenuates myocardial ischemia-reperfusion injury in db/db mice, suggesting the potential therapeutic effects of H2S in treating a heart attack in the setting of type 2 diabetes.

Exercise protects against myocardial ischemia-reperfusion injury via stimulation of ß(3)-adrenergic receptors and increased nitric oxide signaling: role of nitrite and nitrosothiols.

RATIONALE: Exercise training confers sustainable protection against ischemia-reperfusion injury in animal models and has been associated with improved survival following a heart attack in humans. It is still unclear how exercise protects the heart, but it is apparent that endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) play a role. OBJECTIVE: To determine the role of ß(3)-adrenergic receptors (ß(3)-ARs), eNOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of exercise. METHODS AND RESULTS: Here we show that voluntary exercise reduces myocardial injury in mice following a 4-week training period and that these protective effects can be sustained for at least 1 week following the cessation of the training. The sustained cardioprotective effects of exercise are mediated by alterations in the phosphorylation status of eNOS (increase in serine 1177 and decrease in threonine 495), leading to an increase in NO generation and storage of NO metabolites (nitrite and nitrosothiols) in the heart. Further evidence revealed that the alterations in eNOS phosphorylation status and NO generation were mediated by ß(3)-AR stimulation and that in response to exercise a deficiency of ß(3)-ARs leads to an exacerbation of myocardial infarction following ischemia-reperfusion injury. CONCLUSIONS: Our findings clearly demonstrate that exercise protects the heart against myocardial ischemia-reperfusion injury by stimulation of ß(3)-ARs and increased cardiac storage of nitric oxide metabolites (ie, nitrite and nitrosothiols).

Dual-acting histone deacetylase-topoisomerase I inhibitors.

Current chemotherapy regimens are comprised mostly of single-target drugs which are often plagued by toxic side effects and resistance development. A pharmacological strategy for circumventing these drawbacks could involve designing multivalent ligands that can modulate multiple targets while avoiding the toxicity of a single-targeted agent. Two attractive targets, histone deacetylase (HDAC) and topoisomerase I (Topo I), are cellular modulators that can broadly arrest cancer proliferation through a range of downstream effects. Both are clinically validated targets with multiple inhibitors in therapeutic use. We describe herein the design and synthesis of dual-acting histone deacetylase-topoisomerase I inhibitors. We also show that these dual-acting agents retain activity against HDAC and Topo I, and potently arrest cancer proliferation.

Long term outcomes of the Humeral Intracondylar Repair System for management of canine humeral intracondylar fissures and humeral condylar fractures.

Objective: To document long-term client-reported clinical outcomes and complications for the Humeral Intracondylar Repair System (HIRS) for treatment of humeral intracondylar fissures (HIF) and humeral condylar fractures (HCF) in dogs. Method: Data collection involved the review of clinical records and analysis of an owner questionnaire regarding complication occurrence and client-reported outcome. The "Liverpool Osteoarthritis in Dogs" (LOAD) instrument was incorporated into the questionnaire. Results: Twenty-six cases of HIF and 14 cases of HCF were included in the study, with follow-up times of over 12 months (range 13-97 months). Thirty-seven out of 40 cases reached long-term follow up: 25 out of 26 HIF cases, 11 out of 11 lateral condylar fracture cases and one out of three dicondylar fracture cases. Two cases of HIF suffered a gradual return of lameness in the long term; both dogs had concomitant medial coronoid disease. No other complications were reported in the long term. Excluding cases with concurrent issues affecting exercise, the median LOAD score at follow-up was 4 and 5 (out of 52) for HIF and HCF cases, respectively. At long-term follow-up, 36 out of 37 cases were reported to have regained "full function of the limb." Clinical significance: The results of this study, together with previously reported short and medium-term outcomes, support the use of HIRS for management of humeral intracondylar fissures and humeral condylar fractures.

Floating-Harbor syndrome and polycystic kidneys associated with SRCAP mutation.

Floating-Harbor syndrome (FHS) is a rare genetic disorder recently shown to be caused by mutations in the Snf2-related CREB-binding protein activator protein gene (SRCAP). It comprises three key clinical features of characteristic facies, expressive and receptive speech impairment and short stature. We report on a patient with this syndrome associated with early adult-onset hypertension and bilateral polycystic kidneys. Family screening for polycystic kidney disease was negative and mutations in polycystic kidney disease 1 and 2 genes (PKD1 and PKD2) were absent. Sequencing of the SRCAP gene demonstrated a de novo mutation matching one of the known FHS-associated mutations. The patient required treatment with anti-hypertensives and will require lifelong renal monitoring. We suggest this patient's presentation may be due to the pleiotropic effects of SRCAP mutations. Further, the protein encoded by SRCAP is known to interact with CREB-binding protein, the product of the gene mutated in Rubinstein-Taybi syndrome, which is associated with renal abnormalities. A literature review of the renal findings in patients with Floating-Harbor syndrome identified another patient with possible polycystic kidneys, two patients with early onset hypertension, and a young patient with a ruptured intracranial aneurysm, which can be a feature of classic adult polycystic kidney disease. Collectively, these findings suggest that all patients with Floating-Harbor syndrome should undergo regular blood pressure monitoring and screening for polycystic kidneys by ultrasound at the time of the FHS diagnosis with imaging to be repeated during adulthood if a childhood ultrasound was negative.

TACTICS - Trial of Advanced CT Imaging and Combined Education Support for Drip and Ship: evaluating the effectiveness of an 'implementation intervention' in providing better patient access to reperfusion therapies: protocol for a non-randomised controlled stepped wedge cluster trial in acute stroke.

INTRODUCTION: Stroke reperfusion therapies, comprising intravenous thrombolysis (IVT) and/or endovascular thrombectomy (EVT), are best practice treatments for eligible acute ischemic stroke patients. In Australia, EVT is provided at few, mainly metropolitan, comprehensive stroke centres (CSC). There are significant challenges for Australia's rural and remote populations in accessing EVT, but improved access can be facilitated by a 'drip and ship' approach. TACTICS (Trial of Advanced CT Imaging and Combined Education Support for Drip and Ship) aims to test whether a multicomponent, multidisciplinary implementation intervention can increase the proportion of stroke patients receiving EVT. METHODS AND ANALYSIS: This is a non-randomised controlled, stepped wedge trial involving six clusters across three Australian states. Each cluster comprises one CSC hub and a minimum of three primary stroke centre (PSC) spokes. Hospitals will work in a hub and spoke model of care with access to a multislice CT scanner and CT perfusion image processing software (MIStar, Apollo Medical Imaging). The intervention, underpinned by behavioural theory and technical assistance, will be allocated sequentially, and clusters will move from the preintervention (control) period to the postintervention period. PRIMARY OUTCOME: Proportion of all stroke patients receiving EVT, accounting for clustering. SECONDARY OUTCOMES: Proportion of patients receiving IVT at PSCs, proportion of treated patients (IVT and/or EVT) with good (modified Rankin Scale (mRS) score 0-2) or poor (mRS score 5-6) functional outcomes and European Quality of Life Scale scores 3 months postintervention, proportion of EVT-treated patients with symptomatic haemorrhage, and proportion of reperfusion therapy-treated patients with good versus poor outcome who presented with large vessel occlusion at spokes. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Hunter New England Human Research Ethics Committee (18/09/19/4.13, HREC/18/HNE/241, 2019/ETH01238). Trial results will be disseminated widely through published manuscripts, conference presentations and at national and international platforms regardless of whether the trial was positive or neutral. TRIAL REGISTRATION NUMBER: ACTRN12619000750189; UTNU1111-1230-4161.