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Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50–70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN− and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10–12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease. Refereed/Peer-reviewed

The safety of dabigatran is poorly studied in patients with liver cirrhosis and has rarely been compared to warfarin in terms of bleeding risks.We undertook a retrospective cohort study across three tertiary centres in Auckland, New Zealand, between 2008 to 2020. Adults 18 years and over and those with a clinically confirmed diagnosis of cirrhosis were included. Data collected included demographic data and clinical characteristics, baseline medication and comorbidities. The primary outcome measure was the incidence of any bleeding event that resulted in hospital admission.Overall, 100 patients were included in this study. A total of 52 patients took warfarin, and 48 took dabigatran. Baseline characteristics for both groups were generally similar. The incidence rate of bleeds for patients taking warfarin was 14.4 per 100 person-years (95% CI, 8.8-23.5) compared to 9.1 per 100 person-years (95% CI, 4.5-18.1) for patients taking dabigatran. The incidence rate ratio comparing dabigatran to warfarin was 0.63 (95% CI, 0.23-1.60), p=0.25.Our study found that patients on dabigatran may have a lower bleeding risk than patients taking warfarin, but this was not statistically significant.

BACKGROUND: No previous studies have validated current clinical practice guidelines for the management of non-blanching rashes in children who have received meningococcal B and C vaccinations. The aim of this study was to evaluate the performance of existing clinical practice guidelines in the diagnosis of invasive meningococcal disease in children presenting with a fever and non-blanching rash in the UK.METHODS: The Petechiae in Children (PiC) study was a prospective, multicentre cohort study involving children (aged FINDINGS: Between Nov 9, 2017, and June 30, 2019, 1513 patients were screened, of whom 1329 were eligible and were included in the analysis. The median age of patients was 24 months (IQR 12-48). 1137 (86%) of 1329 patients had a blood test and 596 (45%) received parenteral antibiotics. 19 (1%) patients had confirmed meningococcal disease. All eight clinical practice guidelines had a sensitivity of 1·00 (95% CI 0·82-1·00) for identifying meningococcal disease. The specificities of NICE guidelines CG102 (0·01 [95% CI 0·01-0·02]) and NG51 (0·00 [0·00-0·00]) for identifying meningococcal disease were significantly lower than that of tailored clinical practice guidelines (pINTERPRETATION: Invasive meningococcal disease is a rare cause of non-blanching rashes in children presenting to the emergency department in the UK. Current NICE guidelines perform poorly when compared with tailored clinical practice guidelines. These findings suggest that UK national guidance could be improved by shifting towards a tailored approach.FUNDING: Public Health Agency.

Although metastatic breast cancer (MBC) survival is improving, symptoms remain a significant burden. Returning to a cancer center for symptom management can be challenging. Technology-enabled supportive care platforms are worth exploration. Seventeen patients with MBC were randomized to immediate or delayed start for a 3-month intervention that included daily tablet-based guideline-concordant self-care for pain, distress, fatigue, and sleep disturbance, as well as weekly calls with a patient navigator. The primary outcome was patient acceptability. We also assessed feasibility, patient satisfaction, and cost and compared between group differences for symptoms. RM-ANOVA examined between group differences over time. Hedges’ d effect sizes quantified magnitude of differences in change between immediate and delayed start. Sixty-eight percent of patients approached accepted the tablet-based intervention. Patients interacted with the tablet 48% of possible days. Patient satisfaction ranged from 83 for walking to 49% for the psychological interventions. The cost of delivering Nurse AMIE for 3 months was $570.23. Small nonsignificant improvements were found for fatigue (d=0.24). Nonsignificant, but potentially clinically meaningful, moderate reductions were found for sleep (d=0.65) and distress (d=0.74). A tablet-based supportive care platform that offers guideline-concordant self-care for pain, fatigue, sleep, and distress was observed to be highly acceptable and feasible for patients with metastatic breast cancer. Patient satisfaction scores and initial evaluation of efficacy are promising, and the platform warrants further investigation. Technology-based self-care is a promising option to address symptoms in patients with metastatic breast cancer.

The psychomotor retardation that may be seen in major depression represents an interesting parallel to bradykinesia, a core feature of Parkinson's disease. Psychomotor retardation has been correlated with the severity of depression and is a predictor of response to electroconvulsive therapy (ECT). Psychomotor retardation has typically been assessed by subjective clinical judgement including clinical rating scales. Gross activity levels have also been measured with actigraphy previously. The Parkinson's KinetiGraph (PKG) was developed to assess bradykinesia, dyskinesia and tremor in Parkinson's disease and allows for an objective assessment of motor symptoms over time. It has not been used previously to assess motor symptoms in depression. The aim of the current pilot study was to use the PKG to objectively measure both bradykinesia and immobility in depressed inpatients undergoing ECT before, during and at the end of therapy and review correlations with depressive symptomatology and treatment response. The majority of patients (9/12) had PKG defined bradykinesia at baseline and 7/9 of these improved with ECT. All patients with bradykinesia who remitted clinically demonstrated improvements in bradykinesia scores. PKG defined immobility was present at baseline in 11/12 total patients and improved in the majority of these patients (9/11) post ECT. Correlations between clinically assessed melancholia and PKG measures were significant (r = 0.701, p 0.011 at baseline to rs = 0.655, p 0.021 at end). A strong association between bradykinesia and immobility scores and depression severity was not seen. The PKG is a potentially useful wearable technology to objectively assess motor symptoms in depression.

Introduction Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. Methods WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. Results A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). Conclusion A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases.

Accelerating rates of urbanisation are contributing to biodiversity declines worldwide. However, urban green (e.g. parks) and blue spaces (e.g. coast) provide important habitat for species. Emerging evidence also shows that green and blue spaces can benefit human psychological wellbeing, although few studies originate from the Global South and it is unclear whether more biodiverse spaces offer greater wellbeing gains. We examine how bird diversity (abundance, species richness, Shannon diversity, and community composition) in green and coastal blue space in Georgetown, Guyana, is associated with people's wellbeing (positive and negative affect, anxiety) in situ, using point counts and questionnaires. Bird community composition differed between green and coastal sites, and diversity was significantly higher in green sites. Positive affect and anxiety did not differ between green and coastal sites, but negative affect was higher in coastal sites. Mixed-effect models showed no associations between biodiversity and wellbeing, implying other features are contributing to people's positive wellbeing. Despite no association between biodiversity and wellbeing, both green and coastal blue sites are important for wellbeing and supporting different bird communities. City planning authorities and public health professionals should ensure these social and environmental needs are met in developing cities in the Global South.

Parkinson disease (PD) is a complex neurodegenerative disorder that can present heterogeneously with a combination of motor and non-motor symptoms. α-synuclein, a neuronal protein, can undergo aberrant conformational change resulting in the intra-neuronal accumulation of toxic oligomers that form Lewy bodies, the pathological hallmark of PD. There is evidence that pathological α-synuclein exhibits prion-like behaviour in its mode of transmission through the nervous system. The choice of initial dopaminergic treatments should be individually tailored but long term outcomes appear to be equivalent. There is level A evidence supporting the benefit of three different device-assisted therapies in treating troublesome motor fluctuations and dyskinesias. Stem cell transplantation as currently being trialled is predominantly a symptomatic therapy targeting only limited regions of the brain affected by PD, and will need to be proven to be not only as effective but as safe as currently available device-assisted therapies. New modes of treatment including active immunisation against oligomeric α-synuclein and drugs that alter cellular metabolism show some promise. The inability to effectively treat a range of non-motor, non-dopaminergic symptoms remains a major therapeutic challenge.

BackgroundCancer diagnosis can adversely affect mental well-being and overall clinical outcome. We evaluated the efficacy of a group-led creative writing workshop (CWW) on mood in patients with cancer prospectively.MethodsWe conducted a single-institution phase II study. Sixty adult patients with cancer (any type or stage) were randomised 2:1 to CWW (4×CWW sessions, bimonthly over 8 weeks) versus active control (AC) (independent writing at home with the help of a book, four sessions, bimonthly over 8 weeks). The total study duration was 6 months with a follow-up of up to 3 months. Primary objective: changes in overall mood, depression and anxiety symptoms before and after intervention in both arms. Emotional Thermometer Scale (ETS) was used to assess changes in patients’ mood. Additionally, the Patient Health Questionnaire (PHQ)-9 and General Anxiety Disorder Scale (GAD)-7 were used to evaluate depression and anxiety symptoms.ResultsOf 50 evaluable patients (CWW 34, AC 17), 26 patients in the CWW arm attended at least one class and 19 attended at least four classes. Patients in CWW had significant immediate improvement in the overall ETS (post vs preclass scores; pConclusionCWW had a positive effect on mood based on ETS scores, suggesting a potential therapeutic benefit among patients with cancer.

ObjectiveTo determine the feasibility of conducting creative writing workshops (CWW) for patients with cancer to promote improvement in mood.MethodWe piloted a prospective study to determine the feasibility of conducting CWW over a 4-week period. Patients were randomised 2:1 to either an intervention arm (IA) or to standard of care (SOC). Patients in the IA attended four 2-hour long weekly CWW × 4 weeks, whereas those receiving SOC did not participate in the CWW. We used a validated emotion thermometer scale (ETS) to assess changes in patient’s mental health before and after intervention. Patients with metastatic or unresectable cancer were included.Primary endpoint(1) Feasibility and (2) mood scores before and after CWW using ETS.ResultsA total of 16 patients were enrolled: 11 in the IA vs 5 in SOC. Seven out of 11 (63%) patients enrolled in the IA attended at least 75% of classes. Patients in the IA showed a trend towards mood improvement relative to the SOC when comparing initial and final ETS scores. Within the IA group significantly lower postclass total ETS scores were observed relative to preclass ETS scores. Also, a significant decreasing trend over time was observed in the preclass total ETS scores for participants in the IA group.ConclusionsIt is feasible for patients with cancer to attend CWW. Our results also show a positive effect on mood in the CWW arm. Further prospective clinical studies are needed to evaluate the effect of this intervention in patients with cancer.

Urban land cover expansion and human population growth are accelerating worldwide. This is resulting in the loss and degradation of green and blue spaces (e.g. parks, waterways, lakes) in cities, which provide resources to sustain biodiversity and improve human wellbeing. The specific characteristics of these spaces (e.g. sounds, species, safety) that enhance or detract from wellbeing are underexplored, yet this knowledge is needed to inform urban planning, management and policies that will ultimately benefit both people and biodiversity. Research of this kind is rarely conducted in the Global South, where rapid urbanisation threatens biodiversity-rich ecosystems of worldwide significance. Here, we examine how perceptions of green, waterway, and dense urban spaces relate to wellbeing in Georgetown, Guyana. Specifically, we use mediation models to test how perceptions of sound, bird species richness, naturalness, and safety concerns contribute to sites being perceived as restorative which, subsequently, influences wellbeing. We assess the accuracy of these site perceptions with objective measures of sound (using a bioacoustic sound index), bird species richness, and percent coverage of vegetation, water, and impervious surfaces. Results showed that if sites were perceived as species rich, containing natural sounds like birdsong, natural rather than artificial, and safe, they were perceived as more restorative, resulting in improved wellbeing. In general, people's perceptions were consistent with objective measures. Green, compared with waterway and dense urban sites, contained more biophonic sounds, higher species richness, greater vegetation and water coverage. Although waterways were biodiverse, they were dominated by anthrophonic sounds, so were perceived as artificial and non-restorative. We shed light on how city planners might augment specific characteristics to improve the wellbeing of urban dwellers, with implications for biodiversity conservation. Our findings provide a scientific evidence base for urban design and management plans that could deliver multiple co-benefits, particularly in biodiversity-rich cities in neotropical regions.

Protein drugs (PD) are minimally utilized in dental medicine due to high cost and invasive surgical delivery. There is limited clinical advancement in disrupting virulent oral biofilms, despite their high prevalence in causing dental caries. Poor efficacy of antimicrobials following topical treatments or to penetrate and disrupt formed biofilms is a major challenge. We report an exciting low-cost approach using plant-made antimicrobial peptides (PMAMPs) retrocyclin or protegrin with complex secondary structures (cyclic/hairpin) for topical use to control biofilms. The PMAMPs rapidly killed the pathogen Streptococcus mutans and impaired biofilm formation following a single topical application of tooth-mimetic surface. Furthermore, we developed a synergistic approach using PMAMPs combined with matrix-degrading enzymes to facilitate their access into biofilms and kill the embedded bacteria. In addition, we identified a novel role for PMAMPs in delivering drugs to periodontal and gingival cells, 13–48 folds more efficiently than any other tested cell penetrating peptides. Therefore, PDs fused with protegrin expressed in plant cells could potentially play a dual role in delivering therapeutic proteins to gum tissues while killing pathogenic bacteria when delivered as topical oral formulations or in chewing gums. Recent FDA approval of plant-produced PDs augurs well for clinical advancement of this novel concept.

Objective: Restless legs syndrome, now called Willis-Ekbom Disease (RLS/WED), is a sensorimotorrelated sleep disorder. Little is known of the effect of RLS/WED on motor function. The current study investigated upper limb function in RLS/WED patients. We hypothesised that RLS/WED patients exhibit subtle changes in tremor amplitude but normal dexterity and movement speed and rhythmicity compared to healthy controls. Conclusions: Hand function, tremor, and task learning were unaffected in RLS/WED patients. Patients manipulated objects in a normal manner and exhibited normal movement speed, rhythmicity, and tremor. Methods: RLS/WED patients (n = 17, 59 ± 7 years) with moderate disease and healthy controls (n = 17, 58 ± 6 years) completed screening tests and five tasks including object manipulation, maximal pinch grip, flexion and extension of the index finger (tremor assessment), maximal finger tapping (movement speed and rhythmicity assessment), and the grooved pegboard test. Force, acceleration, and/or first dorsal interosseus EMG were recorded during four of the tasks. Results: Task performance did not differ between groups. Learning was evident on tasks with repeated trials and the magnitude of learning did not differ between groups. Significance: Further research is needed to assess other types of movement in RLS/WED patients to gain insight into the motor circuitry affected and the underlying pathophysiology. Refereed/Peer-reviewed

In Australia 1% of individuals aged over 50 years have Parkinson disease (PD). Guidance for commencing device-assisted therapies (DAT) for PD in Australia was developed based on a review of European recommendations and their relevance to the local clinical setting. An online survey and teleconference discussions were held by a group of eight local movement disorder experts to develop consensus. Referral to a movement disorder specialist and consideration of DAT is appropriate when motor fluctuations cause disability or reduced quality of life, response to treatment is inconsistent or motor fluctuations and dyskinesias require frequent treatment adjustment without apparent benefit and levodopa is required four or more times daily. Three types of DAT are available in Australia for patients with PD: continuous subcutaneous apomorphine; continuous levodopa-carbidopa intestinal gel infusion; and deep brain stimulation. All improve consistency of motor response. The most important aspects when considering which DAT to use are the preferences of the patient and their carers, patient comorbidities, age, cognitive function and neuropsychiatric status. Patients and their families need to be provided with treatment options that are suitable to them, with adequate explanations regarding the recommendations and comparison of potential device-related complications. DAT are best managed, where possible, in a specialist centre with experience in all three types of therapy. Proactive and early management of symptoms during disease progression is essential to maintain optimally motor responses and quality of life in patients with PD.

Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, retinopathy, nephropathy and stroke are neurovascular syndromes initially described as distinct entities. Recently they were shown to be one disease caused by C-terminal frame-shift mutations in TREX1 , which was termed ‘retinal vasculopathy with cerebral leukodystrophy’. Here we defined the genetic and clinicopathologic spectrum of this clinically and pathophysiologically poorly characterized and frequently misdiagnosed fatal neurovascular disorder. We identified five different TREX1 mutations in 78 members from 11 unrelated families and by using a standardized study protocol we retrospectively reviewed and aggregated the associated clinical, neuroimaging, and pathology data. Findings were similar across mutations and families. Sixty-four mutation carriers had vascular retinopathy. Neuroimaging revealed (i) punctate, hyperintense, white matter lesions with or without nodular enhancement in 97% of them; (ii) rim-enhancing mass lesions in 84%; and (iii) calcifications in the white matter in 52%. Ninety per cent had clinical manifestations of brain disease, including focal neurological deficits (68%), migraine (59%), cognitive impairment (56%), psychiatric disturbances (42%), and seizures (17%). One mutation carrier had enhancing brain lesions and neurological features but unknown retinopathy status. Additional systemic features included liver disease (78%), anaemia (74%), nephropathy (61%), hypertension (60%), mild Raynaud’s phenomenon (40%), and gastro-intestinal bleeding (27%). Mean (± standard deviation) age at diagnosis was 42.9 ± 8.3 years and at death 53.1 ± 9.6 years. Pathological examination revealed systemic vasculopathy with luminal narrowing and multi-laminated basement membranes. The 13 mutation carriers without retinopathy or brain lesions were on average 8 years younger (mean age: 35.1 ± 10.6 years). Of them, 54% had mild Raynaud’s phenomenon, 42% had migraine, and 23% had psychiatric disturbances. Retinal vasculopathy with cerebral leukodystrophy is an autosomal dominant systemic small-vessel disease due to specific TREX1 mutations and clinically primarily characterized by (i) visual impairment from vascular retinopathy; and (ii) neurological decline and premature death due to progressive enhancing cerebral white matter lesions. Impaired liver and kidney function, anaemia sometimes associated with gastrointestinal bleeding, hypertension, migraine, and Raynaud’s phenomenon appear to be part of the clinical spectrum as well. Penetrance seems high. Because of the pathogenetic basis and the emerging clinical picture with systemic manifestations and conspicuous absence of leukodystrophy, we renamed the disease ‘retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations’. We propose diagnostic criteria to facilitate clinical recognition and future studies. * Abbreviations : AGS : Aicardi-Goutieres syndrome MC : mutation carrier RVCL(-S) : retinal vasculopathy with cerebral leukoencephalopathy (and systemic manifestations)

There has been increasing recognition of pre-motor manifestations of Parkinson's disease (PD) resulting from early brainstem involvement. We sought to determine whether ventilatory control is abnormal. Patients with PD without respiratory disease were recruited. Spirometry, lung volumes, diffusing capacity and respiratory muscle strength were assessed. Occlusion pressure and ventilation were measured with increasing CO(2). Arterial blood gases were taken at rest and following 20 min exposure to 15% O(2). A linear correlation assessed associations between respiratory function and indices of PD severity. 19 subjects (17 males) with mild-moderate PD were studied (mean (SD) age 66 (8) years). Respiratory flows and volumes were normal in 16/19. Maximum inspiratory and expiratory pressures were below LLN in 13/19 and 15/19 respectively. 7/15 had a reduced ventilatory response to hypercapnia and 11/15 had an abnormal occlusion pressure. There was no correlation between impairment of ventilatory response and reduction in respiratory muscle strength. Response to mild hypoxia was normal and there were no associations between disease severity and respiratory function. Our findings suggest that patients with mild-moderate PD have abnormal ventilatory control despite normal lung volumes and flows.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described inflammatory disease of the CNS with a predilection for the hindbrain and responsive to immunotherapy. Five further cases are described with detailed pathology and long term evaluation. CLIPPERS does not represent a benign condition, and without chronic immunosuppression the disease may relapse. The radiological distribution is focused not only in the pons but also in the brachium ponti and cerebellum. Pontocerebellar atrophy occurred early, even in cases treated promptly. Significant cognitive impairment was seen in some cases and was associated with additional cerebral atrophy. The pathology included distinctive histiocytic as well as lymphocytic components and evidence of neuro-axonal injury. Additional subclinical systemic findings on investigation were identified. Relapse was associated with withdrawal of corticosteroids, and disability was least marked in cases where both the presentation and relapses were treated promptly. We propose that the title of the syndrome be amended to chronic lymphocytic inflammation with pontocerebellar perivascular enhancement responsive to steroids to more accurately reflect the distribution of the radiological findings.

•Parkinson disease (PD) is a multisystem neurodegenerative disorder that affects about 1% of the population over the age of 55 years and has mean age of onset of about 60 years. • The Braak hypothesis proposes that the earliest pathological evidence of PD is found in the enteric nervous system, medulla and olfactory bulb, and only subsequently progresses (over years) to the substantia nigra and cortex. • Non-motor symptoms, such as constipation, hyposmia and sleep disorders, may precede typical motor features of PD by several years. • No treatment has been convincingly shown to slow PD progression (ie, a neuroprotective drug remains elusive). • Symptomatic benefit from dopaminergic therapy is usually maintained throughout the course of the disease. • The decision as to whether to commence treatment with either levodopa or a dopamine agonist needs to be individually tailored, but long-term outcomes appear to be equivalent. • Advanced PD is complicated by the loss of non-dopaminergic neurones, resulting in symptoms that are largely unresponsive to dopaminergic therapy. • Treatment with apomorphine, Duodopa or deep-brain stimulation surgery may be beneficial for selected patients with advanced PD. • Non-motor symptoms, such as mood disorders, cognitive impairment, autonomic dysfunction and sleep disorders, are responsible for significant morbidity. Management often requires a multidisciplinary approach. Copyright © 2011 Elsevier B.V.

The presence of hepatic portal venous gas (HPVG) is a rare finding. It is most commonly caused by bowel necrosis and typically carries a grave prognosis. Bevacizumab has emerged as an effective standard therapy in the frontline management of advanced non-small cell lung cancer (NSCLC). Although bevacizumab is associated with gastrointestinal perforation, it has not been shown to cause HPVG. A 75-year-old man, diagnosed with metastatic NSCLC, was treated with palliative chemotherapy consisting of paclitaxel, carboplatin, and bevacizumab for six cycles. He continued on maintenance bevacizumab after that for a total of six doses, given every 3 weeks, with continued stable disease. During a surveillance CT scan 4 weeks after the last dose of bevacizumab, HPVG was shown. This is the first case of HPVG associated with bevacizumab therapy in a patient with metastatic NSCLC. The HPVG may have been an early warning sign of impending bowel perforation, and bevacizumab was immediately discontinued, with HPVG completely resolving on follow-up CT scan 2 weeks later. We recommend that bevacizumab therapy be immediately and permanently discontinued whenever HPVG is observed, as this may help avoid a potentially catastrophic outcome.

An increasing body of research suggests that a number of immune mechanisms play a role in degenerative pathways in Parkinson's disease (PD). In the current work we investigated a posited humoral immune response in this disorder. Sera from PD patients exhibited a significantly enhanced absorbance response on a novel ELISA for anti-melanin antibodies, compared to sera from age-matched control subjects. The enhanced ELISA absorbance response was specific for catecholamine-based melanins and was unrelated to antiparkinsonian dopaminergic medication. Further, the absorbance response was significantly and negatively correlated with disease duration. These data suggest that a specific humoral anti-melanin antibody response is present in PD and is more active in early disease. While the contribution of this novel immune response to the initiation and progression of this disorder is unclear, this finding supports the hypothesis that specific immune responses occurring in PD may respond to therapeutic interventions in this disorder.

Aim To examine time trends and deprivation gradients in fire-related deaths and injuries. Methods A cross-sectional study and time trend analysis using data on fire casualties in England between 1995 and 2004 obtained from the Department for Communities and Local Government. Injury rates were calculated assuming a Poisson distribution. Incidence rate ratios (IRRs) were calculated to compare changes in deprivation gradients over time. Results There were significant reductions in fatal and non-fatal fire injuries in children (fatal injuries IRR χ21 = 11.18, P < 0.001; non-fatal injuries IRR χ22 = 61.44, P < 0.001), adults (fatal injuries IRR χ21 = 15.99, P < 0.001; non-fatal injuries IRR χ22 = 183.25, P < 0.001) and older people (fatal injuries IRR χ21 = 56.88, P < 0.001; non-fatal injuries IRR χ22 = 54.09, P < 0.001) between 1995 and 2004. Adult and child fire deaths were most commonly caused by smokers' materials (e.g. cigarettes, cigars and tobacco), and cigarette lighters and matches, respectively. Cooking appliances caused most non-fatal fire injuries. Injury rates increased with increasing levels of deprivation and deprivation gradients did not change over 10 years. Conclusions Fire prevention interventions should promote the safe use of cooking and heating appliances and the responsible use of smokers' materials, lighters and matches, and should target those at greater risk of fire, including the socially disadvantaged.

Hemifacial spasm (HFS) is characterized by involuntary, irregular contractions of muscles innervated by the facial nerve. Whether the facial nerve has a relative predisposition for ectopic activity has not been clarified. Nerve excitability techniques, which provide information about membrane potential and axonal ion channel function, were initially measured in 12 control subjects looking for biophysical differences that may predispose the facial nerve to generate ectopic activity. In a second series of studies, facial nerve excitability was assessed in nine HFS patients. In both series, stimulus-response behavior, threshold electrotonus, a current threshold relationship, and the recovery of excitability following supramaximal stimulation were recorded following stimulation of the facial nerve. When compared to normative data from nerves in the upper and lower limbs, there was a relative "fanning-in" of threshold electrotonus, reduced superexcitability, and increased subexcitability in facial nerve studies from control subjects (P < 0.05), consistent with relative axonal depolarization. These findings may underlie the propensity for the facial nerve to develop ectopic impulse activity in motor axons. In the HFS patient study, there were no significant differences in distal facial nerve excitability properties from the affected side in HFS patients when compared either to the unaffected side or to normative facial nerve data. It is concluded that the impulse generator underlying HFS must consequently be sited more proximally and does not cause a generalized disturbance of motor axon excitability.

Failure to retain participants in randomised controlled trials and longitudinal studies can cause significant methodological problems. We report the recruitment and retention strategies of a randomised controlled trial to promote fire-related injury prevention in families with pre-school children attending children’s centres in disadvantaged areas in England. Thirty-six children’s centres were cluster randomised into one of three arms of a 12-month fire-related injury prevention trial. Two arms delivered safety interventions and there was one control arm. Retention rates compared the numbers of participants responding to the 12-month questionnaire to the number recruited to the trial. Multivariable random effects logistic regression was used to explore factors independently associated with participant retention. The trial exceeded its required sample size through the use of multiple recruitment strategies. All children’s centres remained in the study, despite increased reorganisation. Parent retention was 68% at 12 months, ranging from 65% to 70% across trial arms and from 62% to 74% across trial sites. There was no significant difference in the rates of retention between trial arms (p = 0.58) or between trial sites (p = 0.16). Retention was significantly lower amongst mothers aged 16–25 years than older mothers [adjusted odds ratio (AOR) 0.57, 95% CI 0.41, 0.78], those living in non-owner occupied accommodation than in owner occupied accommodation (AOR 0.53, 95% CI 0.38, 0.73) and those living in more disadvantaged areas (most versus least disadvantaged quintiles AOR 0.50, 95% CI 0.30, 0.82). Studies recruiting disadvantaged populations should measure and report attrition by socioeconomic factors to enable determination of the extent of attrition bias and estimation of its potential impact on findings. Where differential attrition is anticipated, consideration should be given to over-sampling during recruitment and targeted and more intensive strategies of participant retention in these sub-groups. In transient populations collection of multiple sources of contact information at recruitment and throughout the study may aid retention. Clinicaltrials.gov identifier: NCT01452191 ; Date of registration: 10 October 2011, ISRCTN65067450 .

An estimated 5.6–5.8% of U.S. schoolchildren—nearly 13 million students—receive medication every school day.[1][1] In Florida alone, an average of 19,137 medication doses per day were administered to 405,149 children with reported health conditions during the 2003–04 school year.[2][2]

Assessment of a series of 279 cases with Lewy body disease revealed 14 families having a family history consistent with autosomal dominant inheritance, eight of these with dominant Parkinsonism and six with dominant dementia. Analysis of the age at onset and genetic features in these families revealed significant anticipation only in a subset of parkinsonian families, with no pathological alleles for spinocerebellar ataxias or the common α-synuclein or LRRK2 point mutations.

Background To improve the translation of public health evidence into practice, there is a need to increase practitioner involvement in initiative development, to place greater emphasis on contextual knowledge, and to address intervention processes and outcomes. Evidence that demonstrates the need to reduce childhood fire-related injuries is compelling but its translation into practice is inconsistent and limited. With this knowledge the Keeping Children Safe programme developed an "Injury Prevention Briefing (IPB)" using a 7 step process to combine scientific evidence with practitioner contextual knowledge. The IPB was designed specifically for children’s centres (CCs) to support delivery of key fire safety messages to parents. This paper reports the findings of a nested qualitative study within a clustered randomised controlled trial of the IPB, in which staff described their experiences of IPB implementation to aid understanding of why or how the intervention worked. Methods Interviews were conducted with key staff at 24 CCs participating in the two intervention arms: 1) IPB supplemented by initial training and regular facilitation; 2) IPB sent by post with no facilitation. Framework Analysis was applied to these interview data to explore intervention adherence including; exposure or dose; quality of delivery; participant responsiveness; programme differentiation; and staff experience of IPB implementation. This included barriers, facilitators and suggested improvements. Results 83% of CCs regarded the IPB as a simple, accessible tool which raised awareness, and stimulated discussion and behaviour change. 15 CCs suggested minor modifications to format and content. Four levels of implementation were identified according to content, frequency, duration and coverage. Most CCs (75%) achieved ‘extended’ or ‘essential’ IPB implementation. Three universal factors affected all CCs: organisational change and resourcing; working with hard to engage groups; additional demands of participating in a research study. Six specific factors were associated with the implementation level achieved: staff engagement and training; staff continuity; adaptability and flexibility; other agency support; conflicting priorities; facilitation. CCs achieving high implementation levels increased from 58% (no facilitation) to 92% with facilitation. Conclusion Incorporating service provider perspectives and scientific evidence into health education initiatives enhances potential for successful implementation, particularly when supplemented by ongoing training and facilitation. Electronic supplementary material The online version of this article (doi:10.1186/1471-2458-14-1256) contains supplementary material, which is available to authorized users.

Imatinib mesylate (GLEEVEC, GLIVEC, formerly STI571) has demonstrated unprecedented efficacy as first-line therapy for treatment for all phases of chronic myelogenous leukemia and metastatic and unresectable malignant gastrointestinal stromal tumors. Disposition and biotransformation of imatinib were studied in four male healthy volunteers after a single oral dose of 239 mg of (14)C-labeled imatinib mesylate. Biological fluids were analyzed for total radioactivity, imatinib, and its main metabolite CGP74588. Metabolite patterns were determined by radio-high-performance liquid chromatography with off-line microplate solid scintillation counting and characterized by liquid chromatography-mass spectrometry. Imatinib treatment was well tolerated without serious adverse events. Absorption was rapid (t(max) 1-2 h) and complete with imatinib as the major radioactive compound in plasma. Maximum plasma concentrations were 0.921 +/- 0.095 mug/ml (mean +/- S.D., n = 4) for imatinib and 0.115 +/- 0.026 mug/ml for the pharmacologically active N-desmethyl metabolite (CGP74588). Mean plasma terminal elimination half-lives were 13.5 +/- 0.9 h for imatinib, 20.6 +/- 1.7 h for CGP74588, and 57.3 +/- 12.5 h for (14)C radioactivity. Imatinib was predominantly cleared through oxidative metabolism. Approximately 65 and 9% of total systemic exposure [AUC(0-24 h) (area under the concentration time curve) of radioactivity] corresponded to imatinib and CGP74588, respectively. The remaining proportion corresponded mainly to oxidized derivatives of imatinib and CGP74588. Imatinib and its metabolites were excreted predominantly via the biliary-fecal route. Excretion of radioactivity was slow with a mean radiocarbon recovery of 80% within 7 days (67% in feces, 13% in urine). Approximately 28 and 13% of the dose in the excreta corresponded to imatinib and CGP74588, respectively.

Imatinib mesylate, licensed to treat chronic myelogenous leukemia and gastrointestinal stromal tumors, is metabolized by cytochrome P450 3A and undergoes little renal excretion, but its biliary excretion by humans is uncharacterized. Liquid chromatography-mass spectrometry was used to quantitate imatinib and its metabolite CGP 74588 in the bile of two patients with biliary stents; the ratio of imatinib:CGP 74588 in each was approximately 9:1. In the first patient, who was receiving long-term therapy with imatinib 400 mg/day and had normal liver function tests, biliary imatinib accounted for 17.7% of the daily dose and CGP 74588 accounted for 2.1%. In the second patient, who had elevated liver function tests and was studied after his first dose of imatinib 300 mg, biliary imatinib accounted for only 1.8% of the daily dose and CGP 74588 accounted for 0.2%. These data show both the qualitative similarities and the quantitative variability in biliary excretion of imatinib and its principal metabolite.

We describe 8 patients who presented with continuous, irregular movements occurring independently in individual fingers and, in some cases, toes, in the setting of mild dystonia present since early childhood and not associated with major disability. The finger movements varied from low-amplitude quivering or wriggling to larger amplitude movements in the plane of abduction-adduction as well as flexion-extension; they were asymmetrical but not unilateral. Quivering or working of the facial muscles was seen in 5 patients. Most patients reported worsening of the movements over the years, but there was no other evidence of a progressive neurological disease. We classify the movement disorder as athetosis as described by Hammond and Shaw and the syndrome as mild athetoid cerebral palsy.

This study statistically evaluated a set of commonly measured tremor parameters to determine their individual and combined ability to discriminate between essential tremor (ET) and Parkinsonian tremor (PT). Accelerometer and surface electromyographic (EMG) records of moderate to severe upper limb tremor in 20 patients with ET and 22 patients with PT were used to quantitatively compare tremor amplitude, frequency and pattern of muscle bursting in two resting and three non resting postures. The group statistics showed significant differences between ET and PT with respect to tremor frequency in all five postures, tremor amplitude at rest and muscle bursting patterns. Discriminant function analysis showed that no single parameter or combination of parameters was able to correctly classify all patients. Frequency was much more discriminating than amplitude or muscle bursting patterns in all limb postures. The best amplitude discrimination was obtained when the hand and forearm were both fully supported. Muscle bursting patterns were poorly discriminating and did not assist in correct classification of single patients. Group statistics confirmed a highly significant biological difference between the two tremor types. Optimal classification of single PT (86% correct) and ET (95% correct) patients was obtained using frequency and two selected amplitude parameters from the resting limb. Limb posture was an important variable in optimising the discriminative ability of tremor studies. The implications for routine tremor studies are summarised.

Background The UK has one of the highest rates for deaths from fire and flames in children aged 0-14 years compared to other high income countries. Evidence shows that smoke alarms can reduce the risk of fire-related injury but little exists on their cost-effectiveness. We aimed to compare the cost effectiveness of different interventions for the uptake of 'functioning' smoke alarms and consequently for the prevention of fire-related injuries in children in the UK. Methods We carried out a decision model-based probabilistic cost-effectiveness analysis. We used a hypothetical population of newborns and evaluated the impact of living in a household with or without a functioning smoke alarm during the first 5 years of their life on overall lifetime costs and quality of life from a public health perspective. We compared seven interventions, ranging from usual care to more complex interventions comprising of education, free/low cost equipment giveaway, equipment fitting and/or home safety inspection. Results Education and free/low cost equipment was the most cost-effective intervention with an estimated incremental cost-effectiveness ratio of [pound sign]34,200 per QALY gained compared to usual care. This was reduced to approximately £4,500 per QALY gained when 1.8 children under the age of 5 were assumed per household. Conclusions Assessing cost-effectiveness, as well as effectiveness, is important in a public sector system operating under a fixed budget restraint. As highlighted in this study, the more effective interventions (in this case the more complex interventions) may not necessarily be the ones considered the most cost-effective.

Highlights • We performed an overview of published systematic reviews and a systematic review of primary studies evaluating the effectiveness of interventions to prevent scalds in childhood. • There is little evidence that interventions are effective in reducing the incidence of scalds in children. • There is no consistent evidence on the effectiveness of interventions on the safe handling of hot food or drinks nor improving kitchen safety practices. • Education, home safety checks along with thermometers or thermostatic mixing valves is effective in reducing hot water temperature., Objective To synthesise and evaluate the evidence of the effectiveness of interventions to prevent scalds in children. Methods An overview of systematic reviews (SR) and a SR of primary studies were performed evaluating interventions to prevent scalds in children. A comprehensive literature search was conducted covering various resources up to October 2012. Experimental and controlled observational studies reporting scald injuries, safety practices and safety equipment use were included. Results Fourteen systematic reviews and 39 primary studies were included. There is little evidence that interventions are effective in reducing the incidence of scalds in children. More evidence was found that inventions are effective in promoting safe hot tap water temperature, especially when home safety education, home safety checks and discounted or free safety equipment including thermometers and thermostatic mixing valves were provided. No consistent evidence was found for the effectiveness of interventions on the safe handling of hot food or drinks nor improving kitchen safety practices. Conclusion Education, home safety checks along with thermometers or thermostatic mixing valves should be promoted to reduce tap water scalds. Further research is needed to evaluate the effectiveness of interventions on scald injuries and to disentangle the effects of multifaceted interventions on scald injuries and safety practices.

Background Childhood unintentional and suspected poisonings are a serious public health problem. Evidence from systematic reviews demonstrates that home safety education in combination with safety equipment provision increases the safe storage of medicines and other products. There is lack of evidence that poisoning prevention practices reduce poisoning rates. Objectives To estimate ORs for medically attended poisonings in children aged 0–4 years for items of safety equipment, home hazards and parental safety practices aimed at preventing poisoning, and to explore differential effects by child and family factors. Design Multicentre case-control study in UK hospitals with validation of parent-reported exposures using home observations. Cases are aged 0–4 years with a medically attended poisoning occurring at home, matched on age and sex with community controls. Children attending hospital for other types of injury will serve as unmatched hospital controls. Matched analyses will use conditional logistic regression; unmatched analyses will use unconditional logistic regression to adjust for confounding variables. The study requires 266 poisoning cases and 1064 matched controls to detect an OR of 0.64 for safe storage of medicinal products and of 0.65 for non-medicinal products, with 80% power, a 5% significance level and a correlation between exposures in cases and controls of 0.1. Main outcome measures Unintentional childhood poisoning. Discussion This will be the largest study to date exploring modifiable risk factors for poisoning in young children. Findings will inform: policy makers developing poison prevention strategies, practitioners delivering poison prevention interventions, parents to reduce the risk of poisoning in their homes.

Children's centres were established across England to provide a range of services including early education, social care and health to pre-school children and their families. We surveyed children's centres to ascertain the activities they were undertaking to prevent unintentional injuries in the under fives. A postal questionnaire was sent to a sample of children's centre managers (n = 694). It included questions on current activities, knowledge and attitudes to injury prevention, health priorities and partnership working. Responses were received from 384 (56%) children's centres. Overall, 58% considered unintentional injury prevention to be one of the three main child health priorities for their centre. Over half the respondents (59%) did not know if there was an injury prevention group in their area, and 21% did not know if there was a home safety equipment scheme. Knowledge of how child injury deaths occur in the home was poor. Only 11% knew the major cause of injury deaths in children under five. Lack of both staff time and funding were seen as important barriers by children's centre staff to undertake injury prevention activities. Nearly all stated that training (97%) and assistance with planning injury prevention (94%) would be helpful to their centres. Children's centres need further support if they are to effectively tackle this important public health area.

Abnormal substantia nigra morphology in healthy individuals, viewed with transcranial ultrasound, is a significant risk factor for Parkinson's disease. However, little is known about the functional consequences of this abnormality (termed 'hyperechogenicity') on movement. The aim of the current study was to investigate hand function in healthy older adults with (SN?) and without (SN-) substantia nigra hyperechogenicity during object manipulation. We hypothesised that SN? subjects would exhibit increased grip force and a slower rate of force application compared to SN- subjects. Twenty-six healthy older adults (8 SN? aged 58 ± 8 years, 18 SN- aged 57 ± 6 years) were asked to grip and lift a light-weight object with the dominant hand. Horizontal grip force, vertical lift force, acceleration, and first dorsal interosseus EMG were recorded during three trials. During the first trial, SN? subjects exhibited a longer period between grip onset and lift onset (i.e. preload duration; 0.27 ± 0.25 s) than SN- subjects (0.13 ± 0.08 s; P = 0.046). They also exerted a greater downward force prior to lift off (-0.54 ± 0.42 N vs. -0.21 ± 0.12 N; P = 0.005) and used a greater grip force to lift the object (19.5 ± 7.0 N vs. 14.0 ± 4.3 N; P = 0.022) than SNsubjects. No between group differences were observed in subsequent trials. SN? subjects exhibit impaired planning for manipulation of new objects. SN? individuals overestimate the grip force required, despite a longer contact period prior to lifting the object. The pattern of impairment observed in SN? subjects shares similarities with de novo Parkinson's disease patients. Refereed/Peer-reviewed

Background:- The UK has one of the highest fatality rates for deaths from fire-related injuries in children aged 0–14 years; these injuries have the steepest social gradient of all injuries in the UK. Children’s centres provide children under five years old and their families with a range of services and information, including home safety, but their effectiveness in promoting injury prevention has yet to be evaluated. We developed a fire prevention intervention for use in children’s centres comprising an Injury Prevention Briefing (IPB) which provides evidence on what works and best practice from those running injury prevention programmes, and a facilitation package to support implementation of the IPB. This protocol describes the design and methods of a trial evaluating the effectiveness and cost-effectiveness of the IPB and facilitation package in promoting fire prevention. Methods/Design:- Pragmatic, multicentre cluster randomised controlled trial, with a nested qualitative study, in four study centres in England. Children’s centres in the most disadvantaged areas will be eligible to participate and will be randomised to one of three treatment arms comprising: IPB with facilitation package; IPB with no facilitation package; usual care (control). The primary outcome measure will be the proportion of families who have a fire escape plan at follow-up. Eleven children’s centres per arm are required to detect an absolute difference in the percentage of families with a fire escape plan of 20% in either of the two intervention arms compared with the control arm, with 80% power and a 5% significance level (2-sided), an intraclass correlation coefficient of 0.05 and assuming outcomes are assessed on 20 families per children’s centre. Secondary outcomes include the assessment of the cost-effectiveness of the intervention, other fire safety behaviours and factors associated with degree of implementation of the IPB. Discussion:- This will be the first trial to develop and evaluate a fire prevention intervention for use in children’s centres in the UK. Its findings will be generalisable to children’s centres in the most disadvantaged areas of the UK and may also be generalisable to similar interventions to prevent other types of injury. Trial registration:- http://NCT01452191 webcite (date of registration: 13/10/2011).

Vancomycin, a macrocyclic antibiotic, is an amphoteric glycopeptide produced by Streptomyces orientalis which has proven to be a viable chiral selector for high performance liquid chromatograph (HPLC) (D. W. Armstrong, Y. Tang, S. Chen, Y. Zhou, C. Bagwill and J-R. Chen, Anal. Chem. (1994; 66: 1473). While it is related to other glycopeptide antibiotics, vancomycin has a number of unique structural features, including 18 stereogenic centers, five aromatic rings, and two side chains one of which is a carbohydrate dimer. Therefore, a vancomycin-based stationary phase appears to be multimodal in that it can be utilized in both normal-phase and reversed-phase liquid chromatography. Consequently, the enantiomeric separation may be operative via several mechanisms, including π–π complexation, dipole stacking, inclusion, hydrogen bonding, or combinations of these interactions. LC/MS/MS is a powerful tool for quantitative analysis when evaluated on the basis of speed, specificity, reliability and sensitivity. For these reasons, the present paper explored the feasibility of bonded macrocyclic glycopeptide phases for chiral LC/MS/MS quantitative analysis. Methylphenidate was used as a model compound. A rapid chiral bioanalytical method (

OBJECTIVES—To describe the clinical and neuroradiological features of basilar impression in patients with osteogenesis imperfecta type IV. METHODS—Four patients with basilar impression were ascertained in a population study of osteogenesis imperfecta. All four had detailed clinical and neuroradiological examination with both CT and MRI of the craniocervical junction andposterior fossa structures. RESULTS—All four showed significant compression of the posterior fossa structures and surgical decompression was performed with relief of symptoms. CONCLUSION—Symptoms of cough headache and trigeminal neuralgia occurring in patients with osteogenesis imperfecta are indications for detailed clinical and neuroradiological investigation to document basilar impression.

A 1996 World Health Organisation report, Investing in Health Research and Development , warns that worldwide, “the epidemic of injuries may be among the most neglected health problems of the late 20th century” .1 We see evidence of this neglect in investment in injury research, and in the paucity of evaluated studies on injury prevention for children and young people. More neglected still, is a concerted attempt to implement established interventions at national and local levels throughout the UK. The path to implementation is broken too often. In this chapter we explore the barriers and opportunities in the UK for implementing injury prevention for this age group in a more widespread and systematic manner. We first examine the picture of injury prevention at national and local levels. This leads to the conclusion that there would be significant benefits from having national lead agencies for this problem along with improved local coordination. To this end we look at: Three examples are then presented. The first examines the scope for injury prevention in the primary health care setting. It focuses on an individual approach to children, young people and their families, and represents a possible opportunity for health promotion. The other examples both involve multiagency approaches. Example two is a multiagency programme to promote cycle helmet use. Example three documents the use of a Safe Community approach. In the UK, no single agency or profession “owns” the prevention of unintentional injuries to children and young people, either at national government or local levels. This can lead, at worst, to a failure to act, or at best to a lack of coordination or duplication of …

The isolation of embryonic stem cells (ESCs) has furthered our understanding of normal embryonic development and fueled the progression of stem cell derived therapies. However, the generation of ESCs requires the destruction of an embryo, making the use of these cells ethically controversial. In 2006 the Yamanaka group overcame this ethical controversy when they described a protocol whereby somatic cells could be dedifferentiated into a pluripotent state following the transduction of a four transcription factor cocktail. Following this initial study numerous groups have described protocols to generate induced pluripotent stem cells (iPSCs). These protocols have simplified the reprogramming strategy by employing polycistronic reprogramming cassettes and flanking such polycistronic cassettes with loxP or piggyBac recognition sequences. Thus, these strategies allow for excision of the entire transgene cassette, limiting the potential for the integration of exogenous transgenes to have detrimental effect. Others have prevented the potentially deleterious effects of integrative reprogramming strategies by using non-integrating adenoviral vectors, traditional recombinant DNA transfection, transfection of minicircle DNA, or transfection of episomally maintained EBNA1/OriP plasmids. Interestingly, transfection of mRNA or miRNA has also been shown to be capable of reprogramming cells, and multiple groups have developed protocols using cell penetrating peptide tagged reprogramming factors to de-differentiate somatic cells in the absence of exogenous nucleic acid. Despite the numerous different reprogramming strategies that have been developed, the reprogramming process remains extremely inefficient. To overcome this inefficiency multiple groups have successfully used small molecules such as valproic acid, sodium butyrate, PD0325901, and others to generate iPSCs.The fast paced field of cellular reprogramming has recently produced protocols to generate iPSCs using non integrative techniques with an ever improving efficiency. These recent developments have brought us one step closer to developing a safe and efficient method to reprogram cells for clinical use. However, a lot of work is still needed before iPSCs can be implemented in a clinical setting.

OBJECTIVE: To determine whether advocacy targeted at local politicians leads to action to reduce the risk of pedestrian injury in deprived areas. DESIGN: Cluster randomised controlled trial. SETTING: 239 electoral wards in 57 local authorities in England and Wales. PARTICIPANTS: 617 elected local politicians. INTERVENTIONS: Intervention group politicians were provided with tailored information packs, including maps of casualty sites, numbers injured and a synopsis of effective interventions. MAIN OUTCOME MEASURES: 25-30 months post intervention, primary outcomes included: electoral ward level: percentage of road traffic calmed; proportion with new interventions; school level: percentage with 20 mph zones, Safe Routes to School, pedestrian training or road safety education; politician level: percentage lobbying for safety measures. Secondary outcomes included politicians' interest and involvement in injury prevention, and facilitators and barriers to implementation. RESULTS: PRIMARY OUTCOMES DID NOT SIGNIFICANTLY DIFFER: % difference in traffic calming (0.07, 95%CI: -0.07 to 0.20); proportion of schools with 20 mph zones (RR 1.47, 95%CI: 0.93 to 2.32), Safe Routes to School (RR 1.34, 95%CI: 0.83 to 2.17), pedestrian training (RR 1.23, 95%CI: 0.95 to 1.61) or other safety education (RR 1.16, 95%CI: 0.97 to 1.39). Intervention group politicians reported greater interest in child injury prevention (RR 1.09, 95%CI 1.03 to 1.16), belief in potential to help prevent injuries (RR 1.36, 95%CI 1.16 to 1.61), particularly pedestrian safety (RR 1.55, 95%CI 1.19 to 2.03). 63% of intervention politicians reported supporting new pedestrian safety schemes. The majority found the advocacy information surprising, interesting, effectively presented, and could identify suitable local interventions. CONCLUSIONS: This study demonstrates the feasibility of an innovative approach to translational public health by targeting local politicians in a randomised controlled trial. The intervention package was positively viewed and raised interest but changes in interventions were not statistically significance. Longer term supported advocacy may be needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN91381117. Language: en

This study evaluates the correlation between imatinib trough plasma concentrations (C(min)) and clinical response and safety in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase in the Tyrosine Kinase Inhibitor OPtimization and Selectivity (TOPS) trial.Patients were randomized 1:2 to 400 mg/day or 800 mg/day imatinib. Imatinib C(min) levels were collected at pre-dose before treatment, and at the end of months 1 (day 29), 6, 9, and 12.Imatinib C(min) were stable over time in the 400 mg/day dose arm, but showed a slight decrease in the 800 mg/day arm due to dose adjustments between months 1-6. The overall median imatinib C(min) levels were 1040, 1200, 1935, and 2690 ng/mL for the actual 300, 400, 600, and 800 mg/day doses, respectively. The rates of major molecular response (MMR) at 3, 6, 9, and 12 months, and complete cytogenetic response (CCyR) at 6 and 12 months were significantly lower among patients with the lowest imatinib C(min) levels at Day 29 (1165 ng/mL, 25th percentile). There was an apparent association between high imatinib C(min) and the occurrence of grade 3/4 neutropenia and all-grade rash, diarrhea, arthralgia/myalgia, and all-cause edema. Conclusions Imatinib C(min) levels were relatively stable over time and proportional to the dose administered. Patients with an imatinib C(min) above 1165 ng/mL on Day 29 achieved MMR faster and had higher MMR and CCyR rates at 12 months. There appeared to be an association between imatinib C(min) and the frequency of some adverse events. This trial was registered at http://www.clinicaltrials.gov as NCT00124748.

Objective: To examine the safety and efficacy of onabotulinumtoxinA (Botox) for plantarflexor overactivity following stroke. Design: Double-blind randomized controlled trial, open-label extension phase. Setting: Neurology rehabilitation facilities. Subjects: Eighty-five subjects with lower limb hypertonia received 200 U ( n = 28) or 300 U ( n = 28) of onabotulinumtoxinA or saline ( n = 29) injection. Primary measures: Plantarflexor Ashworth scores at 12 weeks post injection and adverse events. Secondary measures: self-reported spasm frequency and pain, physician rating of hypertonia severity, gait quality and active dorsiflexion. Results: Differences were not seen between onabotulinumtoxinA groups; hence data were pooled. Incidence of adverse events was not different between groups ( P = 0.61). Reduction in hypertonia was not different between groups at 12 weeks ( P = 0.53); however for subjects with Ashworth scores of >3 at baseline, 14/31 in the onabotulinumtoxinA group demonstrated a reduction of >1 grade versus 1/17 receiving placebo injection ( P = 0.01). Overall, onabotulinumtoxinA-injected subjects demonstrated significantly greater improvement in spasm frequency (22/54 versus 4/29, P = 0.01), pain reduction (8/54 versus 1/29, P = 0.02), active dorsiflexion (8/54 versus 1/29 P = 0.03) and gait quality (17/54 versus 6/29, P = 0.02) than controls. In the open-label phase, a second onabotulinumtoxinA injection was associated with greater hypertonia reduction ( P = 0.005) and gait quality ( P = 0.002) compared with single injection. Conclusions: OnabotulinumtoxinA injection for ankle flexor overactivity after stroke was safe and well tolerated but did not alter local spasticity at 12 weeks; it did reduce spasms and improve gait quality. There were no detectable differences between higher and lower doses. A second injection may be associated with greater change.

Unintentional injuries are the second most common cause of child death, accounting for one in seven deaths between the ages of 1 and 14 years.1 These deaths represent just the tip of the iceberg. Every year, around 100 000 children are admitted to hospital2 and 2 million attend emergency departments.3 How many seek treatment only from their GP is not known. The impact of injuries on children, their families, and society can be considerable. The immediate effect of an injury is pain, followed by the psychological trauma of having to visit hospital, and loss of enjoyment of everyday activities such as play. But children can also be left disabled and disfigured, and lose education, potentially affecting the rest of their lives. Caring for an injured child can cause family breakdown and loss of employment, as well as having immediate economic consequences. Society has to bear the costs of treatment, rehabilitation, and long-term support. Unintentional injuries are often thought of as accidents, but they are not random, unpredictable events as the term accident implies. We can identify children at risk of injuries and the injuries they are likely to suffer. Those from disadvantaged families are at greatest risk.4 Not surprisingly, the types of injuries experienced are strongly related to a child's stage of development. For example, the more active children become, the more likely they are to run and trip, and climb and fall; the exploratory stage of child development results in children putting objects in their mouth leading to choking and poisoning. Copying adult tasks, such as food preparation, can lead to lacerations and burns. GPs and primary health care teams (PHCTs) have multiple opportunities to contribute to injury prevention and these are highlighted in three …

Mohr-Tranebjaerg syndrome (MTS) is an X-linked recessive disorder characterized by deafness and dystonia. However the phenotypic expression of dystonia has not been systematically defined. We report clinical, neurophysiological, and ophthalmological data on 6 subjects from 3 Australian kindreds, including 2 with novel mutations, together with a systematic review of the literature, in order to define the phenotypic expression of dystonia. Profound hearing impairment in affected males develops by infancy and precedes the development of dystonia, which varies in time of onset from the first to the sixth decades, with a peak in the second and third decades. Dystonia in MTS tends to be focal, segmental, or multifocal in distribution at onset, with a predilection for the upper body, variably involving the head, neck, and upper limbs. The majority of patients have progression or generalization of their dystonia regardless of age of onset. Within our 3 kindreds, we observed relative intrafamilial homogeneity but interfamilial variation. The median time to the development of moderate-severely disabling dystonia in these subjects was 11 years. Associated features included progressive cognitive decline, pyramidal signs, and in 1 patient, gait freezing and postural instability. Optic atrophy and cortical visual impairment were both observed. We report for the first time a female patient who developed multiple disabling neurological complications of MTS. Our findings more clearly define and expand the phenotype of both the dystonia and other neurological features of MTS and have implications for the diagnosis and management of this condition.