The metformin in tuberous sclerosis (MiTS) study:A randomised double-blind placebo-controlled trial

Background: Tuberous Sclerosis Complex (TSC) is a genetic disorder characterised by the development of benign tumours secondary to loss of inhibitory regulation of the mTOR (mechanistic Target of Rapamycin) intracellular growth pathway. Metformin inhibits the mTOR pathway. We investigated whether metformin would reduce growth of hamartomas associated with tuberous sclerosis complex. / Methods: In this multicentre randomized, double-blind, placebo-controlled trial, patients with a clinical diagnosis of tuberous sclerosis, aged over 10 years and with at least one renal angiomyolipoma of greater than 1 cm in diameter were enrolled. Participants were randomly allocated (1:1) by a secure website to receive metformin or placebo for 12 months. The primary outcome was percentage volume change of renal angiomyolipomas (AML) at 12 months compared to baseline. Secondary outcomes were percentage change at 12 months from baseline in volume of cerebral Subependymal Giant Cell Astrocytomas (SEGA); appearance of facial and ungual hamartomas; frequency of epileptic seizures; and adaptive behaviour. The trial is registered with The International Standard Randomised Controlled Trial Number (ISRCTN), number 92545532, and the European Union Drug Regulating Authorities Clinical Trials (EUDRACT), number 2011-001319-30. / Findings: Between 1 November 2012 and 30 September 2015 72 patients were screened and 55 were randomly assigned to metformin (28) or placebo (27). Four participants withdrew between randomisation and starting treatment. All 51 patients who started therapy completed the trial and were assessed for outcome at 12 months. The median percentage change in angiomyolipoma (AML) volume was +7.6% (IQR -1.8% to +42.6%) for the placebo group and +8.9% (IQR 1.3% to 19.5%) for the metformin group (p = 0.28). Twenty-seven patients had SEGAs: 13 received placebo and 14 metformin. The median percentage change in SEGA volume was +3.0% (IQR -22.8% to +27.7%) for the placebo group and – 20.8% (IQR – 47.1% to - 5.0%) for the metformin group (p = 0.03). Twenty-one patients were assessed for seizure frequency: 9 received placebo and 12 received metformin. In the metformin group, a mean reduction of 43.7% from baseline in seizures was observed and in the placebo group a 3.1% mean reduction was observed, with a difference in response of 40.6% (95% CI -3.1% to +84.2%, p = 0.03). There were no significant differences between metformin and placebo groups for the other secondary outcomes. There were no deaths. Three serious adverse events (SAEs) occurred during the trial (all patients on metformin). / Interpretation: Metformin did not reduce AML volume. Metformin did reduce SEGA volume and seizure frequency compared with placebo. There may be a role for metformin in slowing or reversing growth of some life-threatening hamartomas in TSC and for reducing seizure frequency. Further study is justified. / Funding: This study was funded by the National Institute for Health and Research (NIHR) through the The Research for Patient Benefit Programme (RfPB)

Prem Baby Triple P: a randomised controlled trial of enhanced parenting capacity to improve developmental outcomes in preterm infants

Background Very preterm birth (gestation) is associated with motor, cognitive, behavioural and educational problems in children and maternal depression and withdrawal. Early interventions that target parenting have the greatest potential to create sustained effects on child development and parental psychopathology. Triple P (Positive Parenting Program) has shown positive effects on child behaviour and adjustment, parenting practices and family functioning. Baby Triple P for Preterm infants, has been developed to target parents of very preterm infants. This study tests the effectiveness of Baby Triple P for Preterm infants in improving child and parent/couple outcomes at 24 months corrected age (CA). Methods/Design Families will be randomised to receive either Baby Triple P for Preterm infants or Care as Usual (CAU). Baby Triple P for Preterm infants involves 4 × 2 hr group sessions at the hospital plus 4 × 30 min telephone consultations soon after transfer (42 weeks C.A.). After discharge participants will be linked to community based Triple P and intervention maintenance up to 24 months C.A. Assessments will be: baseline, post-intervention (6 weeks C.A.), at 12 and 24 months C.A. The primary outcome measure is the Infant Toddler Social & Emotional Assessment (ITSEA) at 24 months C.A. Child behavioural and emotional problems will be coded using the mother-toddler version of the Family Observation Schedule at 24 months C.A. Secondary outcome will be the Bayley Scales of Infant and Toddler Development (BSID III) cognitive development, language and motor abilities. Proximal targets of parenting style, parental self-efficacy, parental mental health, parental adjustment, parent-infant attachment, couple relationship satisfaction and couple communication will also be assessed. Our sample size based on the ITSEA, has 80% power, predicted effect size of 0.33 and an 85% retention rate, requires 165 families are required in each group (total sample of 330 families). Discussion This protocol presents the study design, methods and intervention to be analysed in a randomised trial of Baby Triple P for Preterm infants compared to Care as Usual (CAU) for families of very preterm infants. Publications of all outcomes will be published in peer reviewed journals according to CONSORT guidelines

Cognitive training for freezing of gait in Parkinson's disease: a randomized controlled trial.

The pathophysiological mechanism of freezing of gait (FoG) has been linked to executive dysfunction. Cognitive training (CT) is a non-pharmacological intervention which has been shown to improve executive functioning in Parkinson's disease (PD). This study aimed to explore whether targeted CT can reduce the severity of FoG in PD. Patients with PD who self-reported FoG and were free from dementia were randomly allocated to receive either a CT intervention or an active control. Both groups were clinician-facilitated and conducted twice-weekly for seven weeks. The primary outcome was percentage of time spent frozen during a Timed Up and Go task, assessed both on and off dopaminergic medications. Secondary outcomes included multiple neuropsychological and psychosocial measures. A full analysis was first conducted on all participants randomized, followed by a sample of interest including only those who had objective FoG at baseline, and completed the intervention. Sixty-five patients were randomized into the study. The sample of interest included 20 in the CT group and 18 in the active control group. The primary outcome of percentage time spent frozen during a gait task was significantly improved in the CT group compared to active controls in the on-state. There were no differences in the off-state. Patients who received CT also demonstrated improved processing speed and reduced daytime sleepiness compared to those in the active control. The findings suggest that CT can reduce the severity of FoG in the on-state, however replication in a larger sample is required

Improving together: better science writing through peer learning

Science, in our case the climate and geosciences, is increasingly interdisciplinary. Scientists must therefore communicate across disciplinary boundaries. For this communication to be successful, scientists must write clearly and concisely, yet the historically poor standard of scientific writing does not seem to be improving. Scientific writing must improve, and the key to long-term improvement lies with the early-career scientist (ECS). Many interventions exist for an ECS to improve their writing, like style guides and courses. However, momentum is often difficult to maintain after these interventions are completed. Continuity is key to improving writing. This paper introduces the ClimateSnack project, which aims to motivate ECSs to develop and continue to improve their writing and communication skills. The project adopts a peer-learning framework where ECSs voluntarily form writing groups at different institutes around the world. The group members learn, discuss, and improve their writing skills together. Several ClimateSnack writing groups have formed. This paper examines why some of the groups have flourished and others have dissolved. We identify the challenges involved in making a writing group successful and effective, notably the leadership of self-organized groups, and both individual and institutional time management. Within some of the groups, peer learning clearly offers a powerful tool to improve writing as well as bringing other benefits, including improved general communication skills and increased confidence

Falkland Island peatland development processes and the pervasive presence of fire

Palaeoecological analyses of Falkland Island peat profiles have largely been confined to pollen analyses. In order to improve understanding of long-term Falkland Island peat development processes, the plant macrofossil and stable isotope stratigraphy of an 11,550 year Falkland Island Cortaderia pilosa (‘whitegrass’) peat profile was investigated. The peatland developed into an acid, whitegrass peatland via a poor fen stage. Macrofossil charcoal indicate that local fires have frequently occurred throughout the development of the peatland. Raman spectroscopy analyses indicate changes in the intensity of burning which are likely to be related to changes in fuel types, abundance of fine fuels due to reduced evapotranspiration/higher rainfall (under weaker Southern Westerly Winds), peat moisture and human disturbance. Stable isotope and thermogravimetric analyses were used to identify a period of enhanced decomposition of the peat matrices dating from ∼7020 cal yr BP, which possibly reflects increasing strength of the Southern Westerly winds. The application of Raman spectroscopy and thermogravimetric analyses to the Falkland Island peat profile identified changes in fire intensity and decomposition which were not detectable using the techniques of macrofossil charcoal and plant macrofossil analyses.</p

Predicting COVID-19 infection risk in people who are immunocompromised by antibody testing.

People with blood cancers have an increased risk of severe COVID-19 disease despite booster vaccine doses.1 This group, like other disease groups at increased risk of severe COVID-19, includes individuals with highly heterogeneous immune responses to vaccination.2 Although vaccine response studies and population studies identify similar diseases and treatments associated with increased risk of severe COVID-19, a direct correlation between antibody levels after vaccination and infection risk has been difficult to define. Identification of a laboratory correlate of infection risk would allow doctors and policy makers to target additional COVID-19 treatment or prophylactic efforts to people who are most in need

A novel topographic parameterization scheme indicates that martian gullies display the signature of liquid water

Martian gullies resemble gullies carved by water on Earth, yet are thought to have formed in an extremely cold (2-driven processes. That this argument persists demonstrates the limitations of morphological interpretations made from 2D images, especially when similar-looking landforms can form by very different processes. To overcome this we have devised a parameterization scheme, based on statistical discriminant analysis and hydrological terrain analysis of meter-scale digital topography data, which can distinguish between dry and wet surface processes acting on a landscape. Applying this approach to new meter-scale topographic datasets of Earth, the Moon and Mars, we demonstrate that martian gullied slopes are dissimilar to dry, gullied slopes on Earth and the Moon, but are similar to both terrestrial debris flows and fluvial gullies. We conclude that liquid water was integral to the process by which martian gullies formed. Finally, our work shows that quantitative 3D analyses of landscape have great potential as a tool in planetary science, enabling remote assessment of processes acting on planetary surfaces