High-potency ligands for DREADD imaging and activation in rodents and monkeys.

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated 18F positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [18F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping

Caring for Caregivers (C4C): study protocol for a pilot feasibility randomised control trial of Positive Written Disclosure for older adult caregivers of people with psychosis

Background: The caregivers of people who experience psychosis are themselves at risk of developing physical and mental health problems. This risk is increased for older adult caregivers who also have to manage the lifestyle and health changes associated with ageing. As a consequence, older adult caregivers are in particular need of support; we propose a Written Emotional Disclosure (WED) intervention, called Positive Written Disclosure (PWD). Methods/design: This is a pilot randomised controlled trial of PWD compared to a neutral writing control and a no writing condition. We aim to recruit 60 participants, 20 in each arm. This study will utilise a mixed-methods approach and collect quantitative (questionnaires) and qualitative (interviews) data. Quantitative data will be collected at baseline and 1, 3, and 6 months post baseline. Participants who complete a writing task (PWD or neutral writing control) will be invited to complete an exit interview to discuss their experiences of the intervention and study. The study is supported by a patient and public involvement group. Discussion: The results of this trial will determine whether a definitive trial is justified. If so, the quantitative and qualitative findings will be used to refine the intervention and study protocols

Aquatic therapy for boys with Duchenne muscular dystrophy (DMD): an external pilot randomised controlled trial

Background: Standard treatment of Duchenne muscular dystrophy (DMD) includes regular physiotherapy. There are no data to show whether adding aquatic therapy (AT) to land-based exercises helps maintain motor function. We assessed the feasibility of recruiting and collecting data from boys with DMD in a parallel-group pilot randomised trial (primary objective), also assessing how intervention and trial procedures work. Methods: Ambulant boys with DMD aged 7–16 years established on steroids, with North Star Ambulatory Assessment (NSAA) score ≥8, who were able to complete a 10-m walk test without aids or assistance, were randomly allocated (1:1) to 6 months of either optimised land-based exercises 4 to 6 days/week, defined by local community physiotherapists, or the same 4 days/week plus AT 2 days/week. Those unable to commit to a programme, with >20% variation between NSAA scores 4 weeks apart, or contraindications to AT were excluded. The main outcome measures included feasibility of recruiting 40 participants in 6 months from six UK centres, clinical outcomes including NSAA, independent assessment of treatment optimisation, participant/therapist views on acceptability of intervention and research protocols, value of information (VoI) analysis and cost-impact analysis. Results: Over 6 months, 348 boys were screened: most lived too far from centres or were enrolled in other trials; 12 (30% of the targets) were randomised to AT (n = 8) or control (n = 4). The mean change in NSAA at 6 months was −5.5 (SD 7.8) in the control arm and −2.8 (SD 4.1) in the AT arm. Harms included fatigue in two boys, pain in one. Physiotherapists and parents valued AT but believed it should be delivered in community settings. Randomisation was unattractive to families, who had already decided that AT was useful and who often preferred to enrol in drug studies. The AT prescription was considered to be optimised for three boys, with other boys given programmes that were too extensive and insufficiently focused. Recruitment was insufficient for VoI analysis. Conclusions: Neither a UK-based RCT of AT nor a twice weekly AT therapy delivered at tertiary centres is feasible. Our study will help in the optimisation of AT service provision and the design of future research. Trial registration: ISRCTN4100295

Ancient DNA Elucidates the Controversy about the Flightless Island Hens (Gallinula sp.) of Tristan da Cunha

A persistent controversy surrounds the flightless island hen of Tristan da Cunha, Gallinula nesiotis. Some believe that it became extinct by the end of the 19th century. Others suppose that it still inhabits Tristan. There is no consensus about Gallinula comeri, the name introduced for the flightless moorhen from the nearby island of Gough. On the basis of DNA sequencing of both recently collected and historical material, we conclude that G. nesiotis and G. comeri are different taxa, that G. nesiotis indeed became extinct, and that G. comeri now inhabits both islands. This study confirms that among gallinules seemingly radical adaptations (such as the loss of flight) can readily evolve in parallel on different islands, while conspicuous changes in other morphological characters fail to occur

The Hippocampus Is Coupled with the Default Network during Memory Retrieval but Not during Memory Encoding

The brain's default mode network (DMN) is activated during internally-oriented tasks and shows strong coherence in spontaneous rest activity. Despite a surge of recent interest, the functional role of the DMN remains poorly understood. Interestingly, the DMN activates during retrieval of past events but deactivates during encoding of novel events into memory. One hypothesis is that these opposing effects reflect a difference between attentional orienting towards internal events, such as retrieved memories, vs. external events, such as to-be-encoded stimuli. Another hypothesis is that hippocampal regions are coupled with the DMN during retrieval but decoupled from the DMN during encoding. The present fMRI study investigated these two hypotheses by combining a resting-state coherence analysis with a task that measured the encoding and retrieval of both internally-generated and externally-presented events. Results revealed that the main DMN regions were activated during retrieval but deactivated during encoding. Counter to the internal orienting hypothesis, this pattern was not modulated by whether memory events were internal or external. Consistent with the hippocampal coupling hypothesis, the hippocampus behaved like other DMN regions during retrieval but not during encoding. Taken together, our findings clarify the relationship between the DMN and the neural correlates of memory retrieval and encoding

Mitochondrial Associated Ubiquitin Fold Modifier-1 Mediated Protein Conjugation in Leishmania donovani

In this report, we demonstrate the existence of the ubiquitin fold modifier-1 (Ufm1) and its conjugation pathway in trypanosomatid parasite Leishmania donovani. LdUfm1 is activated by E1-like enzyme LdUba5. LdUfc1 (E2) specifically interacted with LdUfm1 and LdUba5 to conjugate LdUfm1 to proteinaceous targets. Mass spectrometry analysis revealed that LdUfm1 is conjugated to Leishmania protein targets that are associated with mitochondria. Immunofluorescence experiments showed that Leishmania Ufm1, Uba5 and Ufc1 are associated with the mitochondria. The demonstration that all the components of this system as well as the substrates are associated with mitochondrion suggests it may have physiological roles not yet described in any other organism. Overexpression of a non-conjugatable form of LdUfm1 and an active site mutant of LdUba5 resulted in reduced survival of Leishmania in the macrophage. Since mitochondrial activities are developmentally regulated in the life cycle of trypanosomatids, Ufm1 mediated modifications of mitochondrial proteins may be important in such regulation. Thus, Ufm1 conjugation pathway in Leishmania could be explored as a potential drug target in the control of Leishmaniasis

Fever, hyperglycaemia and swallowing dysfunction management in acute stroke: A cluster randomised controlled trial of knowledge transfer

Background: Hyperglycaemia, fever, and swallowing dysfunction are poorly managed in the admission phase of acute stroke, and patient outcomes are compromised. Use of evidence-based guidelines could improve care but have not been effectively implemented. Our study aims to develop and trial an intervention based on multidisciplinary team-building to improve management of fever, hyperglycaemia, and swallowing dysfunction in patients following acute stroke. Methods and design: Metropolitan acute stroke units (ASUs) located in New South Wales, Australia will be stratified by service category (A or B) and, within strata, by baseline patient recruitment numbers (high or low) in this prospective, multicentre, single-blind, cluster randomised controlled trial (CRCT). ASUs then will be randomised independently to either intervention or control groups. ASUs allocated to the intervention group will receive: unit-based workshops to identify local barriers and enablers; a standardised core education program; evidence-based clinical treatment protocols; and ongoing engagement of local staff. Control group ASUs will receive only an abridged version of the National Clinical Guidelines for Acute Stroke Management. The following outcome measures will be collected at 90 days post-hospital admission: patient death, disability (modified Rankin Score); dependency (Barthel Index) and Health Status (SF-36). Additional measures include: performance of swallowing screening within 24 hours of admission; glycaemic control and temperature control. Discussion: This is a unique study of research transfer in acute stroke. Providing optimal inpatient care during the admission phase is essential if we are to combat the rising incidence of debilitating stroke. Our CRCT will also allow us to test interventions focussed on multidisciplinary ASU teams rather than individual disciplines, an imperative of modern hospital services

Multicentre cohort study to define and validate pathological assessment of response to neoadjuvant therapy in oesophagogastric adenocarcinoma

BACKGROUND: This multicentre cohort study sought to define a robust pathological indicator of clinically meaningful response to neoadjuvant chemotherapy in oesophageal adenocarcinoma. METHODS: A questionnaire was distributed to 11 UK upper gastrointestinal cancer centres to determine the use of assessment of response to neoadjuvant chemotherapy. Records of consecutive patients undergoing oesophagogastric resection at seven centres between January 2000 and December 2013 were reviewed. Pathological response to neoadjuvant chemotherapy was assessed using the Mandard Tumour Regression Grade (TRG) and lymph node downstaging. RESULTS: TRG (8 of 11 centres) was the most widely used system to assess response to neoadjuvant chemotherapy, but there was discordance on how it was used in practice. Of 1392 patients, 1293 had TRG assessment; data were available for clinical and pathological nodal status (cN and pN) in 981 patients, and TRG, cN and pN in 885. There was a significant difference in survival between responders (TRG 1–2; median overall survival (OS) not reached) and non-responders (TRG 3–5; median OS 2·22 (95 per cent c.i. 1·94 to 2·51) years; P < 0·001); the hazard ratio was 2·46 (95 per cent c.i. 1·22 to 4·95; P = 0·012). Among local non-responders, the presence of lymph node downstaging was associated with significantly improved OS compared with that of patients without lymph node downstaging (median OS not reached versus 1·92 (1·68 to 2·16) years; P < 0·001). CONCLUSION: A clinically meaningful local response to neoadjuvant chemotherapy was restricted to the small minority of patients (14·8 per cent) with TRG 1–2. Among local non-responders, a subset of patients (21·3 per cent) derived benefit from neoadjuvant chemotherapy by lymph node downstaging and their survival mirrored that of local responders