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OBJECTIVES/GOALS: Maternal opioid use disorder (OUD) is linked to poor fetal outcomes. While it has been established that opioids can cross from maternal to fetal circulation, the mechanisms underlying these adverse outcomes remain poorly defined. This study aims to uncover OUD-associated immunological changes in maternal and fetal circulation. METHODS/STUDY POPULATION: To study the effect of maternal OUD on the maternal immune system at delivery, we collected maternal blood samples at delivery from healthy pregnant women (controls) and pregnant women with a diagnosis of severe OUD. To study the impact of maternal OUD on newborn immunity, we also collected umbilical cord blood (UCB) at delivery. Flow cytometry was used to determine the frequency and phenotype of circulating immune cell subsets and responses to stimulation. Isolated monocytes were stimulated with bacterial/viral agonist cocktails, while T and NK cells were stimulated with PMA/ionomycin. The impact of maternal OUD on circulating immune mediators was determined by Luminex and on monocyte activation markers sCD14 and CRP by ELISA. RESULTS/ANTICIPATED RESULTS: In maternal circulation, OUD was associated with a significant decrease in markers of inflammation, cell proliferation, and activation. Frequencies of immune cell subsets were impacted by OUD, shown by an expansion of CD8+ EMRA T cells, marginal-zone B cells, mDCs, non-classical monocytes, and CD16low NK cells. While no differences were seen in T and NK cell responses to stimulation, monocytes and pDCs had significantly lower responses to bacterial and viral agonist stimulation. Analysis of UCB revealed increased levels of pro-apoptotic/T cell exhaustion mediators and pro-inflammatory cytokines, albeit decreased levels of several chemokines and growth factors. The UCB immune landscape is altered with maternal OUD, as demonstrated by a shift from naive to memory CD8+ T cells and a decrease in pDC frequency. DISCUSSION/SIGNIFICANCE: OUD dampens maternal peripheral immunity, possibly contributing to poor placental function or premature/delayed labor. Monocytes and pDCs lack antimicrobial functionality, suggesting increased infection susceptibility with OUD. Finally, these implications extend to the fetal compartment, shown by heightened immune activation in UCB.

Introduction: The mechanistic associations between small vessel disease (SVD) and dementia are still poorly understood. The APOE ε4 allele, recognised as the strongest genetic risk factor for Alzheimer's disease, has been previously implicated in SVD, although it remains unclear whether this association is gene-dose dependent. An emerging neuroimaging biomarker of SVD is Peak Width of Skeletonised Mean Diffusivity (PSMD), obtained from histogram analyses of diffusion weighted imaging (DWI) datasets. Here, we investigated the relationship between APOE ε4 gene dose and PSMD, as a surrogate marker of SVD, in a group of cognitively normal middle-aged adults. Methods: The study included data from 1954 asymptomatic middle-aged adults from the ALFA (ALzheimer and FAmilies) and PREVENT-Dementia cohorts (See Table 1 for sample characteristics). PSMD was calculated from the DWI datasets using a publicly available script, and harmonised using COMBAT to account for site-related differences. Using non-parametric permutation models, our primary analyses focused on the (a) comparison of group differences (APOE ε4 heterozygotes vs homozygotes vs non-carriers) in PSMD, adjusting for age, sex, years of formal education, and sites; and (b) potential interactions between APOE ε4 gene dose and age on PSMD values. Marginal predictions were used to estimate the earliest age at which differences might emerge between the APOE ε4 groups and non-carriers. Results: There were no significant differences in PSMD values across the non-carriers (n=1,197), heterozygous carriers (n=659), and homozygous APOE ε4 carriers (n=98) (p = 0.6; Figure 1). However, there was a statistically significant interaction between APOE ε4 gene dose and age on PSMD. Specifically, homozygous APOE ε4 carriers exhibited a steeper increase in PSMD with age compared to non-carriers and heterozygous carriers (T = 4.7, p

Introduction: Cerebral small vessel disease (SVD) is a major cause of cognitive impairment and stroke. Neuroinflammation and blood-brain barrier (BBB) leakage may play a role in pathogenesis, but no definitive causal link has been established. In a rodent SVD model, minocycline treatment reduced brain lesions, neuroinflammation and BBB permeability. We tested whether these processes can be altered in SVD. Methods: MINERVA was a phase II, double-blind, randomised controlled trial in moderate-to-severe symptomatic SVD. Participants with lacunar stroke and confluent white matter hyperintensities underwent simultaneous dynamic contrast-enhanced MRI to measure BBB permeability and 11C- PK11195 positron emission tomography (PET) to quantify microglial signal (figure 1). They were randomised to either minocycline 100mg bd or placebo for three months, after which PET-MRI was repeated. The co-primary outcomes were volumes of ‘hotspots’ of increased BBB permeability and 11C-PK11195 binding in the normal appearing white matter above the 95th percentile of healthy control reference values. A sample size of 44 allowed detection of a 20% reduction in these metrics (power = 80%, α=0.05). Results: 44 patients were recruited from September 2019 - June 2022 at 23.1±24.7 months after lacunar stroke. Mean age was 69.9±10.8 years and 28/44 (63.6%) were male. 86.4% had a history of hypertension, 75.0% of hypercholesterolaemia and 18.2% were diabetic. Participants had mean white matter lesion volume of 31.3±26.0cc and median 2 (IQR 1–3) lacunes. The BBB permeability ‘hotspot’ tissue was 4.08±3.69% in the treatment group at baseline and 6.19±5.09% at follow-up; ‘hotspot’ tissue was 8.49±8.45% in the placebo group at baseline and 13.04±9.24% at follow-up (relative risk of treatment 0.97, 95% CI 0.91–1.03). The 11C-PK11195 ‘hotspot’ tissue was 10.71±4.04% in the treatment group at baseline and 9.97±5.50% at follow-up; ‘hotspot’ tissue was 10.11±4.67% in the placebo group at baseline and 7.79±5.67% at follow-up (RR 1.01, 95% CI 0.98–1.04; figure 2). Discussion: Minocycline does not alter BBB permeability or microglial activity (measured using DCE-MRI and 11C-PK11195 respectively) in SVD patients. Secondary outcomes include changes in a panel of serum inflammatory biomarkers, and one-year progression of MRI white matter damage and cognitive performance.International Clinical Trials Registry Platform reference: ISRCTN15483452 (http://isrctn.com/ISRCTN15483452)

High throughput sequencing has generated an enormous amount of information about the genes expressed in various cell types and tissues throughout the body, and about how gene expression changes over time and in diseased conditions. This knowledge has made targeted gene knockdowns an important tool in screening and identifying the roles of genes that are differentially expressed among specific cells of interest. While many approaches are available and optimized in mammalian models, there are still several limitations in the zebrafish model. In this article, we describe two approaches to target specific genes in the retina for knockdown: cell-penetrating, translation-blocking Vivo-Morpholino oligonucleotides and commercially available lipid nanoparticle reagents to deliver siRNA. We targeted expression of the PCNA gene in the retina of a P23H rhodopsin transgenic zebrafish model, in which rapidly proliferating progenitor cells replace degenerated rod photoreceptors. Retinas collected 48 h after intravitreal injections in adult zebrafish reveal that both Vivo-Morpholinos and lipid encapsulated siRNAs were able to successfully knock down expression of PCNA. However, only retinas injected with Vivo-Morpholinos showed a significant decrease in the formation of P23H rhodopsin-expressing rods, a downstream effect of PCNA inhibition. Surprisingly, Vivo-Morpholinos were able to exit the injected eye and enter the contralateral non-injected eye to inhibit PCNA expression. In this article we describe the techniques, concentrations, and considerations we found necessary to successfully target and inhibit genes through Vivo-Morpholinos and lipid encapsulated siRNAs.

Electrical synapses, formed of gap junctions, are ubiquitous components of the central nervous system (CNS) that shape neuronal circuit connectivity and dynamics. In the retina, electrical synapses can create a circuit, control the signal-to-noise ratio in individual neurons, and support the coordinated neuronal firing of ganglion cells, hence, regulating signal processing at the network, single-cell, and dendritic level. We, the authors, and Steve Massey have had a long interest in gap junctions in retinal circuits, in general, and in the network of photoreceptors, in particular. Our combined efforts, based on a wide array of techniques of molecular biology, microscopy, and electrophysiology, have provided fundamental insights into the molecular structure and properties of the rod/cone gap junction. Yet, a full understanding of how rod/cone coupling controls circuit dynamics necessitates knowing its operating range. It is well established that rod/cone coupling can be greatly reduced or eliminated by bright-light adaptation or pharmacological treatment; however, the upper end of its dynamic range has long remained elusive. This held true until Steve Massey’s recent interest for connectomics led to the development of a new strategy to assess this issue. The effort proved effective in establishing, with precision, the connectivity rules between rods and cones and estimating the theoretical upper limit of rod/cone electrical coupling. Comparing electrophysiological measurements and morphological data indicates that under pharmacological manipulation, rod/cone coupling can reach the theoretical maximum of its operating range, implying that, under these conditions, all the gap junction channels present at the junctions are open. As such, channel open probability is likely the main determinant of rod/cone coupling that can change momentarily in a time-of-day- and light-dependent manner. In this article we briefly review our current knowledge of the molecular structure of the rod/cone gap junction and of the mechanisms behind its modulation, and we highlight the recent work led by Steve Massey. Steve’s contribution has been critical toward asserting the modulation depth of rod/cone coupling as well as elevating the rod/cone gap junction as one of the most suitable models to examine the role of electrical synapses and their plasticity in neural processing.

Background Agitation is common and impacts negatively on people with dementia and carers. Non-drug patient-centred care is first-line treatment, but we need other treatment when this fails. Current evidence is sparse on safer and effective alternatives to antipsychotics. Objectives To assess clinical and cost-effectiveness and safety of mirtazapine and carbamazepine in treating agitation in dementia. Design Pragmatic, phase III, multicentre, double-blind, superiority, randomised, placebo-controlled trial of the clinical effectiveness of mirtazapine over 12 weeks (carbamazepine arm discontinued). Setting Twenty-six UK secondary care centres. Participants Eligibility: probable or possible Alzheimer’s disease, agitation unresponsive to non-drug treatment, Cohen-Mansfield Agitation Inventory score ≥ 45. Interventions Mirtazapine (target 45 mg), carbamazepine (target 300 mg) and placebo. Outcome measures Primary: Cohen-Mansfield Agitation Inventory score 12 weeks post randomisation. Main economic outcome evaluation: incremental cost per six-point difference in Cohen-Mansfield Agitation Inventory score at 12 weeks, from health and social care system perspective. Data from participants and informants at baseline, 6 and 12 weeks. Long-term follow-up Cohen-Mansfield Agitation Inventory data collected by telephone from informants at 6 and 12 months. Randomisation and blinding Participants allocated 1 : 1 : 1 ratio (to discontinuation of the carbamazepine arm, 1 : 1 thereafter) to receive placebo or carbamazepine or mirtazapine, with treatment as usual. Random allocation was block stratified by centre and residence type with random block lengths of three or six (after discontinuation of carbamazepine, two or four). Double-blind, with drug and placebo identically encapsulated. Referring clinicians, participants, trial management team and research workers who did assessments were masked to group allocation. Results Two hundred and forty-four participants recruited and randomised (102 mirtazapine, 102 placebo, 40 carbamazepine). The carbamazepine arm was discontinued due to slow overall recruitment; carbamazepine/placebo analyses are therefore statistically underpowered and not detailed in the abstract. Mean difference placebo-mirtazapine (−1.74, 95% confidence interval −7.17 to 3.69; p = 0.53). Harms: The number of controls with adverse events (65/102, 64%) was similar to the mirtazapine group (67/102, 66%). However, there were more deaths in the mirtazapine group (n = 7) by week 16 than in the control group (n = 1). Post hoc analysis suggests this was of marginal statistical significance (p = 0.065); this difference did not persist at 6- and 12-month assessments. At 12 weeks, the costs of unpaid care by the dyadic carer were significantly higher in the mirtazapine than placebo group [difference: £1120 (95% confidence interval £56 to £2184)]. In the cost-effectiveness analyses, mean raw and adjusted outcome scores and costs of the complete cases samples showed no differences between groups. Limitations Our study has four important potential limitations: (1) we dropped the proposed carbamazepine group; (2) the trial was not powered to investigate a mortality difference between the groups; (3) recruitment beyond February 2020, was constrained by the COVID-19 pandemic; and (4) generalisability is limited by recruitment of participants from old-age psychiatry services and care homes. Conclusions The data suggest mirtazapine is not clinically or cost-effective (compared to placebo) for agitation in dementia. There is little reason to recommend mirtazapine for people with dementia with agitation. Future work Effective and cost-effective management strategies for agitation in dementia are needed where non-pharmacological approaches are unsuccessful. Study registration This trial is registered as ISRCTN17411897/NCT03031184. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 23. See the NIHR Journals Library website for further project information. Plain language summary It is common for people with Alzheimer’s disease to experience agitation, for example feeling restless or unsettled. If left untreated, agitation can lead to poorer quality of life and increased hospitalisation and strain for family carers. Often these symptoms are treated with medications that are usually used to manage psychosis (antipsychotic drugs), but such medication has limited effectiveness and can cause serious adverse effects to patients, including risk of increased death. Two medications that are already commonly prescribed for other health issues, mirtazapine (an antidepressant) and carbamazepine (a drug used to treat epilepsy), had been identified as a possible alternative way of treating agitation in Alzheimer’s disease that might not have the harms associated with antipsychotic medication. In this study, we compared the effects of giving mirtazapine or carbamazepine with a dummy drug (placebo) in people with Alzheimer’s disease who were experiencing agitation. The results of the study showed that neither medication was any more effective than the placebo in reducing agitation over 12 weeks in terms of improving symptoms, or in economic terms. Mirtazapine may lead to additional carer costs as compared to placebo. The study findings are stronger for mirtazapine than carbamazepine because the carbamazepine arm was stopped when it had recruited less than half the numbers needed. That was done because the study was not recruiting quickly enough to support both the mirtazapine and the carbamazepine arms. The findings from this study show that mirtazapine should not be recommended to treat agitation in Alzheimer’s disease. More work is needed to formulate effective ways and to test new drug and non-drug treatments for agitation in dementia. Scientific summary Background Agitation is common in people with dementia and impacts negatively on the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this fails. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed efficacy and safety of mirtazapine (an antidepressant) and carbamazepine (an anticonvulsant) prescribed for agitation in dementia. Aim To assess the safety, clinical and cost-effectiveness of mirtazapine and carbamazepine in the treatment of agitation in dementia. Primary objectives To determine if mirtazapine is more clinically effective in reducing agitated behaviours in dementia than placebo, measured by Cohen-Mansfield Agitation Inventory (CMAI) score 12 weeks post randomisation. To determine if carbamazepine is more clinically effective in reducing agitated behaviours in dementia than placebo measured by CMAI score 12 weeks post randomisation. Methods Design Pragmatic, phase III, multicentre, double-blind, superiority, randomised, placebo-controlled trial of the clinical effectiveness of mirtazapine and carbamazepine over 12 weeks. Intervention (1) Mirtazapine, (2) carbamazepine and (3) placebo. Target dose: 45 mg of mirtazapine or 300 mg of carbamazepine. Inclusion and exclusion criteria Patients were eligible if the following criteria were met: a clinical diagnosis of probable or possible Alzheimer’s disease a diagnosis of co-existing agitated behaviours evidence that the agitated behaviours have not responded to management an assessment of CMAI (Long Form) score of 45 or greater written informed consent to enter and be randomised into the trial availability of a suitable informant. Exclusion criteria included: current treatment with antidepressants [including Monoamine Oxidase Inhibitors (MAOIs)], anticonvulsants or antipsychotics contraindications to the administration of mirtazapine or carbamazepine patients with second-degree atrioventricular block patients with a history of bone marrow depression or history of hepatic porphyrias cases too critical for randomisation (i.e. where there is a suicide risk or where the patient presents a risk of harm to others) female subjects under the age of 55 years of childbearing potential. Setting Participants were drawn from existing patients and new patient referrals to old age psychiatric services, memory clinics, specific Participant Identification Centres, primary care centres and those in care homes in 26 UK sites. Consent Capacity to consent was assessed before proceeding with the consent process and included consideration of the provision of assent by the patient and consent on their behalf by their legal representative. If the patient had capacity to consent, the carer consented to the provision of information on data for measures on the patient (e.g. CMAI) and also on themselves in terms of impact. Randomisation and blinding Participants were allocated in a 1 : 1 : 1 ratio (up to the discontinuation of the carbamazepine arm and 1 : 1 thereafter) to receive placebo or carbamazepine or mirtazapine, together with treatment as usual. Random allocation was block stratified by centre and type of residence (care home vs. own household) with random block lengths of three or six up to the discontinuation of the carbamazepine arm and thereafter of two or four. The trial was double-blind, with drug and placebo identically encapsulated. Referring clinicians, participants, the trial management team and the research workers who did baseline and follow-up assessments were masked to group allocation. Outcomes Primary outcome CMAI score (Long Form) at 12 weeks. Secondary outcomes Costs derived from Client Service Receipt Inventory, and quality-adjusted life-years from cost data alongside supplemented information from Dementia-Specific Quality of Life and EuroQol-5 Dimensions, five-level version interviews 12 weeks post randomisation. CMAI score and cost at 6 weeks post randomisation. Patient and carer quality of life, and carer outcomes at 6 and 12 weeks post randomisation. Adverse events from week 0 to week 16 and adherence at 6 and 12 weeks post randomisation. CMAI score, adverse events and adherence at 6 and 12 weeks, conditional on evidence of effectiveness of Investigational Medicinal Product over placebo. Longer-term follow-up: CMAI score, institutionalisation, death and clinical management at 26 and 52 weeks post randomisation. Sample size and statistical analysis An initial calculated sample size of 400 (randomised 1 : 1 : 1) provided 90% power using two-sided 5% significance tests to detect a drug versus placebo mean difference in CMAI score at 12 weeks of 6 points. This equated to an effect size of d = 0.4 (assuming a common standard deviation of 15) or a clinically significant 30% decrease in CMAI from placebo to active drug. With a realistic 15% attrition, a sample of 471 (157 per arm) was aimed for. Mid-trial, with the discontinuation of the carbamazepine arm, the sample size calculation was revisited with emerging data and it was adjusted so that the aim (excluding those randomised to carbamazepine) was for an overall sample of 222 (randomised 1 : 1) to provide 80% power using two-sided 5% significance tests to detect a mirtazapine versus placebo mean difference in CMAI score at 12 weeks of six points, assuming attrition of no more than 10%. Analyses were based on intention-to-treat (all participants were analysed according to the group to which they were randomised, irrespective of the treatment or dose received). The primary outcome (CMAI at 12 weeks) was analysed using a general linear regression model including baseline CMAI score as a covariate. General linear regression models were created for secondary outcomes. Economic evaluation The primary outcome for the economic evaluation was the incremental cost per six-point difference in CMAI score at 12 weeks, from a health and social care system perspective. Patient and public involvement Ensuring the involvement of people living with dementia and their family carers was integral to the Study of Mirtazapine for Agitated Behaviours in Dementia (SYMBAD) trial from the application for funding and trial design stage through to its conduct, analysis and communication. SN was a co-applicant and led on public/carer involvement in the trial throughout, and she was supported by a Lived Experience Advisory Panel (LEAP) group hosted by Sussex Partnership Foundation Trust (SPFT) co-ordinated by JF and the NIHR DeNDRoN (Dementias and Neurodegenerative Diseases Research Network) group. Protocol change Due to slower than expected recruitment the carbamazepine arm was discontinued in August 2018 when 40 people had been randomised to it. This summary therefore focusses on the mirtazapine versus placebo comparisons. Results Between January 2017 and February 2020, 204 participants were recruited and randomised to either the mirtazapine (n = 102) or placebo arm (n = 102). Mean CMAI scores at 12 weeks were not significantly different between participants allocated to receive mirtazapine and placebo [adjusted mean difference −1.74, 95% confidence interval (CI) −7.17 to 3.69; p = 0.53, direction of change in favour of mirtazapine but not statistically significant]. The number of controls with adverse events [65/102 (64%)] was similar to that in the mirtazapine group [67/102 (66%)]. There were more deaths in the mirtazapine group (n = 7) by week 16 than in the control group (n = 1), with post hoc analysis suggesting this was of marginal statistical significance (p = 0.065), but this difference did not persist at 6- and 12-month follow-ups. The cost-effectiveness analyses similarly showed no evidence of benefit of mirtazapine over placebo, and no difference in costs between groups at 12 weeks. The carbamazepine arm closed in August 2018 when there had been 40 randomisations to that group, we therefore do not have statistical power for comparisons with placebo. However, exploratory analyses using the same modelling as for mirtazapine versus placebo showed there was also little evidence of any benefits compared to placebo (adjusted mean difference 2.46, 95% CI −5.01 to 9.93; p = 0.52), with similar levels of adverse events reported [27/40 (68%)]. Conclusions This is a trial with negative findings but important clinical implications. The data suggest that mirtazapine is not clinically effective or cost-effective (compared to placebo) for clinically significant agitation in dementia. Our findings suggest that there is little reason to recommend the use of mirtazapine for people with dementia who experience agitation. Effective and cost-effective management strategies for agitation in dementia are needed, particularly where non-pharmacological approaches have been unsuccessful, and for people with dementia and their carers living in community settings. Trial registration This trial is registered as ISRCTN17411897 and ClinicalTrials.gov as NCT03031184. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment, Vol. 27, No. 23. See the NIHR Journals Library website for further project information.

Abstract INTRODUCTION Although many cognitive measures have been developed to assess cognitive decline due to Alzheimer's disease (AD), there is little consensus on optimal measures, leading to varied assessments across research cohorts and clinical trials making it difficult to pool cognitive measures across studies. METHODS We used a two‐stage approach to harmonize cognitive data across cohorts and derive a cross‐cohort score of cognitive impairment due to AD. First, we pool and harmonize cognitive data from international cohorts of varying size and ethnic diversity. Next, we derived cognitive composites that leverage maximal data from the harmonized dataset. RESULTS We show that our cognitive composites are robust across cohorts and achieve greater or comparable sensitivity to AD‐related cognitive decline compared to the Mini‐Mental State Examination and Preclinical Alzheimer Cognitive Composite. Finally, we used an independent cohort validating both our harmonization approach and composite measures. DISCUSSION Our easy to implement and readily available pipeline offers an approach for researchers to harmonize their cognitive data with large publicly available cohorts, providing a simple way to pool data for the development or validation of findings related to cognitive decline due to AD.

IntroductionUnderstanding how photoreceptor genes are regulated is important for investigating retinal development and disease. While much is known about gene regulation in cones, the mechanism by which tandemly-replicated opsins, such as human long wavelength-sensitive and middle wavelength-sensitive opsins, are differentially regulated remains elusive. In this study, we aimed to further our understanding of transcriptional heterogeneity in cones that express tandemly-replicated opsins and the regulation of such differential expression using zebrafish, which express the tandemly-replicated opsins lws1 and lws2.MethodsWe performed bulk and single cell RNA-Seq of LWS1 and LWS2 cones, evaluated expression patterns of selected genes of interest using multiplex fluorescence in situ hybridization, and used exogenous thyroid hormone (TH) treatments to test selected genes for potential control by thyroid hormone: a potent, endogenous regulator of lws1 and lws2 expression.ResultsOur studies indicate that additional transcriptional differences beyond opsin expression exist between LWS1 and LWS2 cones. Bulk RNA-Seq results showed 95 transcripts enriched in LWS1 cones and 186 transcripts enriched in LWS2 cones (FC > 2, FDR < 0.05). In situ hybridization results also reveal underlying heterogeneity within the lws1- and lws2-expressing populations. This heterogeneity is evident in cones of mature zebrafish, and further heterogeneity is revealed in transcriptional responses to TH treatments.DiscussionWe found some evidence of coordinate regulation of lws opsins and other genes by exogenous TH in LWS1 vs. LWS2 cones, as well as evidence of gene regulation not mediated by TH. The transcriptional differences between LWS1 and LWS2 cones are likely controlled by multiple signals, including TH.

Environmental concerns and energy efficiency have been driving the transportation innovation in the past decades. In this framework, hybrid city transport has been receiving the attention of the industry. The challenges for this application are the required high-power density, lower maintenance cost and the high-temperature environment due to the integration with the internal combustion engine. A multiport converter is proposed to realise the requirements of the automotive industry to achieve greater performance in driveline electrification. The platform suggests the combination of previously discrete power electronics converter modules into one physical package commonising parts such as the microcontroller, heatsink and busbars. This paper provides an overview of design considerations for engine start-stop within a series-parallel topology and how it is achieved using the multiport converter. Finally, a comparison between the multiport and discrete converter approach is made compared and findings presented, highlighting the advantages of the integrated solution.

Abstract Background After the success of PET/CT as a clinical diagnostic tool, the introduction of PET/MRI is a natural development aimed at further improving combined diagnostic imaging and reduced ionising radiation dose for half-body imaging. As with PET and CT, the combination of PET and MRI presents a series of issues that need to be addressed regarding workforce training and education. At present, there is a lack of agreement over the competencies, training requirements and educational pathways needed for PET/MRI operation. In the UK, following the establishment of the MR-PET imaging network, a task force was created to investigate the status of the workforce training, identify gaps and make recommendations regarding staff training. To do this, we ran a national survey on the status of the workforce training and the local practices across the UK’s seven PET/MRI sites, reviewed the literature, and convened a panel of experts, to assess all the evidence and make recommendations regarding PET/MRI competencies and training of nuclear medicine technologists and radiographers. Results There is limited literature available specifically on competencies and training for technologists and radiographers. The recommendations on the topic needed revisiting and adapting to the UK MR-PET network. The online survey confirmed the need for developing PET/MRI competencies and training pathways. Local organisational structures and practices were shared across the seven sites, based on models derived from experience outside the UK. The panel of experts agreed on the need for PET/MRI competencies and training strategies. Professional organisations started collaborative discussions with partners from both Nuclear Medicine and Radiography to set training priorities. Multidisciplinary collaboration and partnership were suggested as a key to a successful implementation of competencies and training. Conclusions The report identified the need for establishing competencies for the PET/MRI workforce, particularly for technologists and radiographers. It also helped defining these competencies as well as identifying the demand for bespoke training and the development of local and national courses to be implemented to fulfil this new training need.

Synaptic signaling complexes are held together by scaffold proteins, each of which is selectively capable of interacting with a number of other proteins. In previous studies of rabbit retina, we found Synapse-Associated Protein-102 (SAP102) and Channel Associated Protein of Synapse-110 (Chapsyn110) selectively localized in the tips of horizontal cell processes at contacts with rod and cone photoreceptors, along with several interacting ion channels. We have examined the equivalent suites of proteins in mouse retina and found similarities and differences. In the mouse retina we identified Chapsyn110 as the scaffold selectively localized in the tips of horizontal cells contacting photoreceptors, with Sap102 more diffusely present. As in rabbit, the inward rectifier potassium channel Kir2.1 was present with Chapsyn110 on the tips of horizontal cell dendrites within photoreceptor invaginations, where it could provide a hyperpolarization-activated current that could contribute to ephaptic signaling in the photoreceptor synapses. Pannexin 1 and Pannexin 2, thought to play a role in ephaptic and/or pH mediated signaling, were present in the outer plexiform layer, but likely not in the horizontal cells. Polyamines regulate many ion channels and control the degree of rectification of Kir2.1 by imposing a voltage-dependent block. During the day polyamine immunolabeling was unexpectedly high in photoreceptor terminals compared to other areas of the retina. This content was significantly lower at night, when polyamine content was predominantly in Müller glia, indicating daily rhythms of polyamine content. Both rod and cone terminals displayed the same rhythm. While polyamine content was not prominent in horizontal cells, if polyamines are released, they may regulate the activity of Kir2.1 channels located in the tips of HCs. The rhythmic change in polyamine content of photoreceptor terminals suggests that a daily rhythm tunes the behavior of suites of ion channels within the photoreceptor synapses.

Background: Assistive technology and telecare have been promoted to manage the risks associated with independent living for people with dementia, but there is limited evidence of their effectiveness. Objectives: This trial aimed to establish whether or not assistive technology and telecare assessments and interventions extend the time that people with dementia can continue to live independently at home and whether or not they are cost-effective. Caregiver burden, the quality of life of caregivers and of people with dementia and whether or not assistive technology and telecare reduce safety risks were also investigated. Design: This was a pragmatic, randomised controlled trial. Blinding was not undertaken as it was not feasible to do so. All consenting participants were included in an intention-to-treat analysis. Setting: This trial was set in 12 councils in England with adult social services responsibilities. Participants: Participants were people with dementia living in the community who had an identified need that might benefit from assistive technology and telecare. Interventions: Participants were randomly assigned to receive either assistive technology and telecare recommended by a health or social care professional to meet their assessed needs (a full assistive technology and telecare package) or a pendant alarm, non-monitored smoke and carbon monoxide detectors and a key safe (a basic assistive technology and telecare package). Main outcome measures: The primary outcomes were time to admission to care and cost-effectiveness. Secondary outcomes assessed caregivers using the 10-item Center for Epidemiological Studies Depression Scale, the State–Trait Anxiety Inventory 6-item scale and the Zarit Burden Interview. Results: Of 495 participants, 248 were randomised to receive full assistive technology and telecare and 247 received the limited control. Comparing the assistive technology and telecare group with the control group, the hazard ratio for institutionalisation was 0.76 (95% confidence interval 0.58 to 1.01; p = 0.054). After adjusting for an imbalance in the baseline activities of daily living score between trial arms, the hazard ratio was 0.84 (95% confidence interval 0.63 to 1.12; p = 0.20). At 104 weeks, there were no significant differences between groups in health and social care resource use costs (intervention group – control group difference: mean –£909, 95% confidence interval –£5336 to £3345) or in societal costs (intervention group – control group difference: mean –£3545; 95% confidence interval –£13,914 to £6581). At 104 weeks, based on quality-adjusted life-years derived from the participant-rated EuroQol-5 Dimensions questionnaire, the intervention group had 0.105 (95% confidence interval –0.204 to –0.007) fewer quality-adjusted life-years than the control group. The number of quality-adjusted life-years derived from the proxy-rated EuroQol-5 Dimensions questionnaire did not differ between groups. Caregiver outcomes did not differ between groups over 24 weeks. Limitations: Compliance with the assigned trial arm was variable, as was the quality of assistive technology and telecare needs assessments. Attrition from assessments led to data loss additional to that attributable to care home admission and censoring events. Conclusions: A full package of assistive technology and telecare did not increase the length of time that participants with dementia remained in the community, and nor did it decrease caregiver burden, depression or anxiety, relative to a basic package of assistive technology and telecare. Use of the full assistive technology and telecare package did not increase participants’ health and social care or societal costs. Quality-adjusted life-years based on participants’ EuroQol-5 Dimensions questionnaire responses were reduced in the intervention group compared with the control group; groups did not differ in the number of quality-adjusted life-years based on the proxy-rated EuroQol-5 Dimensions questionnaire. Future work: Future work could examine whether or not improved assessment that is more personalised to an individual is beneficial. Trial registration: Current Controlled Trials ISRCTN86537017. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 19. See the NIHR Journals Library website for further project information.

Background: Minocycline is an anti-inflammatory drug and protects against the toxic effects of β-amyloid in vitro and in animal models of Alzheimer’s disease. To the best of our knowledge, no randomised placebo-controlled clinical trials in patients with Alzheimer’s disease looking at the efficacy and tolerability of minocycline have been carried out. Objectives: The trial investigated whether or not minocycline was superior to placebo in slowing down the rate of decline in cognitive and functional ability over 2 years. The safety and tolerability of minocycline were also assessed. Design: A Phase II, three-arm, randomised, double-blind, multicentre trial with a semifactorial design. Participants continued on trial treatment for up to 24 months. Setting: Patients were identified from memory services, both within the 32 participating NHS trusts and within the network of memory services supported by the Dementias and Neurodegenerative Diseases Research Network (also known as DeNDRoN). Participants: Patients with standardised Mini Mental State Examination scores of > 23 points and with Alzheimer’s disease assessed by the National Institute on Aging–Alzheimer’s Association’s criteria were identified from memory services. Intervention: Patients with mild Alzheimer’s disease were randomly allocated 1 : 1 : 1 to receive one of three treatments: arm 1 – 400 mg per day of minocycline; arm 2 – 200 mg per day of minocycline; or arm 3 – placebo. Patients continued treatment for 24 months. Participants, investigators and outcome assessors were blind to treatment allocation. Main outcome measures: Primary outcome measures were decline in standardised Mini Mental State Examination and Bristol Activities of Daily Living Scale scores of combined minocycline treatment arms versus placebo, as analysed by intention-to-treat repeated measures regression. Results: Between 23 May 2014 and 14 April 2016, 554 participants were randomised. Of the 544 eligible participants, the mean age was 74.3 years and the average standardised Mini Mental State Examination score was 26.4 points. A total of 252 serious adverse events were reported, with the most common categories being neuropsychiatric and cardiocirculatory. Significantly fewer participants completed treatment with 400 mg of minocycline [29% (53/184)] than 200 mg [62% (112/181)] or placebo [64% (114/179)] (p

Abstract Introduction Assistive technology and telecare (ATT) may alleviate psychological burden in informal caregivers of people with dementia. This study assessed the impact of ATT on informal caregivers’ burden and psychological well‐being. Methods Individuals with dementia and their informal caregivers were recruited to a randomized‐controlled trial assessing effectiveness of ATT. Caregivers were allocated to two groups according to their cared‐for person's randomization to a full or basic package of ATT and were assessed on caregiver burden, state anxiety, and depression. Caregivers’ data from three assessments over 6 months of the trial were analyzed. Results No significant between‐ or within‐group differences at any time point on caregivers’ burden, anxiety, and depression levels were found. Discussion Full ATT for people with dementia did not impact caregivers’ psychological outcomes compared to basic ATT. The length of follow up was restricted to 6 months.

Abstract Context This commentary discusses the implications of disease-modifying treatments for Alzheimer’s disease which seem likely to appear in the next few years and results from a meeting of British experts in neurodegenerative diseases in Edinburgh. The availability of such treatments would help change public and professional attitudes and accelerate engagement with the prodromal and preclinical populations who might benefit from them. However, this would require an updated understanding of Alzheimer’s disease, namely the important distinction between Alzheimer’s disease and Alzheimer’s dementia. Consensus Since treatments are likely to be most effective in the early stages, identification of clinically relevant brain changes (for example, amyloid burden using imaging or cerebrospinal fluid biomarkers) will be crucial. While current biomarkers could be useful in identifying eligibility for new therapies, trial data are not available to aid decisions about stopping or continuing treatment in clinical practice. Therefore, effective monitoring of safety and effectiveness when these treatments are introduced into clinical practice will be necessary to inform wide-scale use. Equity of access is key but there is a tension between universal access for everyone with a diagnosis of Alzheimer’s disease and specifying an eligible population most likely to respond. We propose the resources necessary for an optimal care pathway as well as the necessary education and training for primary and secondary care. Conclusion The majority of current services in the UK and elsewhere would not be able to accommodate the specialist investigations required to select patients and prescribe these therapies. Therefore, a stepped approach would be necessary: from innovating sentinel clinical-academic centres that already have capacity to deliver the necessary phase IV trials, through early adoption in a hub and spoke model, to nationwide adoption for true equity of access. The optimism generated by recent and anticipated developments in the understanding and treatment of Alzheimer’s disease presents a great opportunity to innovate and adapt our services to incorporate the next exciting development in the field of dementia.

The presence of the signalling lipid Sphingosine 1-phosphate (S1P) in erythrocytes has unclear physiological implications. Here the authors show that the S1P-generating enzyme Sphingosine kinase type 1 and its product S1P play an important role in the red blood cell adaptation to hypoxic environments in mice and humans.

What is the relationship between the sense of perceived discrimination among members of a marginalized racial, ethnic, or religious group and their political attitudes towards other marginalized groups within their society? Research on minority groups in politics has established that the feeling that one’s own group is socially deprived and discriminated against is generally associated with an increase in within-group solidarity, observable in members’ stronger expressions of collective identity—also called “group consciousness” or “linked fate”—as well as their robust support for political parties and policies seen as directly benefitting members of their in group. Yet an underappreciated strand of this same research suggests that a strong sense of in-group deprivation may also lead to greater empathy and political support for other marginalized minorities, a phenomenon we refer to as intergroup solidarity. In this paper, we use the case of Muslim Americans to test the hypothesis that perceptions of group deprivation can lead to increased intergroup solidarity with other socially marginalized racial, ethnic, and religious minorities. We find that Muslims who feel that they have been discriminated against and/or who believe Muslims as a group are a target of discrimination are more likely to embrace the struggles of other groups and recognize the marginalization of other groups. Our findings suggest that in-group political consciousness raising may be a first step toward intergroup coalition building among those who suffer from discrimination and marginalization.

More than 1.5 million people suffer from Retinitis Pigmentosa, with many experiencing partial to complete vision loss. Regenerative therapies offer some hope, but their development is challenged by the limited regenerative capacity of mammalian model systems. As a step toward investigating regenerative therapies, we developed a zebrafish model of Retinitis Pigmentosa that displays ongoing regeneration. We used Tol2 transgenesis to express mouse rhodopsin carrying the P23H mutation and an epitope tag in zebrafish rod photoreceptors. Adult and juvenile fish were examined by immunofluorescence, TUNEL and BrdU incorporation assays. P23H transgenic fish expressed the transgene in rods from 3 days post fertilization onward. Rods expressing the mutant rhodopsin formed very small or no outer segments and the mutant protein was delocalized over the entire cell. Adult fish displayed thinning of the outer nuclear layer (ONL) and loss of rod outer segments, but retained a single, sparse row of rods. Adult fish displayed ongoing apoptotic cell death in the ONL and an abundance of proliferating cells, predominantly in the ONL. There was a modest remodeling of bipolar and Müller glial cells. This transgenic fish will provide a useful model system to study rod photoreceptor regeneration and integration.

Calmodulin binding is a nearly universal property of gap junction proteins, imparting a calcium-dependent uncoupling behavior that can serve in an emergency to decouple a stressed cell from its neighbors. However, gap junctions that function as electrical synapses within networks of neurons routinely encounter large fluctuations in local cytoplasmic calcium concentration; frequent uncoupling would be impractical and counterproductive. We have studied the properties and functional consequences of calmodulin binding to the electrical synapse protein Connexin 35 (Cx35 or gjd2b), homologous to mammalian Connexin 36 (Cx36 or gjd2). We find that specializations in Cx35 calmodulin binding sites make it relatively impervious to moderately high levels of cytoplasmic calcium. Calmodulin binding to a site in the C-terminus causes uncoupling when calcium reaches low micromolar concentrations, a behavior prevented by mutations that eliminate calmodulin binding. However, milder stimuli promote calcium/calmodulin-dependent protein kinase II activity that potentiates coupling without interference from calmodulin binding. A second calmodulin binding site in the end of the Cx35 cytoplasmic loop, homologous to a calmodulin binding site present in many connexins, binds calmodulin with very low affinity and stoichiometry. Together, the calmodulin binding sites cause Cx35 to uncouple only at extreme levels of intracellular calcium.

Objective To evaluate the association of biochemically validated prenatal tobacco use with serum progesterone and estradiol in the second trimester of pregnancy, controlling for demographic and personal factors. Study design This secondary analysis of a multicenter longitudinal study included 114 women with singleton pregnancies. Multiple regression analysis assessed whether prenatal tobacco use was related to hormone levels during the second trimester, controlling for covariates (age, body mass index, and race or ethnicity, with gestational age added to subsequent models). Result In the initial regressions, tobacco users had significantly lower progesterone level compared with nonsmokers ( p = .037), while estradiol was unrelated to prenatal tobacco use. Women with greater body mass index also had significantly lower progesterone ( p = .028), but body mass index was unrelated to estradiol. With gestational age as an additional covariate, prenatal tobacco use was no longer a significant predictor of progesterone, but both body mass index and gestational age were significant ( F = 10.6, p

Neurodegenerative dementia often has multiple types of underlying pathology, for example, beta-amyloid, misfolded tau, chronic neuroinflammation and neurodegeneration may coexist in Alzheimer’s disease. However, the relationship between them is often unclear, in other words, whether one pathology is upstream or downstream of others can be very difficult to investigate directly. This is partly because the underlying pathology in dementia may precede detectable symptoms by several years if not decades. The time scale associated with disease progression in dementia generally exceeds that in conventional longitudinal imaging studies in humans, so it is difficult to directly observe the temporal ordering of different pathologies. Also, animal studies are not always transferable to patients due to obvious differences between the two systems. To investigate the disease progression and relationships among underlying pathological changes, we propose a novel computational modeling approach for multimodal MRI and PET inspired by reaction rate equation in chemical kinetics. We also discuss the possibility and prerequisites to use cross-sectional data to generate preliminary hypothesis for future longitudinal studies. It has been shown that the rate of change in some biomarkers can be approximated by the average trajectory across patients at different stages of disease severity in cross-sectional studies. The relationship modeled in our approach is akin to that in the control theory, and can be assessed by demonstrating that the presence of one disease related biomarker predicts dynamics in another. We argue that the proposed framework has important implications for trials targeting different pathologies in dementia.

Abstract Objective To assess differences in cytokine levels in cervicovaginal fluid (CVF) and serum across trimesters between women with preterm births (PTBs) and full-term births. Study Design This multicenter study enrolled 302 women with a singleton gestation. CVF and serum cytokines, interleukin 1α (IL-1α), IL-1β, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and matrix metalloproteinase (MMP)-8, were measured. Women with at least one cytokine assessment and noted PTB status in their medical record were retained in the study (N = 272). Data were analyzed using mixed modeling (main effects of PTBs and time/trimester). Results For the CVF values of IL-6, IL-8, IL-10, TNF-α, and CRP, and serum MMP-8, those who delivered preterm had significantly higher values than the full-term group regardless of trimester. For the serum values of IL-1β, IL-6, and TNF-α, those delivering preterm had significantly lower values than those delivering full-term regardless of trimester. For IL-1β in CVF, the cytokine was significantly higher in the PTB group for second and third trimesters only, relative to the full-term group. Conclusion For each CVF cytokine that differed by birth status, values were higher for PTB than term, averaged over trimester. Numerous cytokine profiles varied across trimesters in women delivering term versus preterm in both CVF and serum.

Both neurons and glia throughout the central nervous system are organized into networks by gap junctions. Among glia, gap junctions facilitate metabolic homeostasis and intercellular communication. Among neurons, gap junctions form electrical synapses that function primarily for communication. However, in neurodegenerative states due to disease or injury gap junctions may be detrimental to survival. Electrical synapses may facilitate hyperactivity and bystander killing among neurons, while gap junction hemichannels in glia may facilitate inflammatory signaling and scar formation. Advances in understanding mechanisms of plasticity of electrical synapses and development of molecular therapeutics to target glial gap junctions and hemichannels offer new hope to pharmacologically limit neuronal degeneration and enhance recovery.

Neural network function is based upon the patterns and types of connections made between neurons. Neuronal synapses are adhesions specialized for communication and they come in two types, chemical and electrical. Communication at chemical synapses occurs via neurotransmitter release whereas electrical synapses utilize gap junctions for direct ionic and metabolic coupling. Electrical synapses are often viewed as symmetrical structures, with the same components making both sides of the gap junction. By contrast, we show that a broad set of electrical synapses in zebrafish, Danio rerio, require two gap-junction-forming Connexins for formation and function. We find that one Connexin functions presynaptically while the other functions postsynaptically in forming the channels. We also show that these synapses are required for the speed and coordination of escape responses. Our data identify a genetic basis for molecular asymmetry at vertebrate electrical synapses and show they are required for appropriate behavioral performance.

Cognitive fluctuations are a core symptom in dementia with Lewy bodies (DLB) and may relate to pathological alterations in distributed brain networks. To test this we analysed resting state fMRI changes in a cohort of fluctuating DLB patients (n = 16) compared with age matched controls (n = 17) with the aim of finding functional connectivity (FC) differences between these two groups and whether these associate with cognitive fluctuations in DLB. Resting state networks (RSNs) were estimated using independent component analysis and FC between the RSN maps and the entirety of the brain was assessed using dual regression. The default mode network (DMN) appeared unaffected in DLB compared to controls but significant cluster differences between DLB and controls were found for the left fronto-parietal, temporal, and sensory–motor networks. Desynchronization of a number of cortical and subcortical areas related to the left fronto-parietal network was associated with the severity and frequency of cognitive fluctuations. Our findings provide empirical evidence for the potential role of attention–executive networks in the aetiology of this core symptom in DLB.

Since the publication of this article [1], it has come to the attention of the authors that information for one of the authors was not included in the competing interests section. Craig Richie has declared potential competing interests with the following companies; Janssen, Eisai, Pfizer, Eli Lilly, Roche Diagnostics, Boeringher Ingleheim, Novartis, AC Immune, Ixico, Aridhia, Amgen, Berry Consultants, Lundbeck, Sanofi, Quintiles (IQVIA) and Takeda. The full competing interests section for this article can be found below.

A 42-year-old male presented with worsening gastroesophageal reflux disease symptoms and cough. The clinical symptoms during the early course of illness were striking for aspiration pneumonia. He was given a prescription of proton pump inhibitors and antibiotics. Rapid decline in the clinical condition with worsening respiratory status was noted. Worsening symptoms of fever, cough, and chest pain prompted further diagnostic work-up suggesting esophageal microperforation. Esophagogram was found to be suggestive of tracheoesophageal fistula. The tracheoesophageal fistula was due to subcarinal lymph node of nontuberculous origin.

The natural colonisation of many remote oceanic islands by bats, including those of the western Indian Ocean, has been facilitated by their unique capability among mammals for powered flight. In the western Indian Ocean region, only the Malagasy islands of Madagascar and the Comoros archipelago have been naturally colonised by non-volant mammals. Despite their greater potential for inter-island dispersal, and thus gene transfer, endemicity of Chiroptera in the western Indian Ocean islands is high. Given their vulnerability to stochastic and anthropogenic disturbances, greater focus needs to be placed on investigating the demographic and ecological history of bats on Western Indian Ocean islands to safeguard not only their future, but also the ecosystem functioning on these islands, for which they are undoubtedly such an integral part. Here, I summarise the taxonomic and life history information available on bats from Western Indian Ocean islands and highlight knowledge gaps and conservation issues that threaten the continued persistence of some species.

It is well established that a decrease in genetic variation can lead to reduced fitness and lack of adaptability to a changing environment. Amphibians are declining on a global scale, and we present a four-point argument as to why this taxonomic group seems especially prone to such genetic processes. We elaborate on the extent of recent fragmentation of amphibian gene pools and we propose the term dissociated populations to describe the residual population structure. To put their well-documented loss of genetic diversity into context, we provide an overview of 34 studies (covering 17 amphibian species) that address a link between genetic variation and >20 different fitness traits in amphibians. Although not all results are unequivocal, clear genetic-fitness-correlations (GFCs) are documented in the majority of the published investigations. In light of the threats faced by amphibians, it is of particular concern that the negative effects of various pollutants, pathogens and increased UV-B radiation are magnified in individuals with little genetic variability. Indeed, ongoing loss of genetic variation might be an important underlying factor in global amphibian declines.

Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD) together, represent the second most common cause of dementia, after Alzheimer’s disease (AD). The synaptic dysfunctions underlying the cognitive decline and psychiatric symptoms observed throughout the development of PDD and DLB are still under investigation. In this study we examined the expression level of Dynamin1 and phospho-CaMKII, key proteins of endocytosis and synaptic plasticity respectively, as potential markers of molecular processes specifically deregulated with DLB and/or PDD. In order to measure the levels of these proteins, we isolated grey matter from post-mortem prefrontal cortex area (BA9), anterior cingulated gyrus (BA24) and parietal cortex (BA40) from DLB and PDD patients in comparison to age-matched controls and a group of AD cases. Clinical and pathological data available included the MMSE score, neuropsychiatric history, and semi-quantitative scores for AD pathology (plaques - tangles) and for α-synuclein (Lewy bodies). Changes in the expression of the synaptic markers, and correlates with neuropathological features and cognitive decline were predominantly found in the prefrontal cortex. On one hand, levels of Dynamin1 were significantly reduced, and correlated with a higher rate of cognitive decline observed in cases from three dementia groups. On the other hand, the fraction of phospho-CaMKII was decreased, and correlated with a high score of plaques and tangles in BA9. Interestingly, the correlation between the rate of cognitive decline and the level of Dynamin1 remained when the analysis was restricted to the PDD and DLB cases, highlighting an association of Dynamin1 with cognitive decline in people with Lewy Body dementia.

Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA) of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs.Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs) and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ) activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ) overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set.Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.

Abstract The distribution of the coypu (Myocastor coypus) in the Iberian Peninsula is restricted to the Atlantic region, even though recent data suggest an expansion into the western part of the Basque Autonomous Community (northern Iberian Peninsula). With the aim of providing new data on coypu distribution in this region, 76 transects (mean length = 1369 m; range = 900-1800 m) along riverbanks and marsh shorelines were surveyed, to record the presence of coypus by means of their signs: footprints, burrows, and droppings. Transects were distributed in 14 river basins, corresponding to 45 UTM 10x10 km squares. Between January and September 2004, we detected 105 activity signs in 4 river basins, verifying the presence of the species in 10 UTM squares. Our results confirm that the coypu is expanding into new areas in the north of the Iberian Peninsula. Riassunto Distribuzione della nutria (Myocastor coypus) nella Regione Autonoma Basca, penisola iberica settentrionale. Nella penisola iberica, la presenza della nutria (Myocastor coypus) è limitata alla regione atlantica, anche se dati recenti suggeriscono una sua espansione nella Regione Autonoma Basca (penisola iberica settentrionale). Con lo scopo di raccogliere nuovi dati sulla distribuzione della nutria in questa regione, i segni di presenza della specie (impronte, tane, feci) sono stati ricercati lungo 76 transetti (lunghezza media = 1369 m; min-max = 900-1800 m), corrispondenti a tratti di corsi d’acqua e sponde di acquitrini. I transetti comprendevano 14 bacini idrografici, corrispondenti a 45 quadrati di 10 km di lato del sistema UTM. Tra gennaio e settembre 2004 sono stati trovati 105 segni di presenza in 4 diversi bacini, accertando la presenza della nutria in 10 quadrati UTM. I risultati confermano la colonizzazione di nuove aree della penisola iberica settentrionale. doi:10.4404/hystrix-20.2-4446

Intuitively, keeping ones distance from a source of infection would appear to be the best way to limit the occurrence of disease. However, this overlooks the importance of repeated infections in maintaining efficient immune defenses. When acquired immunity has partly waned, re-exposure to the pathogenic agent may lead to mild disease that boosts the immune system. This prevents the total loss of immunity that would lead to classical disease in cases of re-infection. Here, using a mathematical model, we show that avoiding the pathogenic agent is detrimental in some situations, e.g. for pathogens that are highly transmissible, are not excessively lethal and that induce rapidly waning immunity. Reducing exposure to pathogenic agents is among the objectives of most, if not all, public health measures. A better understanding of the factors influencing the severity of a disease is required before applying measures that reduce the circulation of pathogenic agents.