A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLC?2 pathway as drug-target

A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer’s disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.Fil:  van der Lee, Sven J.. Vrije Universiteit Amsterdam; Países BajosFil: Conway, Olivia J.. Mayo Clinic Cancer Center; Estados UnidosFil: Jansen, Iris. Vrije Universiteit Amsterdam; Países BajosFil: Carrasquillo, Minerva M.. Mayo Clinic Cancer Center; Estados UnidosFil: Kleineidam, Luca. Universitat Bonn; Alemania. German Center for Neurodegenerative Diseases; Alemania. University Hospital Cologne; AlemaniaFil: van den Akker, Erik. Leiden University. Leiden University Medical Center; Países Bajos. Delft University of Technology; Países BajosFil: Hernández, Isabel. Universitat Internacional de Catalunya; España. Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas ; EspañaFil: van Eijk, Kristel R.. University of Utrecht; Países BajosFil: Stringa, Najada. Vrije Universiteit Amsterdam; Países BajosFil: Chen, Jason A.. University of California at Los Angeles; Estados UnidosFil: Zettergren, Anna. University of Gothenburg; SueciaFil: Andlauer, Till F. M.. Max Planck Institute of Psychiatry; Alemania. Universitat Technical Zu Munich; Alemania. German Competence Network Multiple Sclerosis; AlemaniaFil: Diez Fairen, Monica. University Hospital Mutua de Terrassa; España. Fundacio per la Recerca Biomedica I Social Mutua Terrassa; EspañaFil: Simon Sanchez, Javier. Deutsches Zentrum für Neurodegenerative Erkrankungen; Alemania. Eberhard Karls Universität Tübingen; AlemaniaFil: Lleó, Alberto. Universitat Autònoma de Barcelona; España. Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas ; EspañaFil: Zetterberg, Henrik. Sahlgrenska University Hospital; Suecia. University of Gothenburg; Suecia. University College London; Estados UnidosFil: Nygaard, Marianne. University of Southern Denmark; DinamarcaFil: Blauwendraat, Cornelis. National Institute of Neurological Disorders and Stroke; Estados UnidosFil: Savage, Jeanne E.. Vrije Universiteit Amsterdam; Países BajosFil: Mengel From, Jonas. University of Southern Denmark; DinamarcaFil: Moreno Grau, Sonia. Universitat Internacional de Catalunya; EspañaFil: Wagner, Michael. Universitat Bonn; Alemania. Deutsches Zentrum für Neurodegenerative Erkrankungen; AlemaniaFil: Fortea, Juan. Universitat Autònoma de Barcelona; España. Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas ; EspañaFil: Keogh, Michael J.. University of Newcastle; Reino Unido. University of Cambridge; Reino UnidoFil: Blennow, Kaj. Sahlgrenska University Hospital; Suecia. University of Gothenburg; SueciaFil: Skoog, Ingmar. University of Gothenburg; SueciaFil: Friese, Manuel A.. German Competence Network Multiple Sclerosis; Alemania. Universitätsklinikum Hamburg‐Eppendorf; AlemaniaFil: Pletnikova, Olga. University Johns Hopkins; Estados UnidosFil: Zulaica, Miren. Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas ; España. Instituto Biodonostia; EspañaFil: Dalmasso, Maria Carolina. University Hospital Cologne; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

Comparison of the caries-protective effect of fluoride varnish with treatment as usual in nursery school attendees receiving preventive oral health support through the Childsmile oral health improvement programme - the Protecting Teeth@3 Study:a randomised controlled trial

Background: The Scottish Government set out its policy on addressing the poor oral health of Scottish children in 2005. This led to the establishment of Childsmile, a national programme designed to improve the oral health of children in Scotland. One element of the programme promotes daily tooth brushing in all nurseries in Scotland (Childsmile Core). A second targeted component (Childsmile Nursery) offers twice-yearly application of fluoride varnish to children attending nurseries in deprived areas. Studies suggest that fluoride varnish application can reduce caries in both adult and child populations. This trial aims to explore the effectiveness and cost-effectiveness of additional preventive value fluoride varnish application compared to Childsmile Core. Methods/Design: The Protecting Teeth@3 Study is an ongoing 2 year parallel group randomised treatment as usual controlled trial. Three-year-old children attending the ante pre-school year are randomised (1:1) to the intervention arm (fluoride varnish & treatment as usual) or the control arm (treatment as usual). Children in the intervention arm will have Duraphat® fluoride varnish painted on the primary tooth surfaces and will continue to receive treatment as usual: the core Childsmile Nursery intervention. Children in the treatment as usual arm will receive the same series of contacts, without the application of varnish and will also continue with the Childsmile Core intervention. Interventions are undertaken by Childsmile trained extended duty dental nurses at six-monthly intervals. Participants receive a baseline dental inspection in nursery and an endpoint inspection in Primary 1 at the age of 5 years old. We will use primary and secondary outcome measures to compare the effectiveness of Duraphat® fluoride varnish plus treatment as usual with treatment as usual only in preventing any further dental decay. We will also undertake a full economic evaluation of the trial

Colour terms affect detection of colour and colour-associated objects suppressed from visual awareness

The idea that language can affect how we see the world continues to create controversy. A potentially important study in this field has shown that when an object is suppressed from visual awareness using continuous flash suppression (a form of binocular rivalry), detection of the object is differently affected by a preceding word prime depending on whether the prime matches or does not match the object. This may suggest that language can affect early stages of vision. We replicated this paradigm and further investigated whether colour terms likewise influence the detection of colours or colour-associated object images suppressed from visual awareness by continuous flash suppression. This method presents rapidly changing visual noise to one eye while the target stimulus is presented to the other. It has been shown to delay conscious perception of a target for up to several minutes. In Experiment 1 we presented greyscale photos of objects. They were either preceded by a congruent object label, an incongruent label, or white noise. Detection sensitivity (d’) and hit rates were significantly poorer for suppressed objects preceded by an incongruent label compared to a congruent label or noise. In Experiment 2, targets were coloured discs preceded by a colour term. Detection sensitivity was significantly worse for suppressed colour patches preceded by an incongruent colour term as compared to a congruent term or white noise. In Experiment 3 targets were suppressed greyscale object images preceded by an auditory presentation of a colour term. On congruent trials the colour term matched the object’s stereotypical colour and on incongruent trials the colour term mismatched. Detection sensitivity was significantly poorer on incongruent trials than congruent trials. Overall, these findings suggest that colour terms affect awareness of coloured stimuli and colour- associated objects, and provide new evidence for language-perception interaction in the brain

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Onset of deglacial warming in West Antarctica driven by local orbital forcing

The cause of warming in the Southern Hemisphere during the most recent deglaciation remains a matter of debate[superscript 1,2]. Hypotheses for a Northern Hemisphere trigger, through oceanic redistributions of heat, are based in part on the abrupt onset of warming seen in East Antarctic ice cores and dated to 18,000 years ago, which is several thousand years after high-latitude Northern Hemisphere summer insolation intensity began increasing from its minimum, approximately 24,000 years ago[superscript 3,4]. An alternative explanation is that local solar insolation changes cause the Southern Hemisphere to warm independently[superscript 2,5]. Here we present results from a new, annually resolved ice-core record from West Antarctica that reconciles these two views. The records show that 18,000 years ago snow accumulation in West Antarctica began increasing, coincident with increasing carbon dioxide concentrations, warming in East Antarctica and cooling in the Northern Hemisphere[superscript 6] associated with an abrupt decrease in Atlantic meridional overturning circulation[superscript 7]. However, significant warming in West Antarctica began at least 2,000 years earlier. Circum-Antarctic sea-ice decline, driven by increasing local insolation, is the likely cause of this warming. The marine-influenced West Antarctic records suggest a more active role for the Southern Ocean in the onset of deglaciation than is inferred from ice cores in the East Antarctic interior, which are largely isolated from sea-ice changes.Keywords: Last glacial period, Carbon Dioxide, High resolution, Chronology, Ice core, Circulation, Abrupt climate change, Atmospheric Co2, Greenland, Polar ic

Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial.

BACKGROUND: Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes. METHODS: In this multicentre, open-label, randomised controlled trial, we recruited women aged 18-40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527. FINDINGS: Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy). INTERPRETATION: Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use. FUNDING: Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research

Precise interpolar phasing of abrupt climate change during the last ice age

The last glacial period exhibited abrupt Dansgaard–Oeschger climatic oscillations, evidence of which is preserved in a variety of Northern Hemisphere palaeoclimate archives¹. Ice cores show that Antarctica cooled during the warm phases of the Greenland Dansgaard–Oeschger cycle and vice versa[superscript 2,3], suggesting an interhemispheric redistribution of heat through a mechanism called the bipolar seesaw[superscript 4–6]. Variations in the Atlantic meridional overturning circulation (AMOC) strength are thought to have been important, but much uncertainty remains regarding the dynamics and trigger of these abrupt events[superscript 7–9]. Key information is contained in the relative phasing of hemispheric climate variations, yet the large, poorly constrained difference between gas age and ice age and the relatively low resolution of methane records from Antarctic ice cores have so far precluded methane-based synchronization at the required sub-centennial precision[superscript 2,3,10]. Here we use a recently drilled high-accumulation Antarctic ice core to show that, on average, abrupt Greenland warming leads the corresponding Antarctic cooling onset by 218 ± 92 years (2σ) for Dansgaard–Oeschger events, including the Bølling event; Greenland cooling leads the corresponding onset of Antarctic warming by 208 ± 96 years. Our results demonstrate a north-to-south directionality of the abrupt climatic signal, which is propagated to the Southern Hemisphere high latitudes by oceanic rather than atmospheric processes. The similar interpolar phasing of warming and cooling transitions suggests that the transfer time of the climatic signal is independent of the AMOC background state. Our findings confirm a central role for ocean circulation in the bipolar seesaw and provide clear criteria for assessing hypotheses and model simulations of Dansgaard–Oeschger dynamics

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once