Unhealthy days and quality of life in Irish patients with diabetes

Objectives: To study the determinants of health-related quality of life (HRQoL) in Irish patients with diabetes using the Centres for Disease Controls' (CDC's) 'Unhealthy Days' summary measure and to assesses the agreement between this generic HRQoL measure and the disease-specific Audit of Diabetes Dependant Quality of Life (ADDQoL) measure. Research Design and Methods: Data were analysed from the Diabetes Quality of Life Study, a cross-sectional study of 1,456 people with diabetes in Ireland (71% response rate). Unhealthy days were assessed using the CDC's 'Unhealthy days' summary measure. Quality of life (QoL) was also assessed using the ADDQoL measure. Analyses were conducted primarily using logistic regression. The agreement between the two QoL instruments was measured using the kappa co-efficient. Results: Participants reported a median of 2 unhealthy days per month. In multivariate analyses, female gender (P = 0.001), insulin use (P = 0.030), diabetes complications (P =<0.001) were significantly associated with more unhealthy days. Older patients had fewer unhealthy days per month (P = 0.003). Agreement between the two measures of QoL (unhealthy days measure and ADDQoL) was poor, Kappa = 0.234 Conclusions: The findings highlight the determinants of HRQoL in patients with diabetes using a generic HRQoL summary measure. The 'Unhealthy Days' and the ADDQoL have poor agreement, therefore the 'Unhealthy Days' summary measure may be assessing a different construct. Nonetheless, this study demonstrates that the generic 'Unhealthy Days' summary measure can be used to detect determinants of HRQoL in patients with diabetes

iPrevent®: a tailored, web-based, decision support tool for breast cancer risk assessment and management

We aimed to develop a user-centered, web-based, decision support tool for breast cancer risk assessment and personalized risk management. Using a novel model choice algorithm, iPrevent&reg; selects one of two validated breast cancer risk estimation models (IBIS or BOADICEA), based on risk factor data entered by the user. Resulting risk estimates are presented in simple language and graphic formats for easy comprehension. iPrevent&reg; then presents risk-adapted, evidence-based, guideline-endorsed management options. Development was an iterative process with regular feedback from multidisciplinary experts and consumers. To verify iPrevent&reg;, risk factor data for 127 cases derived from the Australian Breast Cancer Family Study were entered into iPrevent&reg;, IBIS (v7.02), and BOADICEA (v3.0). Consistency of the model chosen by iPrevent&reg; (i.e., IBIS or BOADICEA) with the programmed iPrevent&reg; model choice algorithm was assessed. Estimated breast cancer risks from iPrevent&reg; were compared with those attained directly from the chosen risk assessment model (IBIS or BOADICEA). Risk management interventions displayed by iPrevent&reg; were assessed for appropriateness. Risk estimation model choice was 100% consistent with the programmed iPrevent&reg;logic. Discrepant 10-year and residual lifetime risk estimates of &gt;1% were found for 1 and 4 cases, respectively, none was clinically significant (maximal variation 1.4%). Risk management interventions suggested by iPrevent&reg; were 100% appropriate. iPrevent&reg; successfully integrates the IBIS and BOADICEA risk assessment models into a decision support tool that provides evidence-based, risk-adapted risk management advice. This may help to facilitate precision breast cancer prevention discussions between women and their healthcare providers

A network of change: united action on research integrity

The last decade has seen renewed concern within the scientific community over the reproducibility and transparency of research findings. This paper outlines some of the various responsibilities of stakeholders in addressing the systemic issues that contribute to this concern. In particular, this paper asserts that a united, joined-up approach is needed, in which all stakeholders, including researchers, universities, funders, publishers, and governments, work together to set standards of research integrity and engender scientific progress and innovation. Using two developments as examples: the adoption of Registered Reports as a discrete initiative, and the use of open data as an ongoing norm change, we discuss the importance of collaboration across stakeholders

The regulation of sequence specific NF-kB DNA binding and transcription by IKKβ phosphorylation of NF-kB p50 at serine 80

peer-reviewedPhosphorylation of the NF-kB transcription factor is an important regulatory mechanism for the control of transcription. Here we identify serine 80 (S80) as a phosphorylation site on the p50 subunit of NF-kB, and IKKβ as a p50 kinase. Transcriptomic analysis of cells expressing a p50 S80A mutant reveals a critical role for S80 in selectively regulating the TNF inducible expression of a subset of NF-kB target genes including pro-inflammatory cytokines and chemokines. S80 phosphorylation regulates the binding of p50 to NF-kB binding ( B) sites in a sequence specific manner. Specifically, phosphorylation of S80 reduces the binding of p50 at B sites with an adenine at the −1 position. Our analyses demonstrate that p50 S80 phosphorylation predominantly regulates transcription through the p50:p65 heterodimer, where S80 phosphorylation acts in trans to limit the NF- kB mediated transcription of pro-inflammatory genes. The regulation of a functional class of pro-inflammatory genes by the interaction of S80 phosphorylated p50 with a specific kB sequence describes a novel mechanism for the control of cytokine-induced transcriptional responses

Copy number variant discrepancy resolution using the ClinGen dosage sensitivity map results in updated clinical interpretations in ClinVar

Conflict resolution in genomic variant interpretation is a critical step toward improving patient care. Evaluating interpretation discrepancies in copy number variants (CNVs) typically involves assessing overlapping genomic content with focus on genes/regions that may be subject to dosage sensitivity (haploinsufficiency (HI) and/or triplosensitivity (TS)). CNVs containing dosage sensitive genes/regions are generally interpreted as â likely pathogenicâ (LP) or â pathogenicâ (P), and CNVs involving the same known dosage sensitive gene(s) should receive the same clinical interpretation. We compared the Clinical Genome Resource (ClinGen) Dosage Map, a publicly available resource documenting known HI and TS genes/regions, against germline, clinical CNV interpretations within the ClinVar database. We identified 251 CNVs overlapping known dosage sensitive genes/regions but not classified as LP or P; these were sent back to their original submitting laboratories for reâ evaluation. Of 246 CNVs reâ evaluated, an updated clinical classification was warranted in 157 cases (63.8%); no change was made to the current classification in 79 cases (32.1%); and 10 cases (4.1%) resulted in other types of updates to ClinVar records. This effort will add curated interpretation data into the public domain and allow laboratories to focus attention on more complex discrepancies.The ClinGen Dosage Sensitivity (DS) Map provides evidenceâ based assessments of the haploinsufficiency and triplosensitivity of genes/genomic regions. We identified 251 clinical copy number variants (CNVs) in ClinVar that overlapped known DS genes/regions but were not interpreted as â likely pathogenicâ or â pathogenic;â these were sent back to their original laboratories for reâ evaluation. Of the 246 that were reâ evaluated, 63.0% resulted in updated classifications, showing that the ClinGen DS Map can be an effective initial step in CNV classification discrepancy resolution.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146425/1/humu23610_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146425/2/humu23610.pd

A next generation targeted amplicon sequencing method to screen for insecticide resistance mutations in Aedes aegypti populations reveals a rdl mutation in mosquitoes from Cabo Verde.

Aedes mosquito vectors transmit many viruses of global health concern, including dengue, chikungunya and Zika. These vector-borne viral diseases have a limited number of treatment options, and vaccines vary in their effectiveness. Consequently, integrated vector management is a primary strategy for disease control. However, the increasing emergence and spread of insecticide resistance is threatening the efficacy of vector control methods. Identifying mutations associated with resistance in vector populations is important to monitor the occurrence and evolution of insecticide resistance and inform control strategies. Rapid and cost-effective genome sequencing approaches are urgently needed. Here we present an adaptable targeted amplicon approach for cost-effective implementation within next generation sequencing platforms. This approach can identify single nucleotide polymorphisms (SNPs) and small insertions and deletions (indels) in genes involved in insecticide resistance in Aedes aegypti mosquitoes. We designed and tested eleven amplicons, which included segments of the ace-1 (carbamate target), the Voltage-Gated Sodium Channel (vgsc; pyrethroids, DDT and organochlorines), and rdl (dieldrin) genes; thereby covering established knockdown resistance (kdr) mutations (e.g., S989P, I1011M/V, V1016G/I and F1534C), with the potential to identify novel ones. The amplicon assays were designed with internal barcodes, to facilitate multiplexing of large numbers of mosquitoes at low cost, and were sequenced using an Illumina platform. Our approach was evaluated on 152 Ae. aegypti mosquitoes collected in Cabo Verde, an archipelago with a history of arbovirus outbreaks. The amplicon sequence data revealed 146 SNPs, including four non-synonymous polymorphisms in the vgsc gene, one in ace-1 and the 296S rdl mutation previously associated with resistance to organochlorines. The 296S rdl mutation was identified in 98% of mosquitoes screened, consistent with the past use of an organochlorine compound (e.g., DDT). Overall, our work shows that targeted amplicon sequencing is a rapid, robust, and cost-effective tool that can be used to perform high throughput monitoring of insecticide resistance

Models of <i>KPTN</i>-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.</p

Dealing with Alcohol-related problems in the Night-Time Economy: A Study Protocol for Mapping trends in harm and stakeholder views surrounding local community level interventions

<p>Abstract</p> <p>Background</p> <p>This project will provide a comprehensive investigation into the prevalence of alcohol-related harms and community attitudes in the context of community-based interventions being implemented to reduce harm in two regional centres of Australia. While considerable experimentation and innovation to address these harms has occurred in both Geelong and Newcastle, only limited ad-hoc documentation and analysis has been conducted on changes in the prevalence of harm as a consequence, leaving a considerable gap in terms of a systematic, evidence-based analysis of changes in harm over time and the need for further intervention. Similarly, little evidence has been reported regarding the views of key stakeholder groups, industry, government agencies, patrons or community regarding the need for, and the acceptability of, interventions to reduce harms. This project will aim to provide evidence regarding the impact and acceptability of local initiatives aimed at reducing alcohol-related harms.</p> <p>Methods/Design</p> <p>This study will gather existing police data (assault, property damage and drink driving offences), Emergency Department presentations and Ambulance attendance data. Further, the research team will conduct interviews with licensed venue patrons and collect observational data of licensed venues. Key informant interviews will assess expert knowledge from key industry and government stakeholders, and a community survey will assess community experiences and attitudes towards alcohol-related harm and harm-reduction strategies. Overall, the project will assess: the extent of alcohol-related harm in the context of harm-reduction interventions, and the need for and acceptability of further intervention.</p> <p>Discussion</p> <p>These findings will be used to improve evidence-based practice both nationally and internationally.</p> <p>Ethical Approval</p> <p>This project has been approved by Deakin University HREC.</p

TOI-5126: A hot super-Neptune and warm Neptune pair discovered by TESS\textit{TESS} and CHEOPS\textit{CHEOPS}

We present the confirmation of a hot super-Neptune with an exterior Neptune companion orbiting a bright (V = 10.1 mag) F-dwarf identified by the $\textit{Transiting Exoplanet Survey Satellite}$ ($\textit{TESS}$). The two planets, observed in sectors 45, 46 and 48 of the $\textit{TESS}$ extended mission, are $4.74^{+0.16}_{-0.14}$ $R_{\oplus}$ and $3.86^{+0.17}_{-0.16}$ $R_{\oplus}$ with $5.4588385^{+0.0000070}_{-0.0000072}$ d and $17.8999^{+0.0018}_{-0.0013}$ d orbital periods, respectively. We also obtained precise space based photometric follow-up of the system with ESAs $\textit{CHaracterising ExOplanets Satellite}$ ($\textit{CHEOPS}$) to constrain the radius and ephemeris of TOI-5126 b. TOI 5126 b is located in the "hot Neptune Desert" and is an ideal candidate for follow-up transmission spectroscopy due to its high predicted equilibrium temperature ($T_{eq} = 1442^{+46}_{-40}$ K) implying a cloud-free atmosphere. TOI-5126 c is a warm Neptune ($T_{eq}= 971^{+31}_{-27}$ K) also suitable for follow-up. Tentative transit timing variations (TTVs) have also been identified in analysis, suggesting the presence of at least one additional planet, however this signal may be caused by spot-crossing events, necessitating further precise photometric follow-up to confirm these signals.Comment: Accepted in MNRAS, 18 pages, 14 figure

Linking changes in species composition and biomass in a globally distributed grassland experiment

Global change drivers, such as anthropogenic nutrient inputs, are increasing globally. Nutrient deposition simultaneously alters plant biodiversity, species composition and ecosystem processes like aboveground biomass production. These changes are underpinned by species extinction, colonisation and shifting relative abundance. Here, we use the Price equation to quantify and link the contributions of species that are lost, gained or that persist to change in aboveground biomass in 59 experimental grassland sites. Under ambient (control) conditions, compositional and biomass turnover was high, and losses (i.e. local extinctions) were balanced by gains (i.e. colonisation). Under fertilisation, the decline in species richness resulted from increased species loss and decreases in species gained. Biomass increase under fertilisation resulted mostly from species that persist and to a lesser extent from species gained. Drivers of ecological change can interact relatively independently with diversity, composition and ecosystem processes and functions such as aboveground biomass due to the individual contributions of species lost, gained or persisting.Fil: Ladouceur, Emma. Martin Luther University Halle-Wittenberg; Alemania. Universitat Leipzig; Alemania. German Centre for Integrative Biodiversity Research (iDiv) Leipzig-Halle-Jena; AlemaniaFil: Blowes, Shane A.. Martin Luther University Halle-Wittenberg; Alemania. German Centre for Integrative Biodiversity Research (iDiv) Leipzig-Halle-Jena; AlemaniaFil: Chase, Jonathan M.. German Centre for Integrative Biodiversity Research (iDiv) Leipzig-Halle-Jena; Alemania. Martin Luther University Halle-Wittenberg; AlemaniaFil: Clark, Adam T.. Martin Luther University Halle-Wittenberg; Alemania. German Centre for Integrative Biodiversity Research (iDiv) Leipzig-Halle-Jena; Alemania. University of Graz; AustriaFil: Garbowski, Magda. German Centre for Integrative Biodiversity Research (iDiv) Leipzig-Halle-Jena; Alemania. Universitat Leipzig; AlemaniaFil: Alberti, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Arnillas, Carlos Alberto. University of Toronto; CanadáFil: Bakker, Jonathan. University of Washington; Estados UnidosFil: Barrio, Isabel C.. Agricultural University of Iceland; IslandiaFil: Bharath, Siddharth. Atria University; IndiaFil: Borer, Elizabeth. University of Minnesota; Estados UnidosFil: Brudvig, Lars A.. Michigan State University; Estados UnidosFil: Cadotte, Marc W.. University of Toronto; CanadáFil: Chen, Qingqing. Peking University; ChinaFil: Collins, Scott L.. University of New Mexico; Estados UnidosFil: Dickman, Christopher R.. The University Of Sydney; AustraliaFil: Donohue, Ian. Trinity College Dublin; IrlandaFil: Du, Guozhen. Lanzhou University; ChinaFil: Ebeling, Anne. Universitat Jena; AlemaniaFil: Eisenhauer, Nico. Martin Luther University Halle—Wittenberg; Alemania. German Centre For Integrative Biodiversity Research (idiv) Halle-jena-leipzig; AlemaniaFil: Fay, Philip A.. USDA-ARS Grassland Soil and Water Research Lab; Estados UnidosFil: Hagenah, Nicole. University Of Pretoria; SudáfricaFil: Hautier, Yann. University of Utrecht; Países BajosFil: Jentsch, Anke. University of Bayreuth; AlemaniaFil: Jónsdóttir, Ingibjörg S.. University of Iceland; IslandiaFil: Komatsu, Kimberly J.. Smithsonian Environmental Research Center; Estados UnidosFil: MacDougall, Andrew. University of Guelph; CanadáFil: Martina, Jason P.. Texas State University; Estados UnidosFil: Moore, Joslin L.. Arthur Rylah Institute For Environmental Research; Australia. Monash University; AustraliaFil: Morgan, John W.. La Trobe University; AustraliaFil: Peri, Pablo Luis. Instituto Nacional de Tecnología Agropecuaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin