Diploid-dominant life cycles characterize the early evolution of Fungi.

Most of the described species in kingdom Fungi are contained in two phyla, the Ascomycota and the Basidiomycota (subkingdom Dikarya). As a result, our understanding of the biology of the kingdom is heavily influenced by traits observed in Dikarya, such as aerial spore dispersal and life cycles dominated by mitosis of haploid nuclei. We now appreciate that Fungi comprises numerous phylum-level lineages in addition to those of Dikarya, but the phylogeny and genetic characteristics of most of these lineages are poorly understood due to limited genome sampling. Here, we addressed major evolutionary trends in the non-Dikarya fungi by phylogenomic analysis of 69 newly generated draft genome sequences of the zoosporic (flagellated) lineages of true fungi. Our phylogeny indicated five lineages of zoosporic fungi and placed Blastocladiomycota, which has an alternation of haploid and diploid generations, as branching closer to the Dikarya than to the Chytridiomyceta. Our estimates of heterozygosity based on genome sequence data indicate that the zoosporic lineages plus the Zoopagomycota are frequently characterized by diploid-dominant life cycles. We mapped additional traits, such as ancestral cell-cycle regulators, cell-membrane- and cell-wall-associated genes, and the use of the amino acid selenocysteine on the phylogeny and found that these ancestral traits that are shared with Metazoa have been subject to extensive parallel loss across zoosporic lineages. Together, our results indicate a gradual transition in the genetics and cell biology of fungi from their ancestor and caution against assuming that traits measured in Dikarya are typical of other fungal lineages.

Integrative approach to species delimitation in Rhizophydiales: Novel species of Angulomyces, Gorgonomyces, and Terramyces from northern Thailand.

The Chytridiomycota is a phylum of zoosporic eufungi that inhabit terrestrial, freshwater, and oceanic habitats. Within the phylum, the Rhizophydiales contains several monotypic families theorized to hold a diverse assemblage of fungi yet to be discovered and properly described. Based on morphology alone, many species in this order are difficult or impossible to identify. In this study, we isolated three chytrids from northern Thailand. Phylogenetic analyses placed the isolates in three monotypic genera within Rhizophydiales. Intrageneric genetic distances in the internal transcribed spacer (ITS) ranged between 1.5 and 8.5%. Angulomyces solicola sp. nov. is characterized by larger sporangia, spores, and fewer discharge papilla than A.argentinensis; Gorgonomyces thailandicus sp. nov. has larger zoospores and fewer discharge papillae in culture compared to G. haynaldii; Terramyces chiangraiensis sp. nov. produces larger sporangia than T. subangulosum. We delimited species of Angulomyces, Gorgonomyces and Terramyces using a tripartite approach that employed phylogeny, ITS genetic distances and Poisson tree processes (PTP). Results of these approaches suggest more than one species in each genus. This study contributes to the knowledge of chytrids, an understudied group in Thailand and worldwide.

The unexplored role of sedentary time and physical activity in glucose and lipid metabolism-related placental mRNAs in pregnant women who are obese: the DALI lifestyle randomised controlled trial.

OBJECTIVE: We aimed to explore: (i) the association of sedentary time (ST) and physical activity (PA) during pregnancy with the placental expression of genes related to glucose and lipid metabolism in pregnant women who are obese; (ii) maternal metabolic factors mediating changes in these placental transcripts; and (iii) cord blood markers related to the mRNAs mediating neonatal adiposity. DESIGN: Multicentre randomised controlled trial. SETTING: Hospitals in nine European countries. POPULATION: A cohort of 112 pregnant women with placental tissue. METHODS: Both ST and moderate-to-vigorous PA (MVPA) levels were measured objectively using accelerometry at three time periods during pregnancy. MAIN OUTCOME MEASURES: Placental mRNAs (FATP2, FATP3, FABP4, GLUT1 and PPAR-γ) were measured with NanoString technology. Maternal and fetal metabolic markers and neonatal adiposity were assessed. RESULTS: Longer periods of ST, especially in early to middle pregnancy, was associated with lower placental FATP2 and FATP3 expression (P < 0.05), whereas MVPA at baseline was inversely associated with GLUT1 mRNA (P = 0.02). Although placental FATP2 and FATP3 expression were regulated by the insulin-glucose axis (P < 0.05), no maternal metabolic marker mediated the association of ST/MVPA with placental mRNAs (P > 0.05). Additionally, placental FATP2 expression was inversely associated with cord blood triglycerides and free fatty acids (FFAs; P < 0.01). No cord blood marker mediated neonatal adiposity except for cord blood leptin, which mediated the effects of PPAR-γ on neonatal sum of skinfolds (P < 0.05). CONCLUSIONS: In early to middle pregnancy, ST is associated with the expression of placental genes linked to lipid transport. PA is hardly related to transporter mRNAs. Strategies aimed at reducing sedentary behaviour during pregnancy could modulate placental gene expression, which may help to prevent unfavourable fetal and maternal pregnancy outcomes. TWEETABLE ABSTRACT: Reducing sedentary behaviour in pregnancy might modulate placental expression of genes related to lipid metabolism in women who are obese.

The use of a tablet-based app for investigating the influence of autistic and ADHD traits on performance in a complex drawing task.

This paper describes a smart tablet-based drawing app to digitally record participants' engagement with the Rey-Osterrieth complex figure (ROCF) task, a well-characterised perceptual memory task that assesses local and global memory. Digitisation of the tasks allows for improved ecological validity, especially in children attracted to tablet devices. Further, digital translation of the tasks affords new measures, including accuracy and computation of the fine motor control kinematics employed to carry out the drawing Here, we report a feasibility study to test the relationship between two neurodevelopmental conditions: autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). The smart tablet app was employed with 39 adult participants (18-35) characterised for autistic and ADHD traits, and scored using the ROCF perceptual and organisational scoring systems. Trait scores and conditions were predictor variables in linear regression models. Positive correlations were found between the attention-to-detail, attention-switching and communication subscales of the autistic trait questionnaire and organisational scores on the ROCF task. These findings suggest that autistic traits might be linked to differential performance on the ROCF task. Novelty and future applications of the app are discussed.

Approaches to screening for hyperglycaemia in pregnant women during and after the COVID-19 pandemic.

AIM: To evaluate the diagnostic and prognostic performance of alternative diagnostic strategies to oral glucose tolerance tests, including random plasma glucose, fasting plasma glucose and HbA1c , during the COVID-19 pandemic. METHODS: Retrospective service data (Cambridge, UK; 17 736 consecutive singleton pregnancies, 2004-2008; 826 consecutive gestational diabetes pregnancies, 2014-2019) and 361 women with ≥1 gestational diabetes risk factor (OPHELIA prospective observational study, UK) were included. Pregnancy outcomes included gestational diabetes (National Institute of Health and Clinical Excellence or International Association of Diabetes and Pregnancy Study Groups criteria), diabetes in pregnancy (WHO criteria), Caesarean section, large-for-gestational age infant, neonatal hypoglycaemia and neonatal intensive care unit admission. Receiver-operating characteristic curves and unadjusted logistic regression were used to compare random plasma glucose, fasting plasma glucose and HbA1c performance. RESULTS: Gestational diabetes diagnosis was significantly associated with random plasma glucose at 12 weeks [area under the receiver-operating characteristic curve for both criteria 0.81 (95% CI 0.79-0.83)], fasting plasma glucose [National Institute of Health and Clinical Excellence: area under the receiver-operating characteristic curve 0.75 (95% CI 0.65-0.85); International Association of Diabetes and Pregnancy Study Groups: area under the receiver-operating characteristic curve 0.92 (95% CI 0.85-0.98)] and HbA1c at 28 weeks' gestation [National Institute of Health and Clinical Excellence: 0.83 (95% CI 0.75-0.90); International Association of Diabetes and Pregnancy Study Groups: 0.84 (95% CI 0.77-0.91)]. Each measure predicts some, but not all, pregnancy outcomes studied. At 12 weeks, ~5% of women would be identified using random plasma glucose ≥8.5 mmol/l (sensitivity 42%; specificity 96%) and at 28 weeks using HbA1c ≥39 mmol/mol (sensitivity 26%; specificity 96%) or fasting plasma glucose ≥5.2-5.4 mmol/l (sensitivity 18-41%; specificity 97-98%). CONCLUSIONS: Random plasma glucose at 12 weeks, and fasting plasma glucose or HbA1c at 28 weeks identify women with hyperglycaemia at risk of suboptimal pregnancy outcomes. These opportunistic laboratory tests perform adequately for risk stratification when oral glucose tolerance testing is not available.

Metabolic phenotypes of early gestational diabetes mellitus and their association with adverse pregnancy outcomes.

AIMS: To describe the metabolic phenotypes of early gestational diabetes mellitus and their association with adverse pregnancy outcomes. METHODS: We performed a post hoc analysis using data from the Vitamin D And Lifestyle Intervention for gestational diabetes prevention (DALI) trial conducted across nine European countries (2012-2014). In women with a BMI ≥29 kg/m2 , insulin resistance and secretion were estimated from the oral glucose tolerance test values performed before 20 weeks, using homeostatic model assessment of insulin resistance and Stumvoll first-phase indices, respectively. Women with early gestational diabetes, defined by the International Association of Diabetes and Pregnancy Study Groups criteria, were classified into three groups: GDM-R (above-median insulin resistance alone), GDM-S (below-median insulin secretion alone), and GDM-B (combination of both) and the few remaining women were excluded. RESULTS: Compared with women in the normal glucose tolerance group (n = 651), women in the GDM-R group (n = 143) had higher fasting and post-load glucose values and insulin levels, with a greater risk of having large-for-gestational age babies [adjusted odds ratio 3.30 (95% CI 1.50-7.50)] and caesarean section [adjusted odds ratio 2.30 (95% CI 1.20-4.40)]. Women in the GDM-S (n = 37) and GDM-B (n = 56) groups had comparable pregnancy outcomes with those in the normal glucose tolerance group. CONCLUSIONS: In overweight and obese women with early gestational diabetes, higher degree of insulin resistance alone was more likely to be associated with adverse pregnancy outcomes than lower insulin secretion alone or a combination of both.

Trends in pregnancy outcomes for women with gestational diabetes mellitus in Sweden 1998-2012: a nationwide cohort study.

AIM: To assess whether incidence of maternal and neonatal outcomes for women with or without gestational diabetes mellitus (GDM) have changed over time. METHODS: Population-based cohort study in Sweden including all singleton pregnancies over the period 1998-2012. GDM was diagnosed following Diabetic Pregnancy Study Group 1991 criteria. Poisson regression or negative binomial regression was used to model yearly relative change in numbers of cases and incidence of the outcomes with 95% confidence intervals (CI), and yearly absolute change in birthweight z-score. RESULTS: The study included 1 455 667 pregnancies. The number of pregnancies increased over time and the overall prevalence of GDM was 1%. For women with GDM there was a significantly decreasing trend in incidence per year for large for gestational age (LGA) (0.986, 95% CI 0.975 to 0.996), birthweight z-score (-0.012, 95% CI -0.017 to -0.007) and birth trauma (0.937, 95% CI 0.907 to 0.968). The trend for small for gestational age (SGA) among women with GDM increased by an odds ratio per year (1.016, 95% CI 1.002 to 1.029). No significant interaction tests for maternal characteristics were found. Trends in outcomes for women without diabetes were similar to those for women with GDM. CONCLUSIONS: This study shows that there were improvements in pregnancy outcomes for women with GDM between 1998 and 2012, although the incidence of SGA increased. Improvements followed similar trends in the background population. Inequalities in obstetric outcomes between women with GDM and those without have continued unchanged over 15 years, suggesting that new management strategies are required to reduce this gap.

A low-cost laboratory-based method for predicting newly diagnosed biopsy-proven diabetic nephropathy in people with type 2 diabetes.

AIMS: To identify significant prognostic factors for newly diagnosed biopsy-proven diabetic nephropathy using routine laboratory measures, from which to derive a low-cost explanatory model, and to use this model to examine associations between the potential low-cost test panels and the risk of diabetic nephropathy in people with type 2 diabetes with normal kidney function. METHOD: A population-based case-control study was undertaken to test the association between diabetic nephropathy and 47 laboratory variables using a 'hypothesis-free' strategy and five routinely recorded factors in diabetes care (BMI, systolic and diastolic blood pressure, HbA1c , fasting glucose). Factors that were significant after Bonferroni correction were included in different test panels and used to develop diabetic nephropathy (outcome) explanatory models. Models were derived using risk-set sampling among 950 biopsy-proven diabetic nephropathy cases newly diagnosed in the period between 2012 and 2018 and among 4750 age- and gender-matched controls. RESULTS: A total of 15 Bonferroni-corrected significant laboratory predictors in the three test panels (blood cell, serum electrolytes and blood coagulation) were identified through multivariable analysis and used to develop the three explanatory models. The optimism-adjusted C-statistics and calibration slope were 0.725 (95% CI 0.723-0.728) and 0.978 (95% CI 0.912-0.999) for the blood cell model, 0.688 (95% CI 0.686-0.690) and 0.923 (95% CI 0.706-0.977) for the serum electrolytes model, 0.648 (95% CI 0.639-0.658) and 0.914 (95% CI 0.641-1.115) for the blood coagulation model, respectively. CONCLUSIONS: A total of 15 predictors were significantly associated with newly diagnosed biopsy-proven diabetic nephropathy in type 2 diabetes. The blood cell model appeared to be the low-cost model with the best predictive ability.

Seasonal variations in incidence and maternal-fetal outcomes of gestational diabetes.

AIMS: To determine whether the neonatal and delivery outcomes of gestational diabetes vary seasonally in the context of a relatively cool temperate climate. METHODS: A retrospect cohort of 23 735 women consecutively delivering singleton, live-born term infants in a single tertiary obstetrics centre in the UK (2004-2008) was identified. A total of 985 (4.1%) met the diagnostic criteria for gestational diabetes. Additive dynamic regression models, adjusted for maternal age, BMI, parity and ethnicity, were used to compare gestational diabetes incidence and outcomes over annual cycles. Outcomes included: random plasma glucose at booking; gestational diabetes diagnosis; birth weight centile; and delivery mode. RESULTS: The incidence of gestational diabetes varied by 30% from peak incidence (October births) to lowest incidence (March births; P=0.031). Ambient temperature at time of testing (28 weeks) was strongly positively associated with diagnosis (P<0.001). Significant seasonal variation was evident in birth weight in gestational diabetes-affected pregnancies (average 54th centile June to September; average 60th centile December to March; P=0.027). Emergency Caesarean rates also showed significant seasonal variation of up to 50% (P=0.038), which was closely temporally correlated with increased birth weights. CONCLUSIONS: There is substantial seasonal variation in gestational diabetes incidence and maternal-fetal outcomes, even in a relatively cool temperate climate. The highest average birth weight and greatest risk of emergency Caesarean delivery occurs in women delivering during the spring months. Recognizing seasonal variation in neonatal and delivery outcomes provides new opportunity for individualizing approaches to managing gestational diabetes.

Virtual reality-based treatment for regaining upper extremity function induces cortex grey matter changes in persons with acquired brain injury.

BACKGROUND: Individuals with acquired brain injuries (ABI) are in need of neurorehabilitation and neurorepair. Virtual anatomical interactivity (VAI) presents a digital game-like format in which ABI survivors with upper limb paresis use an unaffected limb to control a standard input device and a commonplace computer mouse to control virtual limb movements and tasks in a virtual world. METHODS: In a prospective cohort study, 35 ambulatory survivors of ABI (25/71% stroke, 10/29% traumatic brain injury) were enrolled. The subjects were divided into three groups: group A received VAI therapy only, group B received VAI and physical/occupational therapy (P/OT), and group C received P/OT only. Motor skills were evaluated by muscle strength (hand key pinch strength, grasp, and three-jaw chuck pinch) and active range of motion (AROM) of the shoulder, elbow, and wrist. Changes were analyzed by ANOVA, ANCOVA, and one-tailed Pearson correlation analysis. MRI data was acquired for group A, and volumetric changes in grey matter were analyzed using voxel-based morphometry (VBM) and correlated with quantified motor skills. RESULTS: AROM of the shoulder, elbow, and wrist improved in all three groups. VBM revealed grey matter increases in five brain areas: the tail of the hippocampus, the left caudate, the rostral cingulate zone, the depth of the central sulcus, and the visual cortex. A positive correlation between the grey matter volumes in three cortical regions (motor and premotor and supplementary motor areas) and motor test results (power and AROM) was detected. CONCLUSIONS: Our findings suggest that the VAI rehabilitation program significantly improved motor function and skills in the affected upper extremities of subjects with acquired brain injuries. Significant increases in grey matter volume in the motor and premotor regions of affected hemisphere and correlations of motor skills and volume in nonaffected brain regions were present, suggesting marked changes in structural brain plasticity. TRIAL REGISTRATION: The trial "Limitations of motor brain activity - use of virtual reality for simulation of therapeutic interventions" has been registered under reference number ISRCTN11757651 .

Brown bullhead at the St. Lawrence River (Cornwall) Area of Concern: health and endocrine status in the context of tissue concentrations of PCBs and mercury.

The St. Lawrence River, at Cornwall Ontario, has accumulated sediment contaminants, mainly mercury (Hg) and polychlorinated biphenyls (PCBs), from industrial point sources over many years. Although those sources are past, the river at Cornwall remains an Area of Concern (AOC). Because of remediation and other changes in the AOC, improved knowledge of contaminants in wild-fish and their putative links to health effects could help decision makers to better assess the AOC's state. Thus, we compared tissue concentrations of Hg, PCBs, morphometric measures of health, and biomarkers of exposure, metabolic-, and reproductive health in native brown bullhead (Ameiurus nebulosus) from the AOC to those of upstream reference fish. Linear discriminant analysis separated the adult fish of both sexes among upstream and downstream sites without misclassification. Burdens of total-Hg (all sites) and PCB toxic equivalents (downstream sites) exceeded the guidance for the protection of wildlife consumers. There were subtle effects of site on physiological variables, particularly in female fish. Total-Hg in tissue correlated negatively to plasma testosterone and 17ß-estradiol in female fish at Cornwall: moreover, concentrations of both hormones were lower within the AOC compared to reference site fish. A similar effect on vitellogenin, which was uncorrelated to E2/T at the downstream sites, indicated the potential for reproductive effects. Downstream fish also had altered thyroidal status (T3, TSH, and ratio of thyroid epithelial cell area to colloid area). Despite spatial and temporal variability of the endocrine-related responses, these subtle effects on fish health within the AOC warrant further study.

Risk factors and outcomes for neonatal hypoglycaemia and neonatal hyperbilirubinaemia in pregnancies complicated by gestational diabetes mellitus: a single centre retrospective 3-year review.

AIM: To determine risk factors associated with neonatal hypoglycaemia and hyperbilirubinaemia, and assess their impact on neonatal outcomes in pregnancies complicated by gestational diabetes mellitus (GDM). METHODS: Retrospective review investigating all pregnancies complicated by GDM at Campbelltown Hospital (Sydney, Australia) between 1 January 2013 and 31 December 2015. Main outcomes measured were neonatal hypoglycaemia (capillary glucose levels < 1.8 mmol/l) and hyperbilirubinaemia (total serum bilirubin levels greater than age-appropriate thresholds for phototherapy). Adjusted odds ratios [95% confidence interval (CI)] are shown, calculated by multivariable logistic regression. RESULTS: Some 60 (7.8%) infants developed hypoglycaemia, 58 (7.5%) developed hyperbilirubinaemia and 13 (1.7%) developed both. Risk of developing hypoglycaemia increased 1.8-fold (95% CI 1.3-2.6, P < 0.001) per gestational week at GDM diagnosis, 1.1-fold (95% CI 1.0-1.3, P = 0.04) per mmol/l maternal fasting glucose, 6.2-fold (95% CI 2.6-16.2, P < 0.001) with maternal history of macrosomia, 10.8-fold (95% CI 4.1-27.6, P < 0.001) with multiple pregnancy and 1.1-fold (95% CI 1.0-1.3, P = 0.04) per gestational week at birth. Risk of hyperbilirubinaemia increased with multiple pregnancy (26.4; 95% CI 11.7-59.7, P < 0.001), and 1.5-fold (95% CI 1.1-2.1, P = 0.01) per gestational week at GDM diagnosis. Hypoglycaemia was associated with a 2.8-fold (95% CI 1.1-7.1, P = 0.03) increased risk of macrosomia, a 5.4-fold (95% CI 1.1-27.3, P = 0.04) excess risk of shoulder dystocia and a 6.4-fold increased risk of 5-min APGAR ≤ 7 (95% CI 1.2-1.7, P < 0.001). Hyperbilirubinaemia was associated with an excess risk of polycythaemia (packed cell volume > 0.6; 97.1, 95% CI 38.9-241.5, P < 0.001). CONCLUSIONS: Neonatal hypoglycaemia and hyperbilirubinaemia largely occur in different pregnancies. Both are associated with earlier GDM diagnosis; however, hypoglycaemia is more associated with maternal glycaemia and its sequelae, and hyperbilirubinaemia is associated with polycythaemia.

Lessons learned from lifestyle prevention trials in gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is associated with an increased risk of adverse outcomes for mother and infant both at birth and later in life. A large body of evidence is now available relating to antenatal prevention of GDM. Overall, despite some individual trials of a variety of lifestyle interventions revealing benefit, many more have shown no effect from the second trimester onwards, even with significant gestational weight gain limitation. At-risk women often seem reluctant to engage in lifestyle changes and frequently cannot adhere to recommended interventions even within a clinical trial setting. Many trials have not considered the heterogeneity of diabetes first discovered in pregnancy, something of importance into the future. Future work should focus on designing interventions acceptable to the population at risk, whether those taking place before or during the first trimester of pregnancy are effective, and whether greater individualization can identify those women most likely to benefit.

Gestational diabetes and adiposity are independent risk factors for perinatal outcomes: a population based cohort study in Sweden.

AIMS: To evaluate the interaction effects of gestational diabetes (GDM) with obesity on perinatal outcomes. METHODS: A population-based cohort study in Sweden excluding women without pre-gestational diabetes with a singleton birth between 1998 and 2012. Logistic regression was performed to evaluate the potential independent associations of GDM and BMI with adverse perinatal outcomes as well as their interactions. Main outcome measures were malformations, stillbirths, perinatal mortality, low Apgar score, fetal distress, prematurity and Erb's palsy. RESULTS: Some 1,294,006 women were included, with a GDM prevalence of 1% (n = 14,833). The rate of overweight/obesity was 67.7% in the GDM-group and 36.1% in the non-GDM-group. No significant interaction existed. Offspring of women with GDM had significantly increased risk of malformations, adjusted odds ratio (aOR) 1.16 (95% confidence intervals 1.06-1.26), prematurity, aOR 1.86 (1.76-1. 98), low Apgar score, aOR 1.36 (1.10-1.70), fetal distress, aOR 1.09 (1.02-1.16) and Erb's palsy aOR 2.26 (1.79-2.86). No risk for stillbirth or perinatal mortality was seen. Offspring of overweight (BMI 25-29.9 kg/m2 ), obese (BMI 30-34.9 kg/m2 ) and severely obese women (BMI ≥ 35.0 kg/m2 ) had significantly increased risks of all outcomes including stillbirth 1.51 (1.40-1.62) to 2.85 (2.52-3.22) and perinatal mortality 1.49 (1.40-1.59) to 2.83 (2.54-3.15). CONCLUSIONS: There is no interaction effect between GDM and BMI for the studied outcomes. Higher BMI and GDM are major independent risk factors for most serious adverse perinatal outcomes. More effective pre-pregnancy and antenatal interventions are required to prevent serious adverse pregnancy outcomes among women with either GDM or high BMI.

Predicting responses to inhibitory synaptic input in substantia nigra pars reticulata neurons.

The changes in firing probability produced by a synaptic input are usually visualized using the poststimulus time histogram (PSTH). It would be useful if postsynaptic firing patterns could be predicted from patterns of afferent synaptic activation, but attempts to predict the PSTH from synaptic potential waveforms using reasoning based on voltage trajectory and spike threshold have not been successful, especially for inhibitory inputs. We measured PSTHs for substantia nigra pars reticulata (SNr) neurons inhibited by optogenetic stimulation of striato-nigral inputs or by matching artificial inhibitory conductances applied by dynamic clamp. The PSTH was predicted by a model based on each SNr cell's phase-resetting curve (PRC). Optogenetic activation of striato-nigral input or artificial synaptic inhibition produced a PSTH consisting of an initial depression of firing followed by oscillatory increases and decreases repeating at the SNr cell's baseline firing rate. The phase resetting model produced PSTHs closely resembling the cell data, including the primary pause in firing and the oscillation. Key features of the PSTH, including the onset rate and duration of the initial inhibitory phase, and the subsequent increase in firing probability could be explained from the characteristic shape of the SNr cell's PRC. The rate of damping of the late oscillation was explained by the influence of asynchronous phase perturbations producing firing rate jitter and wander. Our results demonstrate the utility of phase-resetting models as a general method for predicting firing in spontaneously active neurons and their value in interpretation of the striato-nigral PSTH. NEW & NOTEWORTHY The coupling of patterned presynaptic input to sequences of postsynaptic firing is a Gordian knot, complicated by the multidimensionality of neuronal state and the diversity of potential initial states. Even so, it is fundamental for even the simplest understanding of network dynamics. We show that a simple phase-resetting model constructed from experimental measurements can explain and predict the sequence of spike rate changes following synaptic inhibition of an oscillating basal ganglia output neuron.

Impact of peer support on inpatient and outpatient payments among people with Type 2 diabetes: a prospective cohort study.

AIM: To investigate the impact of a low-cost diabetes peer-support intervention, aimed at reducing inpatient and outpatient care utilization and healthcare payments, by conducting a cohort study that followed up a randomized controlled trial. METHODS: A total of 1121 adults with Type 2 diabetes were recruited through general practices in Cambridgeshire and Hertfordshire, UK, and were followed up for 3.25 financial years after 8-12 months of one-to-one, group or combined diabetes peer support and usual care. Use of, and payments for inpatient and outpatient services were fully recorded in the follow-up. Adjusted mean inpatient and outpatient payments per person were estimated using a two-part model after adjusting for baseline characteristics. RESULTS: The mean age of the recruited adults was 65.6±11.4 years, 60.4% were male, and 16.8% were insulin-treated. Compared with the control group, less healthcare utilization (especially non-elective inpatient care and outpatient consultations) was observed in each of the intervention groups, particularly the combined intervention group. Over the course of 3.25 financial years, significant reductions of 41% (£909.20 per head) were observed for overall inpatient payments (P<0.0001), 51% (£514.67 per head) for non-elective inpatient payments (P=0.005) in the combined intervention group, and 34% (£413.30 per head) and 32% (£388.99 per head) for elective inpatient payments in the one-to-one (P=0.029) and combined intervention (P=0.048) groups, respectively. CONCLUSIONS: Type 2 diabetes peer support, whether delivered using a one-to-one, group or combined approach was associated with reduced inpatient care utilization (particularly non-elective admissions) and payments over 3.25 years.

Loss of Rearranged L-Myc Fusion (RLF) results in defects in heart development in the mouse.

Recently we reported that Rearranged L-Myc Fusion, RLF, acts as an epigenetic modifier maintaining low levels of DNA methylation at CpG island shores and enhancers across the genome. Here we focus on the phenotype of Rlf null mutant mice generated via an ENU mutagenesis screen, to identify genes required for epigenetic regulation. RLF is expressed in a range of fetal mouse tissues, including the fetal heart. Comprehensive timed-mating studies are consistent with our previously reported findings that Rlf homozygous mutant mice rarely survive to adulthood, with the majority dying shortly after birth. Histological analysis of two independent Rlf ENU mutant lines at E11.5-E14.5 showed heart defects resembling those present in humans with Left Ventricular Non-Compaction (LVNC). In situ hybridisation analysis localized expression of Rlf to the endocardium and epicardium of embryonic and postnatal hearts, and transiently to cardiomyocytes during heart looping and early chamber formation stages. RNA-seq analysis of Rlf mutant hearts highlighted defective NOTCH pathway signalling, recently describe as one cause of LVNC. This study provides the first evidence that RLF is required for normal heart development in the mouse. The heart morphological defects present at high penetrance in Rlf mutants are consistent with features of LVNC in humans, and molecular analysis identified attenuated JAGGED 1 expression and NOTCH signalling as likely contributors to these defects. Our study highlights the importance of RLF-dependent epigenetic modifications to DNA for maintaining correct gene regulatory network and intercellular signalling interactions during heart chamber and septal development. Further investigations are needed to define the biochemical role of RLF in the developing heart, and whether RLF mutations are a cause of heart defects in humans.

rs9939609 FTO genotype associations with FTO methylation level influences body mass and telomere length in an Australian rural population.

BACKGROUND: The fat mass- and obesity-associated (FTO) gene influences energy homeostasis in humans. Although the obesity-related variant, rs9939609 has been replicated across a number of cohort studies, there remains significant variance and a low to modest association. Telomere length is another commonly reported obesity risk factor. We hypothesize understanding the associations between FTO rs9939609 with FTO methylation and telomere length will provide a more accurate assessment of obesity risk. METHODS: Overall, 942 participants free of diabetes or pre-diabetes were included in the retrospective study. Leukocyte genomic DNA was analyzed for rs9939609 genotyping, FTO gene methylation and leukocyte telomere length (LTL) measurement. RESULTS: In general linear models, rs9939609 AA genotypes were associated with increased fat percentage (3.15%, P=0.001), fat mass (4.16 kg, P=0.001), body mass index (BMI) (1.38, P=0.006) and waist circumference (3.35 cm, P=0.006), but not with FTO methylation or LTL in this overall population. However, when participants were stratified into higher and lower FTO methylation groups, the AA genotype possesses a 2.04-fold increased obesity risk in comparison to TT genotype (95%CI, 1.07-3.89, P=0.031) in participants with a higher FTO methylation level, but this association was absent in the lower FTO methylation sub-group. Moreover, AT and AA genotype carriers were associated with shorter LTL compared to TT carriers (P=0.020 and P=0.111, respectively) in the higher FTO methylation level group. However, this association was absent in the lower methylation group. Furthermore, FTO gene methylation level was significantly associated with LTL in the 942 samples (P=0.017). CONCLUSIONS: FTO rs9939609 is associated with obesity risk and LTL in this study, where this association is only observed at higher, but not lower, FTO methylation levels of participants. Our data suggest association of multiple factors, including FTO methylation level, may be involved in one of several mechanisms underlying the commonly reported obesity risk of this FTO polymorphism.

Association between pulse pressure and risk of hospital admissions for cardiovascular events among people with Type 2 diabetes: a population-based case-control study.

AIM: To investigate the association between pulse pressure and risk of hospitalization for cardiovascular events among people with Type 2 diabetes. METHODS: A population-based case-control study was carried out using data from medical databases. A total of 588 people with Type 2 diabetes from 18 general practices in Cambridgeshire recorded a first hospitalization for a cardiovascular event between 2009 and 2011, and a total of 2920 age-matched, gender-matched and practice-matched control subjects with Type 2 diabetes were selected based on risk-set sampling. Pulse pressure was assessed before admission in 2008-2009. Further dose-response relationships between pulse pressure and risks were explored using spline models. RESULTS: There was a non-linear relationship between pulse pressure and the risk of hospitalization for a cardiovascular event (P < 0.001 for linearity test). The pulse pressure associated with the lowest risk of hospitalization for a cardiovascular event was 61 (95% CI 57-63) mmHg. CONCLUSION: In people with Type 2 diabetes, pulse pressure is a good predictor of risk of hospitalization for cardiovascular events. The risk is lowest with a pulse pressure of 57-63 mmHg.

Effectiveness of a multidisciplinary team approach to the prevention of readmission for acute glycaemic events.

AIMS: To describe the effect of a combined diabetes specialist/mental health team approach to prevent readmissions for acute glycaemic events among patients with diabetes. METHODS: Consecutive patients with diabetes, readmitted to a single hospital for an acute glycaemic condition, were offered one or more diabetes (including assessment, education, medication, technology use and intensive support) and mental health (including assessment, training and therapies) interventions. The pilot service took place over 11 months, with the preceding 24 months and subsequent 8 months serving as control periods. RESULTS: Of the 58 patients admitted, 50 had Type 1 diabetes and were from within the hospital catchment area, and were discharged home. Of these, 32 (64%) had a pre-existing mental health issue and 14 (28%) had a complex social situation. In all, 96% of patients were met as an inpatient by a team member, and 94% accepted at least one intervention. The mean ±sd number of admissions per patient/month dropped from 0.12 ± 0.10 to 0.05 ± 0.10 (P < 0.001) during the intervention, increasing, once the intervention ended, to 0.16 ± 0.36 (P = 0.002). The mean ± sd length of stay similarly decreased and increased (0.6 ± 0.9 to 0.2 ± 0.7 days; P < 0.001 to 0.006) to 0.6 ± 1.4 days (P = 0.003) per patient/month) across the three periods, as did the mean ±sd tariff paid per patient/month (£258.0 ± 374.0 vs £92.1 ± 245.0 vs £287.3 ± 563.8; P < 0.001 and P = 0.018, respectively). The mean ± sd HbA1c level dropped from 99 ± 22 to 92 ± 24 mmol/mol (11.2 ± 4.2% vs 10.6 ± 4.3%; P = 0.014) but did not increase after the intervention [89 ± 26 mmol/mol (10.4 ± 4.5%)]. CONCLUSIONS: The cost and long-term risks of hospitalization among patients with Type 1 diabetes and recurrent admissions can be reduced by a combined specialist diabetes/mental health team approach.