Whole-brain functional hypoconnectivity as an endophenotype of autism in adolescents.

Endophenotypes are heritable and quantifiable markers that may assist in the identification of the complex genetic underpinnings of psychiatric conditions. Here we examined global hypoconnectivity as an endophenotype of autism spectrum conditions (ASCs). We studied well-matched groups of adolescent males with autism, genetically-related siblings of individuals with autism, and typically-developing control participants. We parcellated the brain into 258 regions and used complex-network analysis to detect a robust hypoconnectivity endophenotype in our participant group. We observed that whole-brain functional connectivity was highest in controls, intermediate in siblings, and lowest in ASC, in task and rest conditions. We identified additional, local endophenotype effects in specific networks including the visual processing and default mode networks. Our analyses are the first to show that whole-brain functional hypoconnectivity is an endophenotype of autism in adolescence, and may thus underlie the heritable similarities seen in adolescents with ASC and their relatives.The authors wish to thank the participants and their families for their participation and the autism support organisations who assisted with recruitment. We thank colleagues at the Brain Mapping Unit for methodological discussions and thank Meng-Chuan Lai, Amber Ruigrok and Richard Bethlehem for the same. Data collection was funded by a Clinical Scientist Fellowship from the UK Medical Research Council (MRC) (G0701919) to MDS. LRC was supported by the Gates Cambridge Scholarship Trust. The study was conducted in associated with the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for Cambridgeshire, and Peterborough National Health Service (NHS) Foundation Trust. The present analysis was funded by a NARSAD Young Investigator award (to MR) and by the Isaac Newton Trust (to MR); RJFY is additionally supported by a Rubicon Fellowship from the Netherlands Organisation for Scientific Research. The Brain Mapping Unit (MR, RLM, RJFY, JS and ETB) is part of the Behavioural & Clinical Neuroscience Institute, which is funded by the MRC and the Wellcome Trust. High performance computing facilities were supported by the NIHR Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.nicl.2015.07.01

Functional network dysconnectivity as a biomarker of treatment resistance in schizophrenia

Schizophrenia may develop from disruptions in functional connectivity regulated by neurotransmitters such as dopamine and acetylcholine. The modulatory effects of these neurotransmitters might explain how antipsychotics attenuate symptoms of schizophrenia and account for the variable response to antipsychotics observed in clinical practice. Based on the putative mechanisms of antipsychotics and evidence of disrupted connectivity in schizophrenia, we hypothesised that functional network connectivity, as assessed using network-based statistics, would exhibit differences between treatment response subtypes of schizophrenia and healthy controls. Resting-state functional MRI data were obtained from 17 healthy controls as well as individuals with schizophrenia who responded well to first-line atypical antipsychotics (first-line responders; FLR, n=18), had failed at least two trials of antipsychotics but responded to clozapine (treatment-resistant schizophrenia; TRS, n=18), or failed at least two trials of antipsychotics and a trial of clozapine (ultra-treatment-resistant schizophrenia; UTRS, n=16). Data were pre-processed using the Advanced Normalisation Toolkit and BrainWavelet Toolbox. Network connectivity was assessed using the Network-Based Statistics toolbox in Matlab. ANOVA revealed a significant difference in functional connectivity between groups that extended between cerebellar and parietal regions to the frontal cortex (p<0.05). Post-hoc T-tests revealed weaker network connectivity in individuals with UTRS compared with healthy controls but no other differences between groups. Results demonstrated distinct differences in functional connectivity between individuals with UTRS and healthy controls. Future work must determine whether these changes occur prior to the onset of treatment and if they can be used to predict resistance to antipsychotics during first-episode psychosis.This work was supported by The University of Auckland Faculty Research and Development Fund Project number 3624739, with support from the New Zealand Pharmacy Education and Research Fund Grant number 263, the New Zealand Schizophrenia Research Group Donation and the Oakley Mental Health Research Foundation. Carolyn McNabb was supported by a Vernon Tews Education Trust scholarship. Meghan McIlwain was supported by a University of Auckland Doctoral Scholarship and a New Zealand Federation of Graduate Women Fellowship. Valerie Anderson was supported by an Edith C. Coan Research Fellowship from The Auckland Medical Research Foundation

Cognitive Behavioral Therapy Lowers Elevated Functional Connectivity in Depressed Adolescents

Imaging studies have implicated altered functional connectivity in adults with major depressive disorder (MDD). Whether similar dysfunction is present in adolescent patients is unclear. The degree of resting-state functional connectivity (rsFC) may reflect abnormalities within emotional (‘hot’) and cognitive control (‘cold’) neural systems. Here, we investigate rsFC of these systems in adolescent patients and changes following cognitive behavioral therapy (CBT). Functional Magnetic Resonance Imaging (fMRI) was acquired from adolescent patients before CBT, and 24-weeks later following completed therapy. Similar data were obtained from control participants. Cross-sectional Cohort: From 82 patients and 34 controls at baseline, rsFC of the amygdala, anterior cingulate cortex (ACC), and pre-frontal cortex (PFC) was calculated for comparison. Longitudinal Cohort: From 17 patients and 30 controls with longitudinal data, treatment effects were tested on rsFC. Patients demonstrated significantly greater rsFC to left amygdala, bilateral supragenual ACC, but not with PFC. Treatment effects were observed in right insula connected to left supragenual ACC, with baseline case-control differences reduced. rsFC changes were significantly correlated with changes in depression severity. Depressed adolescents exhibited heightened connectivity in regions of ‘hot’ emotional processing, known to be associated with depression, where treatment exposure exerted positive effects, without concomitant differences in areas of ‘cold’ cognition.The study was funded by the UK Medical Research Council (grant: G0802226), the National Institute for Health Research (NIHR) (grant: 06-05-01), financial support from the Department of Health, and the Behavioral and Clinical Neuroscience Institute (BCNI), University of Cambridge, the latter being jointly funded by the Medical Research Council and the Wellcome Trust. Additional support was received from the Cambridge Biomedical Research Centre. SC is supported by a Cambridge CONACyT scholarship from the University of Cambridge Overseas Trust and CONACyT

Implementation of chronic kidney disease guidelines for sodium-glucose co-transporter-2 inhibitor use in primary care in the UK: a cross-sectional study.

BACKGROUND: The cardiovascular and kidney benefits of sodium-glucose co-transporter-2 (SGLT2) inhibitors in people with chronic kidney disease (CKD) are well established. The implementation of updated SGLT2 inhibitor guidelines and prescribing in the real-world CKD population remains largely unknown. METHODS: A cross-sectional study of adults with CKD registered with UK primary care practices in the Oxford-Royal College of General Practitioners Research and Surveillance Centre network on the 31st December 2022 was undertaken. Pseudonymised data from electronic health records held securely within the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub (ORCHID) were extracted. An update to a previously described ontological approach was used to identify the study population, using a combination of Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) indicating a diagnosis of CKD and laboratory confirmed CKD based on Kidney Disease: Improving Global Outcomes (KDIGO) diagnostic criteria. We examined the extent to which SGLT2 inhibitor guidelines apply to and are then implemented in adults with CKD. A logistic regression model was used to identify factors associated with SGLT2 inhibitor prescribing, reported as odds ratios (ORs) with 95% confidence intervals (CI). The four guidelines under investigation were the United Kingdom Kidney Association (UKKA) Clinical Practice Guideline SGLT2 Inhibition in Adults with Kidney Disease (October 2021), American Diabetes Association (ADA) and KDIGO Consensus Report on Diabetes Management in CKD (October 2022), National Institute for Health and Care Excellence (NICE) Guideline Type 2 Diabetes in Adults: Management (June 2022), and NICE Technology Appraisal Dapagliflozin for Treating CKD (March 2022). FINDINGS: Of 6,670,829 adults, we identified 516,491 (7.7%) with CKD, including 32.8% (n = 169,443) who had co-existing type 2 diabetes (T2D). 26.8% (n = 138,183) of the overall CKD population had a guideline directed indication for SGLT2 inhibitor treatment. A higher proportion of people with CKD and co-existing T2D were indicated for treatment, compared to those without T2D (62.8% [n = 106,468] vs. 9.1% [n = 31,715]). SGLT2 inhibitors were prescribed to 17.0% (n = 23,466) of those with an indication for treatment, and prescriptions were predominantly in those with co-existing T2D; 22.0% (n = 23,464) in those with T2D, and <0.1% (n = 2) in those without T2D. In adjusted multivariable analysis of people with CKD and T2D, females (OR 0.69, 95% CI 0.67-0.72, p <0.0001), individuals of Black ethnicity (OR 0.84, 95% CI 0.77-0.91, p <0.0001) and those of lower socio-economic status (OR 0.72, 95% CI 0.68-0.76, p <0.0001) were less likely to be prescribed an SGLT2 inhibitor. Those with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 had a lower likelihood of receiving an SGLT2 inhibitor, compared to those with an eGFR ≥60 mL/min/1.73 m2 (eGFR 45-60 mL/min/1.73 m2 OR 0.65, 95% CI 0.62-0.68, p <0.0001, eGFR 30-45 mL/min/1.73 m2 OR 0.73, 95% CI 0.69-0.78, p <0.0001, eGFR 15-30 mL/min/1.73 m2 OR 0.52, 95% CI 0.46-0.60, p <0.0001, eGFR <15 mL/min/1.73 m2 OR 0.03, 95% CI 0.00-0.23, p = 0.0037, respectively). Those with albuminuria (urine albumin-to-creatinine ratio 3-30 mg/mmol) were less likely to be prescribed an SGLT2 inhibitor, compared to those without albuminuria (OR 0.78, 95% CI 0.75-0.82, p <0.0001). INTERPRETATION: SGLT2 inhibitor guidelines in CKD have not yet been successfully implemented into clinical practice, most notably in those without co-existing T2D. Individuals at higher risk of adverse outcomes are paradoxically less likely to receive SGLT2 inhibitor treatment. The timeframe between the publication of guidelines and data extraction may have been too short to observe changes in clinical practice. Enhanced efforts to embed SGLT2 inhibitors equitably into routine care for people with CKD are urgently needed, particularly in those at highest risk of adverse outcomes and in the absence of T2D. FUNDING: None

Adolescent Major Depressive Disorder: Neuroimaging Evidence of Sex Difference during an Affective Go/No-Go Task

Compared to female major depressive disorder (MDD), male MDD often receives less attention. However, research is warranted since there are significant sex differences in the clinical presentation of MDD and a higher rate of suicide in depressed men. To the best of our knowledge, this is the first functional magnetic resonance imaging (fMRI) study with a large sample addressing putative sex differences in MDD during adolescence, a period when one of the most robust findings in psychiatric epidemiology emerges; that females are twice as likely to suffer from MDD than males. Twenty-four depressed and 10 healthy male adolescents, together with 82 depressed and 24 healthy female adolescents, aged 11–18  years, undertook an affective go/no-go task during fMRI acquisition. In response to sad relative to neutral distractors, significant sex differences (in the supramarginal gyrus) and group-by-sex interactions (in the supramarginal gyrus and the posterior cingulate cortex) were found. Furthermore, in contrast to the healthy male adolescents, depressed male adolescents showed decreased activation in the cerebellum with a significant group-by-age interaction in connectivity. Future research may consider altered developmental trajectories and the possible implications of sex-specific treatment and prevention strategies for MDD.The study was funded by the Medical Research Council (grant: G0802226). The IMPACT clinical trial was funded by the NHS Health Technology Assessment (HTA) Programme, Central Manchester and Manchester Children’s University Hospitals NHS Trust, and the Cambridge and Peterborough Mental Health Trust. Additional support was provided by the jointly funded Medical Research Council/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre

A Comparison of Sodium-Glucose Co-Transporter 2 Inhibitor Kidney Outcome Trial Participants with a Real-World Chronic Kidney Disease Primary Care Population.

BACKGROUND/HYPOTHESIS: Observational studies suggest sodium-glucose co-transporter-2 (SGLT2) inhibitor kidney outcome trials are not representative of the broader population of people with chronic kidney disease (CKD). However, there are limited data on the generalisability to those without co-existing type 2 diabetes (T2D), and the representativeness of the EMPA-KIDNEY trial has not been adequately explored. We hypothesised that SGLT2 inhibitor kidney outcome trials are more representative of people with co-existing T2D than those without, and that EMPA-KIDNEY is more representative than previous trials. METHODS: A cross-sectional analysis of adults with CKD in English primary care was conducted using the Oxford-Royal College of General Practitioners Clinical Information Digital Hub. The proportions that met the eligibility criteria of SGLT2 inhibitor kidney outcome trials were determined, and their characteristics described. Logistic regression analyses were performed to identify factors associated with trial eligibility. RESULTS: Of 6,670,829 adults, 516,491 (7.7%) with CKD were identified. In the real-world CKD population, 0.9%, 2.2%, and 8.0% met the CREDENCE, DAPA-CKD, and EMPA-KIDNEY eligibility criteria, respectively. All trials were more representative of people with co-existing T2D than those without T2D. Trial participants were 9-14 years younger than the real-world CKD population, and had more advanced CKD, including higher levels of albuminuria. A higher proportion of the CREDENCE (100%), DAPA-CKD (67.6%) and EMPA-KIDNEY (44.5%) trial participants had T2D compared to the real-world CKD population (32.8%). Renin-angiotensin system inhibitors were prescribed in almost all trial participants, compared to less than half of the real-world CKD population. Females were under-represented and less likely to be eligible for the trials. CONCLUSION: SGLT2 inhibitor kidney outcome trials represent a sub-group of people with CKD at high risk of adverse kidney events. Out study highlights the importance of complementing trials with real-world studies, exploring the effectiveness of SGLT2 inhibitors in the broader population of people with CKD

Immune-Mobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis B-Infected Cells

Background and Aims: Therapies for chronic hepatitis B virus (HBV) infection are urgently needed because of viral integration, persistence of viral antigen expression, inadequate HBV‐specific immune responses, and treatment regimens that require lifelong adherence to suppress the virus. Immune mobilizing monoclonal T Cell receptors against virus (ImmTAV) molecules represent a therapeutic strategy combining an affinity‐enhanced T Cell receptor with an anti‐CD3 T Cell‐activating moiety. This bispecific fusion protein redirects T cells to specifically lyse infected cells expressing the target virus‐derived peptides presented by human leukocyte antigen (HLA). Approach and Results: ImmTAV molecules specific for HLA‐A*02:01‐restricted epitopes from HBV envelope, polymerase, and core antigens were engineered. The ability of ImmTAV‐Env to activate and redirect polyclonal T cells toward cells containing integrated HBV and cells infected with HBV was assessed using cytokine secretion assays and imaging‐based killing assays. Elimination of infected cells was further quantified using a modified fluorescent hybridization of viral RNA assay. Here, we demonstrate that picomolar concentrations of ImmTAV‐Env can redirect T cells from healthy and HBV‐infected donors toward hepatocellular carcinoma (HCC) cells containing integrated HBV DNA resulting in cytokine release, which could be suppressed by the addition of a corticosteroid in vitro. Importantly, ImmTAV‐Env redirection of T cells induced cytolysis of antigen‐positive HCC cells and cells infected with HBV in vitro, causing a reduction of hepatitis B e antigen and specific loss of cells expressing viral RNA. Conclusions: The ImmTAV platform has the potential to enable the elimination of infected cells by redirecting endogenous non‐HBV‐specific T cells, bypassing exhausted HBV‐specific T cells. This represents a promising therapeutic option in the treatment of chronic hepatitis B, with our lead candidate now entering trials

Excess maternal salt intake produces sex-specific hypertension in offspring: putative roles for kidney and gastrointestinal sodium handling.

Hypertension is common and contributes, via cardiovascular disease, towards a large proportion of adult deaths in the Western World. High salt intake leads to high blood pressure, even when occurring prior to birth - a mechanism purported to reside in altered kidney development and later function. Using a combination of in vitro and in vivo approaches we tested whether increased maternal salt intake influences fetal kidney development to render the adult individual more susceptible to salt retention and hypertension. We found that salt-loaded pregnant rat dams were hypernatraemic at day 20 gestation (147±5 vs. 128±5 mmoles/L). Increased extracellular salt impeded murine kidney development in vitro, but had little effect in vivo. Kidneys of the adult offspring had few structural or functional abnormalities, but male and female offspring were hypernatraemic (166±4 vs. 149±2 mmoles/L), with a marked increase in plasma corticosterone (e.g. male offspring; 11.9 [9.3-14.8] vs. 2.8 [2.0-8.3] nmol/L median [IQR]). Furthermore, adult male, but not female, offspring had higher mean arterial blood pressure (effect size, +16 [9-21] mm Hg; mean [95% C.I.]. With no clear indication that the kidneys of salt-exposed offspring retained more sodium per se, we conducted a preliminary investigation of their gastrointestinal electrolyte handling and found increased expression of proximal colon solute carrier family 9 (sodium/hydrogen exchanger), member 3 (SLC9A3) together with altered faecal characteristics and electrolyte handling, relative to control offspring. On the basis of these data we suggest that excess salt exposure, via maternal diet, at a vulnerable period of brain and gut development in the rat neonate lays the foundation for sustained increases in blood pressure later in life. Hence, our evidence further supports the argument that excess dietary salt should be avoided per se, particularly in the range of foods consumed by physiologically immature young

The short-term effect of high versus moderate protein intake on recovery after strength training in resistance-trained individuals

Background: Dietary protein intakes up to 2.9 g.kg-1.d-1 and protein consumption before and after resistance training may enhance recovery, resulting in hypertrophy and strength gains. However, it remains unclear whether protein quantity or nutrient timing is central to positive adaptations. This study investigated the effect of total dietary protein content, whilst controlling for protein timing, on recovery in resistance trainees. Methods: Fourteen resistance-trained individuals underwent two 10-day isocaloric dietary regimes with a protein content of 1.8 g.kg-1.d-1 (PROMOD) or 2.9 g.kg-1.d-1 (PROHIGH) in a randomised, counterbalanced, crossover design. On days 8-10 (T1-T3), participants undertook resistance exercise under controlled conditions, performing 3 sets of squat, bench press and bent-over rows at 80% 1 repetition maximum until volitional exhaustion. Additionally, participants consumed a 0.4 g.kg-1 whey protein concentrate/isolate mix 30 minutes before and after exercise sessions to standardise protein timing specific to training. Recovery was assessed via daily repetition performance, muscle soreness, bioelectrical impedance phase angle, plasma creatine kinase (CK) and tumor necrosis factor-α (TNF-α). Results: No significant differences were reported between conditions for any of the performance repetition count variables (p>0.05). However, within PROMOD only, squat performance total repetition count was significantly lower at T3 (19.7 ± 6.8) compared to T1 (23.0 ± 7.5; p=0.006). Pre and post-exercise CK concentrations significantly increased across test days (p≤0.003), although no differences were reported between conditions. No differences for TNF-α or muscle soreness were reported between dietary conditions. Phase angle was significantly greater at T3 for PROHIGH (8.26 ± 0.82°) compared with PROMOD (8.08 ± 0.80°; p=0.012). Conclusions: When energy intake and peri-exercise protein intake was controlled for, a short term PROHIGH diet did not improve markers of muscle damage or soreness in comparison to a PROMOD approach following repeated days of intensive training. Whilst it is therefore likely that protein intakes (1.8g.kg-1.d-1) may be sufficient for resistance-trained individuals, it is noteworthy that both lower body exercise performance and bioelectrical phase angle were maintained with PROHIGH. Longer term interventions are warranted to determine whether PROMOD intakes are sufficient during prolonged training periods or when extensive exercise (e.g. training twice daily) is undertaken

Tales of future weather

Society is vulnerable to extreme weather events and, by extension, to human impacts on future events. As climate changes weather patterns will change. The search is on for more effective methodologies to aid decision-makers both in mitigation to avoid climate change and in adaptation to changes. The traditional approach uses ensembles of climate model simulations, statistical bias correction, downscaling to the spatial and temporal scales relevant to decision-makers, and then translation into quantities of interest. The veracity of this approach cannot be tested, and it faces in-principle challenges. Alternatively, numerical weather prediction models in a hypothetical climate setting can provide tailored narratives for high-resolution simulations of high-impact weather in a future climate. This 'tales of future weather' approach will aid in the interpretation of lower-resolution simulations. Arguably, it potentially provides complementary, more realistic and more physically consistent pictures of what future weather might look like