Prediction-error signals in anterior cingulate cortex drive task-switching.

Task-switching is a fundamental cognitive ability that allows animals to update their knowledge of current rules or contexts. Detecting discrepancies between predicted and observed events is essential for this process. However, little is known about how the brain computes cognitive prediction-errors and whether neural prediction-error signals are causally related to task-switching behaviours.

The Relationship between Serum Sodium Concentration and Albuminuria: A Retrospective Cohort Study.

Background: Lowering dietary salt intake reduces albuminuria, an early marker of renal damage and a sensitive predictor of adverse cardiovascular outcomes. The mechanisms underlying this effect are uncertain but small changes in serum sodium concentration may be important: this retrospective cohort study investigated the hypothesis that higher serum sodium concentration is a risk factor for albuminuria (defined as a urine albumin:creatinine ratio [UACR], ≥3 mg/mmol).

Methods: Primary care data from the Royal College of General Practitioners Research and Surveillance Centre were used to identify 47,294 individuals with a UACR result available between April 2010 and March 2015, and no known albuminuria prior to this.

A comparison of sodium-glucose co-transporter 2 inhibitor kidney outcome trial participants with a real-world chronic kidney disease primary care population.

Background: 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 generalizability to those without co-existing type 2 diabetes (T2D), and the representativeness of the Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY) trial has not been adequately explored. We hypothesized 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.

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.

ALSUntangled #70: caffeine.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here, we review caffeine which has plausible mechanisms for slowing ALS progression. However, pre-clinical studies are contradictory, and a large case series showed no relationship between caffeine intake and ALS progression rate.

Sodium-glucose cotransporter-2 inhibitors and kidney outcomes in real-world type 2 diabetes populations: A systematic review and meta-analysis of observational studies.

Aim: To conduct a systematic review of observational studies to explore the real-world kidney benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors in a large and diverse population of adults with type 2 diabetes (T2D).

Materials And Methods: We searched MEDLINE, EMBASE and Web of Science for observational studies that investigated kidney disease progression in adults with T2D treated with SGLT2 inhibitors compared to other glucose-lowering therapies. Studies published from database inception to July 2022 were independently reviewed by two authors and evaluated using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool.

Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network.

Mechanisms that entrain and pace rhythmic epileptiform discharges remain debated. Traditionally, the quest to understand them has focused on interneuronal networks driven by synaptic GABAergic connections. However, synchronized interneuronal discharges could also trigger the transient elevations of extracellular GABA across the tissue volume, thus raising tonic conductance (G) of synaptic and extrasynaptic GABA receptors in multiple cells.

Step-Wise Management of Anemia in Patients With Chronic Kidney Disease in Primary Care: Qualitative Study.

Introduction: Anemia is common in chronic kidney disease (CKD) and is associated with increased cardiovascular risk and reduced quality of life, but is often sub-optimally managed. Most patients are managed in primary care alongside other comorbidities. Interventions to improve the management of anemia in CKD in this setting are needed.

Predictors and determinants of albuminuria in people with prediabetes and diabetes based on smoking status: A cross-sectional study using the UK Biobank data.

Background: Smoking is attributed to both micro- and macrovascular complications at any stage of metabolic deregulation including prediabetes. Current global diabetes prevention programmes appear to be glucocentric, and do not fully acknowledge the ramifications of cardiorenal risk factors in smokers and ex-smokers. A more holistic approach is needed to prevent vascular complications in people with prediabetes and diabetes before and after quitting.

Outcome and effect of vaccination in SARS-CoV-2 Omicron infection in hemodialysis patients: a cohort study.

Background: Hemodialysis patients are at high risk of Covid-19, though vaccination has significant efficacy in preventing and reducing the severity of infection. Little information is available on disease severity and vaccine efficacy since the dissemination of the Omicron variant.

Methods: In a multi-center study, during a period of the epidemic driven by the Omicron variant, all hemodialysis patients positive for SARS-CoV-2 were identified.

Severity of COVID-19 after Vaccination among Hemodialysis Patients: An Observational Cohort Study.

Background And Objectives: Patients receiving hemodialysis are at high risk from coronavirus disease 2019 (COVID-19) and demonstrate impaired immune responses to vaccines. There have been several descriptions of their immunologic responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, but few studies have described the clinical efficacy of vaccination in patients on hemodialysis.

Design, Setting, Participants, & Measurements: In a multicenter observational study of the London hemodialysis population undergoing surveillance PCR testing during the period of vaccine rollout with BNT162b2 and AZD1222, all of those positive for SARS-CoV-2 were identified.

Sodium valproate increases activity of the sirtuin pathway resulting in beneficial effects for spinocerebellar ataxia-3 in vivo.

Machado-Joseph disease (MJD, also known as spinocerebellar ataxia type 3) is a fatal neurodegenerative disease that impairs control and coordination of movement. Here we tested whether treatment with the histone deacetylase inhibitor sodium valproate (valproate) prevented a movement phenotype that develops in larvae of a transgenic zebrafish model of the disease. We found that treatment with valproate improved the swimming of the MJD zebrafish, affected levels of acetylated histones 3 and 4, but also increased expression of polyglutamine expanded human ataxin-3.

Risk of COVID-19 Disease, Dialysis Unit Attributes, and Infection Control Strategy among London In-Center Hemodialysis Patients.

Background And Objectives: Patients receiving in-center hemodialysis treatment face unique challenges during the coronavirus disease 2019 (COVID-19) pandemic, specifically the need to attend for treatment that prevents self-isolation. Dialysis unit attributes and isolation strategies that might reduce dialysis center COVID-19 infection rates have not been previously examined.

Design, Setting, Participants, & Measurements: We explored the role of variables, including community disease burden, dialysis unit attributes (size and layout), and infection control strategies, on rates of COVID-19 among patients receiving in-center hemodialysis in London, United Kingdom, between March 2, 2020 and May 31, 2020.

In vivo Validation of Bimolecular Fluorescence Complementation (BiFC) to Investigate Aggregate Formation in Amyotrophic Lateral Sclerosis (ALS).

Amyotrophic lateral sclerosis (ALS) is a form of motor neuron disease (MND) that is characterized by the progressive loss of motor neurons within the spinal cord, brainstem, and motor cortex. Although ALS clinically manifests as a heterogeneous disease, with varying disease onset and survival, a unifying feature is the presence of ubiquitinated cytoplasmic protein inclusion aggregates containing TDP-43. However, the precise mechanisms linking protein inclusions and aggregation to neuronal loss are currently poorly understood.

Systematic Review and Meta-analysis of COVID-19 and Kidney Transplant Recipients, the South West London Kidney Transplant Network Experience.

Introduction: There is paucity of literature comparing outcomes of kidney transplant patients with COVID-19 to that of dialysis and waitlisted patients. This report describes our data, provides comparative analysis, together with a meta-analysis of published studies, and describes our protocols to restart the transplant program.

Methods: Data were analyzed on kidney transplant, dialysis, and waitlisted patients tested positive for SARS-CoV-2 (nasopharyngeal swab polymerase chain reaction [PCR] test) between March 1, 2020, and June 30, 2020, together with a meta-analysis of 16 studies.

The Characteristics, Dynamics, and the Risk of Death in COVID-19 Positive Dialysis Patients in London, UK.

Background: Patients on dialysis with frequent comorbidities, advanced age, and frailty, who visit treatment facilities frequently, are perhaps more prone to SARS-CoV-2 infection and related death-the risk factors and dynamics of which are unknown. The aim of this study was to investigate the hospital outcomes in patients on dialysis infected with SARS-CoV-2.

Methods: Data on 224 patients on hemodialysis between February 29, 2020 and May 15, 2020 with confirmed SARS-CoV-2 were analyzed for outcomes and potential risk factors for death, using a competing risk-regression model assessed by subdistribution hazards ratio (SHR).

"STRESSED OUT": The role of FUS and TDP-43 in amyotrophic lateral sclerosis.

Mutations in fused-in-sarcoma (FUS) and TAR DNA binding protein-43 (TDP-43; TARDBP) are known to cause the severe adult-onset neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Proteinopathy caused by cellular stresses such as endoplasmic reticulum (ER) stress, oxidative stress, mitochondrial stress and proteasomal stress and the formation of stress granules (SGs), cytoplasmic aggregates and inclusions is a hallmark of ALS. FUS and TDP-43, which are DNA/RNA binding proteins that regulate transcription, RNA homeostasis and protein translation are implicated in ALS proteinopathy.

Serotonin 5-HT receptor boosts functional maturation of dendritic spines via RhoA-dependent control of F-actin.

Activity-dependent remodeling of excitatory connections underpins memory formation in the brain. Serotonin receptors are known to contribute to such remodeling, yet the underlying molecular machinery remains poorly understood. Here, we employ high-resolution time-lapse FRET imaging in neuroblastoma cells and neuronal dendrites to establish that activation of serotonin receptor 5-HT (5-HTR) rapidly triggers spatially-restricted RhoA activity and G13-mediated phosphorylation of cofilin, thus locally boosting the filamentous actin fraction.

Chemical reprogramming enhances homology-directed genome editing in zebrafish embryos.

Precise genome editing is limited by the inefficiency of homology-directed repair (HDR) compared to the non-homologous end-joining (NHEJ) of double strand breaks (DSBs). The CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 system generates precise, locus-specific DSBs that can serve as substrates for HDR. We developed an in vivo visual reporter assay to quantify HDR-mediated events at single-cell resolution in zebrafish and used this system to identify small-molecule modulators that shift the DNA repair equilibrium in favor of HDR.

Multiplex imaging relates quantal glutamate release to presynaptic Ca homeostasis at multiple synapses in situ.

Information processing by brain circuits depends on Ca-dependent, stochastic release of the excitatory neurotransmitter glutamate. Whilst optical glutamate sensors have enabled detection of synaptic discharges, understanding presynaptic machinery requires simultaneous readout of glutamate release and nanomolar presynaptic Ca in situ. Here, we find that the fluorescence lifetime of the red-shifted Ca indicator Cal-590 is Ca-sensitive in the nanomolar range, and employ it in combination with green glutamate sensors to relate quantal neurotransmission to presynaptic Ca kinetics.

Kynurenine 3-Monooxygenase Activity in Human Primary Neurons and Effect on Cellular Bioenergetics Identifies New Neurotoxic Mechanisms.

Upregulation of the kynurenine pathway (KP) of tryptophan metabolism is commonly observed in neurodegenerative disease. When activated, L-kynurenine (KYN) increases in the periphery and central nervous system where it is further metabolised to other neuroactive metabolites including 3-hydroxykynurenine (3-HK), kynurenic acid (KYNA) and quinolinic acid (QUIN). Particularly biologically relevant metabolites are 3-HK and QUIN, formed downstream of the enzyme kynurenine 3-monooxygenase (KMO) which plays a pivotal role in maintaining KP homeostasis.

Dual Transcriptomics of Host-Pathogen Interaction of Cystic Fibrosis Isolate PASS1 With Zebrafish.

is a significant cause of mortality in patients with cystic fibrosis (CF). To explore the interaction of the CF isolate PASS1 with the innate immune response, we have used (zebrafish) as an infection model. Confocal laser scanning microscopy (CLSM) enabled visualization of direct interactions between zebrafish macrophages and PASS1.

The effect of dietary salt on blood pressure in individuals receiving chronic dialysis: a systematic review and meta-analysis of randomised controlled trials.

Dietary salt reduction in the general population lowers blood pressure and cardiovascular risk. Despite being widely recommended, there is limited evidence as to whether this is applicable to individuals with end-stage renal disease (ESRD) receiving dialysis. Therefore, we carried out a systematic review and meta-analysis of randomised controlled trials (RCTs) investigating dietary salt reduction in individuals receiving dialysis.