This preface introduces the Journal of Neurochemistry Special Issue on Advances in Epilepsy Research. Epilepsy is a devastating disease characterized by recurrent seizures. Despite the addition of ...numerous therapeutics over the last few decades epilepsy patients resistant to standard of care treatments remains stubbornly high. This highlights a clear unmet clinical need and the importance of new research into this disease. One major advance over the last two decades has been the recognition that genetic factors play a significant role in the underlying pathogenesis of epilepsy. Much of our insights into the pathogenic mechanisms underlying genetic epilepsy has come from research into genes that encode ion channels. In this issue, there are up-to-date reviews discussing epilepsy caused by variation in HCN channels, voltage-dependent sodium channels, voltage-dependent calcium channels, and GABA
receptors. The reviews highlight our understanding of the genotype-phenotype relationships and the identification of precision medicine approaches. Complimenting this is a review on metabolic aspects modulating ion channels in genetic disease. This issue also has fundamental research manuscripts investigating how currently approved drugs may rescue NMDA receptor dysfunction and how in vitro neuron cultures can be used to probe network scale deficits and drug impacts in SCN2A disease. Other primary data manuscripts include those focusing on metabolic therapies, gut microbiota, and new in vivo screening tools for identifying novel anti-seizure drugs. Collectively, manuscripts published as part of this edition highlight recent research gains, especially in our understanding of genetic causes of epilepsy involving ion channels.
Background
This study aimed to investigate the association of acute kidney injury (AKI) with change in estimated glomerular filtration rate (eGFR) in children with advanced chronic kidney disease ...(CKD).
Methods
Single centre, retrospective longitudinal study including all prevalent children aged 1–18 years with nondialysis CKD stages 3–5. Variables associated with CKD were analysed for their potential effect on annualised eGFR change (ΔGFR/year) following multiple regression analysis. Composite end-point including 25% reduction in eGFR or progression to kidney replacement therapy was evaluated.
Results
Of 147 children, 116 had at least 1-year follow-up in a dedicated CKD clinic with mean age 7.3 ± 4.9 years with 91 (78.4%) and 77 (66.4%) with 2- and 3-year follow-up respectively. Mean eGFR at baseline was 29.8 ± 11.9 ml/min/1.73 m
2
with 79 (68%) boys and 82 (71%) with congenital abnormalities of kidneys and urinary tract (CAKUT). Thirty-nine (33.6%) had at least one episode of AKI. Mean ΔGFR/year for all patients was − 1.08 ± 5.64 ml/min/1.73 m
2
but reduced significantly from 2.03 ± 5.82 to − 3.99 ± 5.78 ml/min/1.73 m
2
from youngest to oldest age tertiles (
P
< 0.001). There was a significant difference in primary kidney disease (PKD) (77% versus 59%, with CAKUT,
P
= 0.048) but no difference in AKI incidence (37% versus 31%,
P
= 0.85) between age tertiles. Multiple regression analysis identified age (
β
= − 0.53,
P
< 0.001) and AKI (
β
= − 3.2,
P
= 0.001) as independent predictors of ΔGFR/year. 48.7% versus 22.1% with and without AKI reached composite end-point (
P
= 0.01).
Conclusions
We report AKI in established CKD as a predictor of accelerated kidney disease progression and highlight this as an additional modifiable risk factor to reduce progression of kidney dysfunction.
Graphical abstract
Epilepsy is a common and serious neurologic disease with a strong genetic component. Genetic studies have identified an increasing collection of disease-causing genes. The impact of these genetic ...discoveries is wide reaching-from precise diagnosis and classification of syndromes to the discovery and validation of new drug targets and the development of disease-targeted therapeutic strategies. About 25% of genes identified in epilepsy encode ion channels. Much of our understanding of disease mechanisms comes from work focused on this class of protein. In this study, we review the genetic, molecular, and physiologic evidence supporting the pathogenic role of a number of different voltage- and ligand-activated ion channels in genetic epilepsy. We also review proposed disease mechanisms for each ion channel and highlight targeted therapeutic strategies.
Epileptic encephalopathies are severe disorders emerging in the first days to years of life that commonly include refractory seizures, various types of movement disorders, and different levels of ...developmental delay. In recent years, many de novo occurring variants have been identified in individuals with these devastating disorders. To unravel disease mechanisms, the functional impact of detected variants associated with epileptic encephalopathies is investigated in a range of cellular and animal models. This review addresses efforts to advance and use such models to identify specific molecular and cellular targets for the development of novel therapies. We focus on ion channels as the best‐studied group of epilepsy genes. Given the clinical and genetic heterogeneity of epileptic encephalopathy disorders, experimental models that can reflect this complexity are critical for the development of disease mechanisms‐based targeted therapy. The convergence of technological advances in gene sequencing, stem cell biology, genome editing, and high throughput functional screening together with massive unmet clinical needs provides unprecedented opportunities and imperatives for precision medicine in epileptic encephalopathies.
We review the potential for the development of targeted therapies for the genetic epileptic encephalopathies, severe early onset syndromes presenting with refractory seizures and developmental delay. Using the example of ion channels, we address the available and emerging experimental models and how they can identify specific molecular and cellular targets for the novel disease‐based treatments of severely affected patients.
Complex relationships exist between the gut microflora and their human hosts. Emerging evidence suggests that bacterial dysbiosis within the colon may be involved in the pathogenesis of the metabolic ...syndrome, type 2 diabetes and CVD. The use of dietary prebiotic supplements to restore an optimal balance of intestinal flora may positively affect host metabolism, representing a potential treatment strategy for individuals with cardiometabolic disorders. The present review aimed to examine the current evidence supporting that dietary prebiotic supplementation in adults has beneficial effects on biochemical parameters associated with the development of metabolic abnormalities including obesity, glucose intolerance, dyslipidaemia, hepatic steatosis and low-grade chronic inflammation. Between January 2000 and September 2013, eight computer databases were searched for randomised controlled trials published in English. Human trials were included if at least one group received a dietary prebiotic intervention. In the present review, twenty-six randomised controlled trials involving 831 participants were included. Evidence indicated that dietary prebiotic supplementation increased self-reported feelings of satiety in healthy adults (standardised mean difference − 0·57, 95 % CI − 1·13, − 0·01). Prebiotic supplementation also significantly reduced postprandial glucose ( − 0·76, 95 % CI − 1·41, − 0·12) and insulin ( − 0·77, 95 % CI − 1·50, − 0·04) concentrations. The effects of dietary prebiotics on total energy intake, body weight, peptide YY and glucagon-like peptide-1 concentrations, gastric emptying times, insulin sensitivity, lipids, inflammatory markers and immune function were contradictory. Dietary prebiotic consumption was found to be associated with subjective improvements in satiety and reductions in postprandial glucose and insulin concentrations. Additional evidence is required before recommending prebiotic supplements to individuals with metabolic abnormalities. Large-scale trials of longer duration evaluating gut microbial growth and activity are required.
Background
We developed a paediatric haemodialysis trigger tool (pHTT) for application per haemodialysis (HD) session in children receiving intermittent in-centre HD and systematically monitored ...adverse events.
Methods
Single-centre quality improvement study performed over two 8-week cycles. Data collected prospectively using a ‘per-dialysis session’ pHTT tool including 54 triggers across six domains, adapted from a recently described haemodialysis trigger tool (HTT) for adults. Each trigger was evaluated for level of harm following assessment by two authors. Following a period of training, HD nurses completed the HTT at the end of each dialysis session.
Results
There were 241 triggers over 182 dialysis sessions, with 139 triggers in 91 HD sessions for 15 children, age range 28–205 months, over an 8-week period (first cycle) and 102 triggers in 91 HD sessions for 13 children, age range 28–205 months, over a further 8-week period (second cycle). After interventions informed by the pHTT, the harm rate per session was significantly reduced from 1.03 (94/91) to 0.32 (29/91),
P
< 0.001. There was a significant difference between the distribution of triggers by harm category (
P
< 0.001) and between the proportion of triggers across the various domains of the pHTT (
P
= 0.004) between the two cycles. No triggers were evaluated as causing permanent harm.
Conclusions
This pilot study demonstrates potential benefits of a bedside tool to monitor adverse events during haemodialysis in children. Thus, following interventions informed by the pHTT, the harm rate per session was significantly reduced. Under standard patient safety systems, the vast majority of triggers identified by the pHTT would remain unreported and perhaps lead to missed opportunities to improve patient safety. We propose the use of a paediatric HTT as part of standard care by centres providing HD to children in the future.
Graphical Abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
Machine learning (ML) is increasingly applied to predict adverse postoperative outcomes in cardiac surgery. Commonly used ML models fail to translate to clinical practice due to absent model ...explainability, limited uncertainty quantification, and no flexibility to missing data. We aimed to develop and benchmark a novel ML approach, the uncertainty-aware attention network (UAN), to overcome these common limitations. Two Bayesian uncertainty quantification methods were tested, generalized variational inference (GVI) or a posterior network (PN). The UAN models were compared with an ensemble of XGBoost models and a Bayesian logistic regression model (LR) with imputation. The derivation datasets consisted of 153,932 surgery events from the Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) Cardiac Surgery Database. An external validation consisted of 7343 surgery events which were extracted from the Medical Information Mart for Intensive Care (MIMIC) III critical care dataset. The highest performing model on the external validation dataset was a UAN-GVI with an area under the receiver operating characteristic curve (AUC) of 0.78 (0.01). Model performance improved on high confidence samples with an AUC of 0.81 (0.01). Confidence calibration for aleatoric uncertainty was excellent for all models. Calibration for epistemic uncertainty was more variable, with an ensemble of XGBoost models performing the best with an AUC of 0.84 (0.08). Epistemic uncertainty was improved using the PN approach, compared to GVI. UAN is able to use an interpretable and flexible deep learning approach to provide estimates of model uncertainty alongside state-of-the-art predictions. The model has been made freely available as an easy-to-use web application demonstrating that by designing uncertainty-aware models with innately explainable predictions deep learning may become more suitable for routine clinical use.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We report the conversion of anisoles and olefins to alkenyl anisoles via a transition-metal-catalyzed arene C–H activation and olefin insertion mechanism. The catalyst precursor, ...(η2-C2H4)2Rh(μ-OAc)2, and the in situ oxidant Cu(OPiv)2 (OPiv = pivalate) convert anisoles and olefins (ethylene or propylene) to alkenyl anisoles. When ethylene is used as the olefin, the o/m/p ratio varies between approximately 1:3:1 (selective for 3-methoxystyrene) and 1:5:10 (selective for 4-methoxystyrene). When propylene is the olefin, the o/m/p regioselectivity varies between approximately 1:8:20 and 1:8.5:5. The o/m/p ratios depend on the concentration of pivalic acid and olefin. For example, when using ethylene, at relatively high pivalic acid concentrations and low ethylene concentrations, the o/m/p regioselectivity is 1:3:1. Conversely, again for use of ethylene, at relatively low pivalic acid concentrations and high ethylene concentrations, the o/m/p regioselectivity is 1:5:10. Mechanistic studies of the conversion of anisoles and olefins to alkenyl anisoles provide evidence that the regioselectivity is likely under Curtin–Hammett conditions.
Reduced glomerular filtration rate (GFR) in the absence of albuminuria is a common manifestation of chronic kidney disease (CKD) in diabetes. However, the frequency with which it progresses to ...end-stage kidney disease (ESKD) is unknown.
Multicenter prospective cohort study.
We included 1,908 participants with diabetes and reduced GFR enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study in the United States.
Urinary albumin and protein excretion.
Incident ESKD, CKD progression (ESKD or ≥50% reduction in estimated GFR eGFR from baseline), and annual rate of decline in kidney function.
ESKD was ascertained by self-report and by linkage to the US Renal Data System. We used Cox proportional hazards modeling to estimate the association of albuminuria and proteinuria with incident ESKD or CKD progression and linear mixed-effects models to assess differences in eGFR slopes among those with and without albuminuria.
Mean eGFR at baseline was 41.2mL/min/1.73m2. Normal or mildly increased 24-hour urinary albumin excretion (<30mg/d) at baseline was present in 28% of participants, but in only 5% of those progressing to ESKD. For those with baseline normal or mildly increased albuminuria, moderately increased albuminuria (albumin excretion, 30-299mg/d), and 2 levels of severely increased albuminuria (albumin excretion, 300-999 and ≥1,000mg/d): crude rates of ESKD were 7.4, 34.8, 78.7, and 178.7 per 1,000 person-years, respectively; CKD progression rates were 17.0, 61.4, 130.5, and 295.1 per 1,000 person-years, respectively; and annual rates of eGFR decline were −0.17, −1.35, −2.74, and −4.69mL/min/1.73m2, respectively.
We were unable to compare the results with healthy controls.
In people with diabetes with reduced eGFRs, the absence of albuminuria or proteinuria is common and carries a much lower risk for ESKD, CKD progression, or rapid decline in eGFR compared with those with albuminuria or proteinuria. The rate of eGFR decline in normoalbuminuric CKD was similar to that reported for the general diabetic population.
Fly-In-Fly-Out (FIFO) workers travel to work at isolated locations, and rotate continuous workdays with leave periods at home, and such work practice is common in the offshore oil and gas and onshore ...mining industry worldwide. The COVID-19 pandemic and accompanying public health actions appear to have had a negative impact on several health-related behaviours among the general population. However, little is known about the impact of the COVID-19 pandemic on the health behaviours of FIFO workers, who have shown higher pre-pandemic rates of risky behaviours than the general population in Australia. This study examined the health-related behaviours of FIFO workers in the mining industry during the COVID-19 pandemic. A descriptive cross-sectional study was conducted. FIFO workers from an Australian mining company who underwent COVID-19 screening between May and November 2020 completed an online survey about their regular health-related behaviours. The independent sample t-test and Pearson's chi-square test where appropriate were conducted to examine the differences between males and females for the behavioural outcomes. A total of 768 FIFO workers (633 males and 135 females) participated in the study. Prevalence of smoking was high (32%). Males smoked more cigarettes per day than females (15.2±7.0 vs 13.1±7.1, p = .174). Most participants (74.7%) drank alcohol on more than two days per week. Compared to females, more males (20.2% vs 8.0%) consumed alcohol at short-term harmful levels (p = .010). About a third (34.4%) of the workers (33.5% of males and 38.5% of females, p = .264) engaged in inadequate moderate-vigorous exercises/physical activity. About a third (33.1%) of workers (33.7% of males and 30.4% of females; p = .699) had multiple risk behaviours. Prevalence of multiple risk behaviours was high. Interventions aimed at the prevention of risky health-related behaviours should target the different behavioural patterns and may require emphasis on gender-informed techniques particularly when addressing alcohol consumption.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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