Thalamic epileptic spikes disrupt sleep spindles in patients with epileptic encephalopathy.

In severe epileptic encephalopathies, epileptic activity contributes to progressive cognitive dysfunction. Epileptic encephalopathies share the trait of spike-wave activation during non-rapid eye movement sleep (EE-SWAS), a sleep stage dominated by sleep spindles, brain oscillations known to coordinate offline memory consolidation. Epileptic activity has been proposed to hijack the circuits driving these thalamocortical oscillations, thereby contributing to cognitive impairment. Using a unique dataset of simultaneous human thalamic and cortical recordings in subjects with and without EE-SWAS, we provide evidence for epileptic spike interference of thalamic sleep spindle production in patients with EE-SWAS. First, we show that epileptic spikes and sleep spindles are both predicted by slow oscillations during stage two sleep (N2), but at different phases of the slow oscillation. Next, we demonstrate that sleep activated cortical epileptic spikes propagate to the thalamus (thalamic spike rate increases after a cortical spike, p≈0). We then show that epileptic spikes in the thalamus increase the thalamic spindle refractory period (p≈0). Finally, we show that in three patients with EE-SWAS, there is a downregulation of sleep spindles for 30 seconds after each thalamic spike (p<0.01). These direct human thalamocortical observations support a proposed mechanism for epileptiform activity to impact cognitive function, wherein epileptic spikes inhibit thalamic sleep spindles in epileptic encephalopathy with spike and wave activation during sleep.

Spike ripples localize the epileptogenic zone best: an international intracranial study.

We evaluated whether spike ripples, the combination of epileptiform spikes and ripples, provide a reliable and improved biomarker for the epileptogenic zone compared with other leading interictal biomarkers in a multicentre, international study. We first validated an automated spike ripple detector on intracranial EEG recordings. We then applied this detector to subjects from four centres who subsequently underwent surgical resection with known 1-year outcomes. We evaluated the spike ripple rate in subjects cured after resection [International League Against Epilepsy Class 1 outcome (ILAE 1)] and those with persistent seizures (ILAE 2-6) across sites and recording types. We also evaluated available interictal biomarkers: spike, spike-gamma, wideband high frequency oscillation (HFO, 80-500 Hz), ripple (80-250 Hz) and fast ripple (250-500 Hz) rates using previously validated automated detectors. The proportion of resected events was computed and compared across subject outcomes and biomarkers. Overall, 109 subjects were included. Most spike ripples were removed in subjects with ILAE 1 outcome (P < 0.001), and this was qualitatively observed across all sites and for depth and subdural electrodes (P < 0.001 and P < 0.001, respectively). Among ILAE 1 subjects, the mean spike ripple rate was higher in the resected volume (0.66/min) than in the non-removed tissue (0.08/min, P < 0.001). A higher proportion of spike ripples were removed in subjects with ILAE 1 outcomes compared with ILAE 2-6 outcomes (P = 0.06). Among ILAE 1 subjects, the proportion of spike ripples removed was higher than the proportion of spikes (P < 0.001), spike-gamma (P < 0.001), wideband HFOs (P < 0.001), ripples (P = 0.009) and fast ripples (P = 0.009) removed. At the individual level, more subjects with ILAE 1 outcomes had the majority of spike ripples removed (79%, 38/48) than spikes (69%, P = 0.12), spike-gamma (69%, P = 0.12), wideband HFOs (63%, P = 0.03), ripples (45%, P = 0.01) or fast ripples (36%, P < 0.001) removed. Thus, in this large, multicentre cohort, when surgical resection was successful, the majority of spike ripples were removed. Furthermore, automatically detected spike ripples localize the epileptogenic tissue better than spikes, spike-gamma, wideband HFOs, ripples and fast ripples.

A General, Noise-Driven Mechanism for the 1/f-Like Behavior of Neural Field Spectra.

Consistent observations across recording modalities, experiments, and neural systems find neural field spectra with 1/f-like scaling, eliciting many alternative theories to explain this universal phenomenon. We show that a general dynamical system with stochastic drive and minimal assumptions generates 1/f-like spectra consistent with the range of values observed in vivo without requiring a specific biological mechanism or collective critical behavior.

Distinguishing between different percolation regimes in noisy dynamic networks with an application to epileptic seizures.

In clinical neuroscience, epileptic seizures have been associated with the sudden emergence of coupled activity across the brain. The resulting functional networks-in which edges indicate strong enough coupling between brain regions-are consistent with the notion of percolation, which is a phenomenon in complex networks corresponding to the sudden emergence of a giant connected component. Traditionally, work has concentrated on noise-free percolation with a monotonic process of network growth, but real-world networks are more complex. We develop a class of random graph hidden Markov models (RG-HMMs) for characterizing percolation regimes in noisy, dynamically evolving networks in the presence of edge birth and edge death. This class is used to understand the type of phase transitions undergone in a seizure, and in particular, distinguishing between different percolation regimes in epileptic seizures. We develop a hypothesis testing framework for inferring putative percolation mechanisms. As a necessary precursor, we present an EM algorithm for estimating parameters from a sequence of noisy networks only observed at a longitudinal subsampling of time points. Our results suggest that different types of percolation can occur in human seizures. The type inferred may suggest tailored treatment strategies and provide new insights into the fundamental science of epilepsy.

Mortality patterns in Dutch diabetes outpatients.

AIM: Diabetes mellitus is a major cause of death. Outpatients with diabetes have more complications than patients in general practice; mortality patterns have only been studied in the total diabetes population. This study aims to assess mortality, causes, and predictors in outpatients with diabetes. MATERIALS AND METHODS: A cohort study, included people with diabetes mellitus from the nationwide Dutch Paediatric and Adult Registry of Diabetes (DPARD) visiting diabetes outpatient clinics in 2016-2020. DPARD data were linked to Statistics Netherlands (CBS), comprising data on mortality, ethnicity and education. All-cause and cardiovascular mortality rates were estimated using Cox proportional hazard regression. RESULTS: During a median follow-up of 3.1 years among 12 992 people with diabetes, mortality rates per 10 000 person-years were 67.7 in adult type 1 diabetes and 324.2 in type 2 diabetes. The major cause of non-cardiovascular death was malignancy. During the pandemic years of influenza (2018) and COVID (2020), mortality rates peaked. Age, smoking and an estimated glomerular filtration rate of <60 ml/min were associated with all-cause mortality. In type 2 diabetes, additional factors were male sex, body mass index <20 kg/m2, diabetes duration <1 year and hypertension. CONCLUSIONS: Mortality among Dutch outpatients with diabetes is high. Smoking and renal failure were associated with mortality in both types. Further focus on early detection and treatment of mortality-associated factors may improve clinical outcomes.

Normative Standards for Isokinetic and Anthropometric Classifications of University-Level Netball Players.

CONTEXT: The purpose of the study was to develop normative ranges and standards for knee and shoulder isokinetic and anthropometric values. These standards can be qualitatively interpreted and allow practitioners to classify isokinetic and anthropometric values more objectively for university-level netball players. DESIGN: Posttest only observational study design. All players were only evaluated once during the in-season to generate normative ranges. METHODS: A total of 51 female players volunteered. Participants were evaluated on an isokinetic dynamometer at 60° per second to obtain knee-extensor and knee-flexor values as well as shoulder-flexor and shoulder-extensor values. A total of 16 anthropometric variables were collected including stature, body mass, 8 skinfolds, and 6 circumferences. Between-group differences were calculated to determine whether playing level was a differentiating factor in data. RESULTS: Normative standards were developed for isokinetic parameters associated with the knee and shoulder joints as well as skinfolds and circumference measures. No statistically significant between-group differences were evident (χ2Kruskal-Wallis[2] = 3.96, P = .140). CONCLUSION: These standards can be used by coaches and practitioners to set attainable goals for individual players or those from secondary leagues, classify individual and team-based performances, and facilitate decision-making processes.

Multiple sources of fast traveling waves during human seizures: resolving a controversy.

During human seizures organized waves of voltage activity rapidly sweep across the cortex. Two contradictory theories describe the source of these fast traveling waves: either a slowly advancing narrow region of multiunit activity (an ictal wavefront) or a fixed cortical location. Limited observations and different analyses prevent resolution of these incompatible theories. Here we address this disagreement by combining the methods and microelectrode array recordings (N=11 patients, 2 females, N=31 seizures) from previous human studies to analyze the traveling wave source. We find - inconsistent with both existing theories - a transient relationship between the ictal wavefront and traveling waves, and multiple stable directions of traveling waves in many seizures. Using a computational model that combines elements of both existing theories, we show that interactions between an ictal wavefront and fixed source reproduce the traveling wave dynamics observed in vivo We conclude that combining both existing theories can generate the diversity of ictal traveling waves.Significance StatementThe source of voltage discharges that propagate across cortex during human seizures remains unknown. Two candidate theories exist, each proposing a different discharge source. Support for each theory consists of observations from a small number of human subject recordings, analyzed with separately developed methods. How the different, limited data and different analysis methods impact the evidence for each theory is unclear. To resolve these differences, we combine the unique, human microelectrode array recordings collected separately for each theory and analyze these combined data with a unified approach. We show that neither existing theory adequately describes the data. We then propose a new theory that unifies existing proposals and successfully reproduces the voltage discharge dynamics observed in vivo.

Children with Rolandic epilepsy have micro- and macrostructural abnormalities in white matter constituting networks necessary for language function.

INTRODUCTION: Self-limited epilepsy with centrotemporal spikes is a transient developmental epilepsy with a seizure onset zone localized to the centrotemporal cortex that commonly impacts aspects of language function. To better understand the relationship between these anatomical findings and symptoms, we characterized the language profile and white matter microstructural and macrostructural features in a cohort of children with SeLECTS. METHODS: Children with active SeLECTS (n = 13), resolved SeLECTS (n = 12), and controls (n = 17) underwent high-resolution MRIs including diffusion tensor imaging sequences and multiple standardized neuropsychological measures of language function. We identified the superficial white matter abutting the inferior rolandic cortex and superior temporal gyrus using a cortical parcellation atlas and derived the arcuate fasciculus connecting them using probabilistic tractography. We compared white matter microstructural characteristics (axial, radial and mean diffusivity, and fractional anisotropy) between groups in each region, and tested for linear relationships between diffusivity metrics in these regions and language scores on neuropsychological testing. RESULTS: We found significant differences in several language modalities in children with SeLECTS compared to controls. Children with SeLECTS performed worse on assessments of phonological awareness (p = 0.045) and verbal comprehension (p = 0.050). Reduced performance was more pronounced in children with active SeLECTS compared to controls, namely, phonological awareness (p = 0.028), verbal comprehension (p = 0.028), and verbal category fluency (p = 0.031), with trends toward worse performance also observed in verbal letter fluency (p = 0.052), and the expressive one-word picture vocabulary test (p = 0.068). Children with active SeLECTS perform worse than children with SeLECTS in remission on tests of verbal category fluency (p = 0.009), verbal letter fluency (p = 0.006), and the expressive one-word picture vocabulary test (p = 0.045). We also found abnormal superficial white matter microstructure in centrotemporal ROIs in children with SeLECTS, characterized by increased diffusivity and fractional anisotropy compared to controls (AD p = 0.014, RD p = 0.028, MD p = 0.020, and FA p = 0.024). Structural connectivity of the arcuate fasciculus connecting perisylvian cortical regions was lower in children with SeLECTS (p = 0.045), and in the arcuate fasciculus children with SeLECTS had increased diffusivity (AD p = 0.007, RD p = 0.006, MD p = 0.016), with no difference in fractional anisotropy (p = 0.22). However, linear tests comparing white matter microstructure in areas constituting language networks and language performance did not withstand correction for multiple comparisons in this sample, although a trend was seen between FA in the arcuate fasciculus and verbal category fluency (p = 0.047) and the expressive one-word picture vocabulary test (p = 0.036). CONCLUSION: We found impaired language development in children with SeLECTS, particularly in those with active SeLECTS, as well as abnormalities in the superficial centrotemporal white matter as well as the fibers connecting these regions, the arcuate fasciculus. Although relationships between language performance and white matter abnormalities did not pass correction for multiple comparisons, taken together, these results provide evidence of atypical white matter maturation in fibers involved in language processing, which may contribute to the aspects of language function that are commonly affected by the disorder.

Focal Sleep Spindle Deficits Reveal Focal Thalamocortical Dysfunction and Predict Cognitive Deficits in Sleep Activated Developmental Epilepsy.

Childhood epilepsy with centrotemporal spikes (CECTS) is the most common focal epilepsy syndrome, yet the cause of this disease remains unknown. Now recognized as a mild epileptic encephalopathy, children exhibit sleep-activated focal epileptiform discharges and cognitive difficulties during the active phase of the disease. The association between the abnormal electrophysiology and sleep suggests disruption to thalamocortical circuits. Thalamocortical circuit dysfunction resulting in pathologic epileptiform activity could hinder the production of sleep spindles, a brain rhythm essential for memory processes. Despite this pathophysiologic connection, the relationship between spindles and cognitive symptoms in epileptic encephalopathies has not been previously evaluated. A significant challenge limiting such work has been the poor performance of available automated spindle detection methods in the setting of sharp activities, such as epileptic spikes. Here, we validate a robust new method to accurately measure sleep spindles in patients with epilepsy. We then apply this detector to a prospective cohort of male and female children with CECTS with combined high-density EEGs during sleep and cognitive testing at varying time points of disease. We show that: (1) children have a transient, focal deficit in spindles during the symptomatic phase of disease; (2) spindle rate anticorrelates with spike rate; and (3) spindle rate, but not spike rate, predicts performance on cognitive tasks. These findings demonstrate focal thalamocortical circuit dysfunction and provide a pathophysiological explanation for the shared seizures and cognitive symptoms in CECTS. Further, this work identifies sleep spindles as a potential treatment target of cognitive dysfunction in this common epileptic encephalopathy.SIGNIFICANCE STATEMENT Childhood epilepsy with centrotemporal spikes is the most common idiopathic focal epilepsy syndrome, characterized by self-limited focal seizures and cognitive symptoms. Here, we provide the first evidence that focal thalamocortical circuit dysfunction underlies the shared seizures and cognitive dysfunction observed. In doing so, we identify sleep spindles as a mechanistic biomarker, and potential treatment target, of cognitive dysfunction in this common developmental epilepsy and provide a novel method to reliably quantify spindles in brain recordings from patients with epilepsy.

Quantifying seizure termination patterns reveals limited pathways to seizure end.

OBJECTIVE: Despite their possible importance in the design of novel neuromodulatory approaches and in understanding status epilepticus, the dynamics and mechanisms of seizure termination are not well studied. We examined intracranial recordings from patients with epilepsy to differentiate seizure termination patterns and investigated whether these patterns are indicative of different underlying mechanisms. METHODS: Seizures were classified into one of two termination patterns: (a) those that end simultaneously across the brain (synchronous), and (b) those whose termination is piecemeal across the cortex (asynchronous). Both types ended with either a burst suppression pattern, or continuous seizure activity. These patterns were quantified and compared using burst suppression ratio, absolute energy, and network connectivity. RESULTS: Seizures with electrographic generalization showed burst suppression patterns in 90% of cases, compared with only 60% of seizures which remained focal. Interestingly, we found similar absolute energy and burst suppression ratios in seizures with synchronous and asynchronous termination, while seizures with continuous seizure activity were found to be different from seizures with burst suppression, showing lower energy during seizure and lower burst suppression ratio at the start and end of seizure. Finally, network density was observed to increase with seizure progression, with significantly lower densities in seizures with continuous seizure activity compared to seizures with burst suppression. SIGNIFICANCE: Based on this spatiotemporal classification scheme, we suggest that there are a limited number of seizure termination patterns and dynamics. If this bears out, it would imply that the number of mechanisms underlying seizure termination is also constrained. Seizures with different termination patterns exhibit different dynamics even before their start. This may provide useful clues about how seizures may be managed, which in turn may lead to more targeted modes of therapy for seizure control.

Mechanisms underlying the blood pressure lowering effects of dapagliflozin, exenatide, and their combination in people with type 2 diabetes: a secondary analysis of a randomized trial.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) lower blood pressure (BP). When SGLT2i and GLP-1RA are combined, synergistic effects on BP have been observed. The mechanisms underlying these BP reductions are incompletely understood. The aim of this study was to assess the mechanisms underlying the BP reduction with the SGLT2i dapagliflozin, GLP-1RA exenatide, and dapagliflozin-exenatide compared with placebo in people with obesity and type 2 diabetes. METHODS: Sixty-six people with type 2 diabetes were randomized to 16 weeks of dapagliflozin 10 mg/day, exenatide 10 µg twice daily, dapagliflozin-exenatide, or placebo treatment. The effect of treatments on estimates of: (1) plasma volume (calculated by Strauss formula, bioimpedance spectroscopy, hematocrit, (2) autonomic nervous system activity (heart rate variability), (3) arterial stiffness (pulse wave applanometry), (4) systemic hemodynamic parameters including peripheral vascular resistance, cardiac output and stroke volume (all derived from non-invasively systemic hemodynamic monitoring), and (5) natriuresis (24-hour urine collection) were assessed after 10 days and 16 weeks of treatment. RESULTS: After 10 days, dapagliflozin reduced systolic BP (SBP) by - 4.7 mmHg, and reduced plasma volume. After 16 weeks, dapagliflozin reduced SBP by - 4.4 mmHg, and reduced sympathetic nervous system (SNS) activity. Exenatide had no effect on SBP, but reduced parasympathetic nervous system activity after 10 days and 16 weeks. After 10 days, dapagliflozin-exenatide reduced SBP by - 4.2 mmHg, and reduced plasma volume. After 16 weeks, dapagliflozin-exenatide reduced SBP by - 6.8 mmHg, and the reduction in plasma volume was still observed, but SNS activity was unaffected. CONCLUSIONS: The dapagliflozin-induced plasma volume contraction may contribute to the initial SBP reduction, while a reduction in SNS activity may contribute to the persistent SBP reduction. Dapagliflozin-exenatide resulted in the largest decrease in SBP. The effect on plasma volume was comparable to dapagliflozin monotherapy, and SNS activity was not reduced, therefore other mechanisms are likely to contribute to the blood pressure lowering effect of this combination, which need further investigation. Trial registration Clinicaltrials.gov, NCT03361098.

Combination therapy with exenatide decreases the dapagliflozin-induced changes in brain responses to anticipation and consumption of palatable food in patients with type 2 diabetes: A randomized controlled trial.

AIMS: Sodium-glucose cotransporter-2 inhibitors induce less weight loss than expected. This may be explained by sodium-glucose cotransporter-2 inhibitor-induced alterations in central reward- and satiety circuits, leading to increased appetite and food intake. Glucagon-like peptide-1 receptor agonists reduce appetite and body weight because of direct and indirect effects on the brain. We investigated the separate and combined effects of dapagliflozin and exenatide on the brain in response to the anticipation and consumption of food in people with obesity and type 2 diabetes. MATERIALS AND METHODS: As part of a larger study, this was a 16 week, double-blind, randomized, placebo-controlled trial. Subjects with obesity and type 2 diabetes were randomized (1:1:1:1) to dapagliflozin 10 mg with exenatide-matched placebo, exenatide twice-daily 10 µg with dapagliflozin-matched placebo, dapagliflozin plus exenatide, or double placebo. Using functional magnetic resonance imaging, the effects of treatments on brain responses to the anticipation of food and food receipt were assessed after 10 days and 16 weeks. RESULTS: After 10 days, dapagliflozin increased activation in right amygdala and right caudate nucleus in response to the anticipation of food, and tended to decrease activation in right amygdala in response to actual food receipt. After 16 weeks, no changes in brain activation were observed with dapagliflozin. Dapagliflozin plus exenatide reduced activation in right caudate nucleus and amygdala to the anticipation of food, and decreased activation in the right amygdala in response to food receipt after 16 weeks. CONCLUSIONS: The dapagliflozin-induced changes in brain activation may contribute to the discrepancy between observed and expected weight loss with dapagliflozin. Exenatide blunted the dapagliflozin-induced changes in brain activation, which may contribute to the additional weight loss with combined treatment.

Postprandial renal haemodynamic effects of the dipeptidyl peptidase-4 inhibitor linagliptin versus the sulphonylurea glimepiride in adults with type 2 diabetes (RENALIS): A predefined substudy of a randomized, double-blind trial.

AIM: To determine the effect of the dipeptidyl peptidase-4 inhibitor linagliptin on postprandial glomerular hyperfiltration compared with the sulphonylurea glimepiride in adults with type 2 diabetes (T2D). MATERIALS AND METHODS: In this predefined substudy within a randomized, double-blind, parallel-group, intervention trial, overweight people with T2D without renal impairment were treated with once-daily linagliptin 5 mg (N = 10) or glimepiride 1 mg (N = 13) as an add-on to metformin for 8 weeks. After a standardized liquid protein-rich meal, the glomerular filtration rate (GFR) and effective renal plasma flow were determined by inulin and para-aminohippuric acid clearance, respectively, based on timed urine sampling. Intrarenal haemodynamics were estimated using the Gomez equations. Glucoregulatory/vasoactive hormones, urinary pH and fractional excretions (FE) of sodium, potassium and urea were measured. RESULTS: Compared with glimepiride, linagliptin increased the postprandial filtration fraction (FF; mean difference 2.1%-point; P = .016) and estimated glomerular hydraulic pressure (mean difference 3.0 mmHg; P = .050), and tended to increase GFR (P = .08) and estimated efferent renal arteriolar resistance (RE ; P = .08) from baseline to week 8. No differences in FE were noted. Glimepiride reduced HbA1c more than linagliptin (mean difference -0.40%; P = .004), without between-group differences in time-averaged postprandial glucose levels. In the linagliptin group, change in FF correlated with change in mean arterial pressure (R = 0.807; P = .009) and time-averaged mean glucagon (R = 0.782; P = .008), but not with changes in glucose, insulin, intact glucagon-like peptide-1, renin or FENa . Change in glucagon was associated with change in RE (R = 0.830; P = .003). CONCLUSIONS: In contrast to our hypothesis, compared with glimepiride, linagliptin does not reduce postprandial hyperfiltration, yet appears to increase FF after meal ingestion by increasing blood pressure or RE .

Pursuing the developmental aims of the triarchic model of psychopathy: Creation and validation of triarchic scales for use in the USC: RFAB longitudinal twin project.

The triarchic model was advanced as an integrative, trait-based framework for investigating psychopathy using different assessment methods and across developmental periods. Recent research has shown that the triarchic traits of boldness, meanness, and disinhibition can be operationalized effectively in youth, but longitudinal research is needed to realize the model's potential to advance developmental understanding of psychopathy. We report on the creation and validation of scale measures of the triarchic traits using questionnaire items available in the University of Southern California Risk Factors for Antisocial Behavior (RFAB) project, a large-scale longitudinal study of the development of antisocial behavior that includes measures from multiple modalities (self-report, informant rating, clinical-diagnostic, task-behavioral, physiological). Using a construct-rating and psychometric refinement approach, we developed triarchic scales that showed acceptable reliability, expected intercorrelations, and good temporal stability. The scales showed theory-consistent relations with external criteria including measures of psychopathy, internalizing/externalizing psychopathology, antisocial behavior, and substance use. Findings demonstrate the viability of measuring triarchic traits in the RFAB sample, extend the known nomological network of these traits into the developmental realm, and provide a foundation for follow-up studies examining the etiology of psychopathic traits and their relations with multimodal measures of cognitive-affective function and proneness to clinical problems.

Application of the Force-velocity-power Concept to the 3-min all-out Running Test.

Force-velocity-power (FVP) profiling offers insights related to key factors that may enhance or hinder sprinting performances. Whether the same FVP principles could be applied to the sprinting portion of the 3-minute all-out test for running (3MT) has not been previously investigated. Twenty moderately trained participants volunteered for the study (age: 24.75 ± 3.58 yrs; height: 1.69±0.11 m; mass: 73.74±12.26 kg). After familiarization of all testing procedures, participants completed: (i) a 40-m all-out sprint test, and (ii) a 3MT. Theoretical maximal force and power, but not velocity, were significantly higher for the 40-m sprint test. Most FVP variables from the two tests were weakly to moderately correlated, with the exception of maximal velocity. Finally, maximal velocity and relative peak power were predictive of D', explaining approximately 51% of the variance in D'. Although similar maximal velocities are attained during both the 40-m sprint and the 3MT, the underlying mechanisms are markedly different. The FVP parameters obtained from either test are likely not interchangeable but do provide valuable insights regarding the potential mechanisms by which D' may be improved.

Kidney hemodynamic function in men and postmenopausal women with type 2 diabetes and preserved kidney function.

The progression of kidney disease may differ between sexes in type 2 diabetes (T2D), with previous studies reporting a slower decline in women. Glomerular hyperfiltration is a key factor driving the kidney function decline. The current study aimed to investigate the differences in kidney hemodynamic function between men and women with T2D. A cross-sectional analysis of pooled data from three studies compared kidney hemodynamic function between men and postmenopausal women with T2D without overt nephropathy. The outcome measures were glomerular filtration rate (GFR; inulin clearance), effective renal plasma flow (ERPF; p-aminohippurate clearance), filtration fraction (GFR/ERPF), and renal vascular resistance (RVR; mean arterial pressure/renal blood flow). Glomerular hydraulic pressure (PGLO) as well as afferent and efferent vascular resistance were estimated by Gomez formulae. Sex differences were assessed with linear regression models adjusted for systolic blood pressure, glucose, use of renin-angiotensin system blockers, and body mass index. In total, 101 men [age: 63 (58-68) yr, body mass index: 31.5 ± 3.9 kg/m2, GFR: 111 ± 18 mL/min, HbA1c: 7.4 ± 0.7%] and 27 women [age: 66 (62-69) yr, body mass index: 30.9 ± 4.5 kg/m2, GFR: 97 ± 11 mL/min, HbA1c: 7.1 ± 0.5%] were included. GFR was higher in men versus women [11.0 mL/min (95% confidence interval: 3.6, 18.4)]. Although statistically nonsignificant, PGLO trended higher in men [1.9 mmHg (95% confidence interval: -0.1, 4.0)], whereas RVR [-0.012 mmHg/L/min (95% confidence interval: -0.022, -0.002)] and afferent vascular resistance were lower [-361 dyn/s/cm5 (95% confidence interval: -801, 78)]. In conclusion, in adults without overt nephropathy, GFR was higher in men compared with women. PGLO also trended to be higher in men. Both findings are possibly related to afferent vasodilation and suggest greater prevalence of hyperfiltration. This could contribute to accelerated GFR loss over time in men with T2D.NEW & NOTEWORTHY In adults with type 2 diabetes, men had higher markers of hyperfiltration, which could potentially explain the accelerated progression of diabetic kidney disease in men compared with women.

Effects of a Hypercaloric and Hypocaloric Diet on Insulin-Induced Microvascular Recruitment, Glucose Uptake, and Lipolysis in Healthy Lean Men.

OBJECTIVE: In mice fed a high-fat diet, impairment of insulin signaling in endothelium is an early phenomenon that precedes decreased insulin sensitivity of skeletal muscle, adipose tissue, and liver. We assessed in humans whether short-term overfeeding affects insulin-induced microvascular recruitment in skeletal muscle and adipose tissue before changes occur in glucose uptake and lipolysis. Approach and Results: Fifteen healthy males underwent a hypercaloric and subsequent hypocaloric diet intervention. Before, during, and after the hypercaloric diet, and upon return to baseline weight, all participants underwent (1) a hyperinsulinemic-euglycemic clamp to determine insulin-induced glucose uptake and suppression of lipolysis (2) contrast-enhanced ultrasonography to measure insulin-induced microvascular recruitment in skeletal muscle and adipose tissue. In addition, we assessed insulin-induced vasodilation of isolated skeletal muscle resistance arteries by pressure myography after the hypercaloric diet in study participants and controls (n=5). The hypercaloric diet increased body weight (3.5 kg; P<0.001) and fat percentage (3.5%; P<0.001) but did not affect glucose uptake nor lipolysis. The hypercaloric diet increased adipose tissue microvascular recruitment (P=0.041) and decreased the ratio between skeletal muscle and adipose tissue microvascular blood volume during hyperinsulinemia (P=0.019). Insulin-induced vasodilation of isolated skeletal muscle arterioles was significantly lower in participants compared with controls (P<0.001). The hypocaloric diet reversed all of these changes, except the increase in adipose tissue microvascular recruitment. CONCLUSIONS: In lean men, short-term overfeeding reduces insulin-induced vasodilation of skeletal muscle resistance arteries and shifts the distribution of tissue perfusion during hyperinsulinemia from skeletal muscle to adipose tissue without affecting glucose uptake and lipolysis. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02628301.

DPARD: rationale, design and initial results from the Dutch national diabetes registry.

BACKGROUND: Treatment of diabetes mellitus has majorly improved over the past century, however, the disease burden is high and its prevalence still expanding. Further insight in the diabetes population is imperative to improve the quality of diabetes care by enhancement of knowledge-based diabetes management strategies. To this end, in 2017 a Dutch nationwide consortium of diabetologists, paediatric endocrinologists, and diabetes patients has founded a national outpatient diabetes care registry named Dutch Pediatric and Adult Registry of Diabetes (DPARD). We aim to describe the implementation of DPARD and to provide an overview of the characteristics of patients included during the first 2 years. METHODS: For the DPARD cohort with long-term follow-up of observational nature, hospital data are gathered directly from electronic health records and securely transferred and stored. DPARD provides weekly updated clinical information on the diabetes population care on a hospital-level benchmarked against the national average. RESULTS: Between November 2017 and January 2020, 20,857 patients were included from 8 (11%) Dutch hospitals with a level of care distribution representative of all diabetic outpatients in the Netherlands. Among patients with known diabetes type, 41% had type 1 diabetes, 51% type 2 diabetes, and 8% had diabetes due to other causes. Characteristics of the total patient population were similar to patients with unknown diabetes classification. HbA1c levels decreased over the years, while BMI levels showed an increase over time. CONCLUSIONS: The national DPARD registry aims to facilitate investigation of prevalence and long-term outcomes of Dutch outpatients with diabetes mellitus and their treatment, thus allowing for quality improvement of diabetes care as well as allowing for comparison of diabetes care on an international level.

The value of ambulatory blood pressure measurement to detect masked diastolic hypotension in older patients treated for hypertension.

OBJECTIVE: assess how many patients with low ambulatory diastolic blood pressure (DBP) are not identified when relying on office DBP alone, and thus have 'masked diastolic hypotension'. DESIGN: cross-sectional, retrospective cohort study. SETTING: academic hospital. SUBJECTS: 848 patients treated for hypertension who received ambulatory blood pressure monitoring (ABPM). METHODS: cut-off value between on- and off-target systolic blood pressure (SBP): 140 mmHg. Cut-off for low office and/or ambulatory DBP: DBP ≤ 70 mmHg. 'Masked diastolic hypotension' was defined as office DBP > 70 mmHg and mean ambulatory DBP ≤ 70 mmHg. RESULTS: mean age of the sample was 60 ± 13 years, 50% was female, 37% had diabetes, 42% preexisting cardiovascular disease (CVD), mean office blood pressure (BP) was 134/79 mmHg. In all patients (n = 848), low office DBP was present in n = 84(10%), while n = 183(22%) had low ambulatory DBP. In all patients with normal-to-high office DBP (n = 764), n = 122(16%) had 'masked diastolic hypotension'. In this group, ambulatory DBP was 14-19 mmHg lower than office DBP. Patients with low ambulatory DBP were older, had more (cardiovascular) comorbidities, and used more (antihypertensive) drugs. Antihypertensive drugs were lowered or discontinued in 30% of all patients with 'masked diastolic hypotension' due to side effects. CONCLUSIONS: 'masked diastolic hypotension' is common among patients treated for hypertension, particularly in older patients with CVD (e.g. coronary artery disease, diabetes), patient groups in which the European Society of Cardiology/Hypertension guideline advises to prevent low DBP. Although it remains to be examined at which BP levels the harms of low DBP outweigh the benefits of lowering SBP, our observations are aimed to increase awareness among physicians.

Biomechanics without Borders: Teaching Biomechanics in Brazil and South Africa.

The "Biomechanics without Borders: Teaching Biomechanics in Brazil and South Africa" involved academics from different countries combining efforts to improve remote education. In addition to the live discussions, the event resulted in the availability of online content to help academic staffs improve teaching strategies in the field of human movement sciences.