Closed-Loop Targeted Memory Reactivation during Sleep Improves Spatial Navigation

Sounds associated with newly learned information that are replayed during non-rapid eye movement (NREM) sleep can improve recall in simple tasks. The mechanism for this improvement is presumed to be reactivation of the newly learned memory during sleep when consolidation takes place. We have developed an EEG-based closed-loop system to precisely deliver sensory stimulation at the time of down-state to up-state transitions during NREM sleep. Here, we demonstrate that applying this technology to participants performing a realistic navigation task in virtual reality results in a significant improvement in navigation efficiency after sleep that is accompanied by increases in the spectral power especially in the fast (12\u201315 Hz) sleep spindle band. Our results show promise for the application of sleep-based interventions to drive improvement in real-world tasks

Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatophepatitis

OBJECTIVE: Insulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH.DESIGN: 14 patients were randomised to 1.8mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes.RESULTS: Liraglutide reduced BMI (-1.9 vs. +0.04 kg/m2;p&lt;0.001), HbA1c (-0.3 vs. +0.3%;p&lt;0.01), cholesterol-LDL (-0.7 vs. +0.05 mmol/L;p&lt;0.01), ALT (-54 vs -4.0 IU/L;p&lt;0.01) and serum leptin, adiponectin, and CCL-2 (all p&lt;0.05). Liraglutide increased hepatic insulin sensitivity (-9.36 vs. -2.54% suppression of hepatic endogenous glucose production with low-dose insulin;p&lt;0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (-24.9 vs. +54.8 pmol/L insulin required to ½ maximally suppress serum NEFA; p&lt;0.05), and specifically within subcutaneous adipose tissue (p&lt;0.05). In addition, liraglutide decreased hepatic DNL in-vivo (-1.26 vs. +1.30%; p&lt;0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p&lt;0.01).CONCLUSIONS: Liraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of NASH. Liraglutide may offer the potential for a disease-modifying intervention in NASH.</p

Using ACTH Challenges to Validate Techniques for Adrenocortical Activity Analysis in Various African Wildlife Species

Abstract: Monitoring adrenocortical activity using fecal hormonal analysis can provide information on how environmental changes are affecting non-domestic species health and success in the field; however, this noninvasive method needs proper validation to ensure that analysis reflects true physiological events. Our objectives were to use adrenocorticotropic hormone (ACTH) challenges as a physiological validation method to test the suitability of a new corticosterone enzyme immunoassay (EIA) to accurately assess the adrenocortical activity using fecal samples in four African wildlife species-the black rhinoceros (rhino; Diceros bicornis), African elephant (Loxodonta africana), chimpanzee (Pan troglodytes) and African lion (Panthera leo krugeri). In the rhino and elephant, fecal Glucocorticoid metabolites (GC) surged 75 and 51 h post-ACTH injection, respectively. In the chimpanzee, fecal GC metabolites peaked at 29 h post-injection. And the lion had a peak of fecal GC at 24 h post-ACTH. This study determined that adrenocortical activity was reflected in concentrations of fecal GC metabolites suggesting that this corticosterone EIA is an effective technique for the monitoring stress in four African species

Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatophepatitis

Background & AimsInsulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH.MethodsFourteen patients were randomised to 1.8mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomised, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes.ResultsLiraglutide reduced BMI (−1.9 vs. +0.04kg/m2; p<0.001), HbA1c (−0.3 vs. +0.3%; p<0.01), cholesterol-LDL (−0.7 vs. +0.05mmol/L; p<0.01), ALT (−54 vs. −4.0IU/L; p<0.01) and serum leptin, adiponectin, and CCL-2 (all p<0.05). Liraglutide increased hepatic insulin sensitivity (−9.36 vs. −2.54% suppression of hepatic endogenous glucose production with low-dose insulin; p<0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (−24.9 vs. +54.8pmol/L insulin required to ½ maximally suppress serum non-esterified fatty acids; p<0.05), and specifically within subcutaneous adipose tissue (p<0.05). In addition, liraglutide decreased hepatic de novo lipogenesis in vivo (−1.26 vs. +1.30%; p<0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p<0.01).ConclusionsLiraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of NASH. Liraglutide may offer the potential for a disease-modifying intervention in NASH

Diagnosing and treating leprosy in a non-endemic setting in a national centre, London, United Kingdom 1995-2018

Background Leprosy is rare in the United Kingdom (UK), but migration from endemic countries results in new cases being diagnosed each year. We documented the clinical presentation of leprosy in a non-endemic setting. Methods Demographic and clinical data on all new cases of leprosy managed in the Leprosy Clinic at the Hospital for Tropical Diseases, London between 1995 and 2018 were analysed. Results 157 individuals with a median age of 34 (range 13-85) years were included. 67.5% were male. Patients came from 34 different countries and most contracted leprosy before migrating to the UK. Eighty-two (51.6%) acquired the infection in India, Sri Lanka, Bangladesh, Nepal and Pakistan. 30 patients (19.1%) acquired leprosy in Africa, including 11 from Nigeria. Seven patients were born in Europe; three acquired their leprosy infection in Africa, three in South East Asia, and one in Europe. The mean interval between arrival in the UK and symptom onset was 5.87 years (SD 10.33), the longest time to diagnosis was 20 years. Borderline tuberculoid leprosy (n=71, 42.0%), and lepromatous leprosy (n=,53 33.1%) were the commonest Ridley Jopling types. Dermatologists were the specialists diagnosing leprosy most often. Individuals were treated with World Health Organization recommended drug regimens (rifampicin, dapsone and clofazimine). Conclusion Leprosy is not a disease of travellers but develops after residence in an leprosy endemic area. The number of individuals from a leprosy endemic country reflect both the leprosy prevalence and the migration rates to the United Kingdom. There are challenges in diagnosing leprosy in non-endemic areas and clinicians need to recognise the symptoms and signs of leprosy

Ejection Fraction, Biomarkers, and Outcomes and Impact of Vericiguat on Outcomes Across EF in VICTORIA

Background: Vericiguat reduced the risk of cardiovascular death (CVD) or hospitalization for heart failure (HF) in patients with worsening HF and reduced left ventricular ejection fraction (LVEF).Objectives: The authors assessed the association of LVEF with biomarker levels, risk of outcome, and whether the effect of vericiguat was homogeneous across LVEF in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction) trial.Methods: Patients were grouped by LVEF tertiles (≤24%, 25%-33%, and &gt;33%). Patient characteristics, clinical outcomes, and efficacy and safety of vericiguat were examined by tertile. Prespecified biomarkers including N-terminal pro–B-type natriuretic peptide, cardiac troponin T, growth differentiation factor 15, interleukin 6, high-sensitivity C-reactive protein, and cystatin C were examined.Results: The mean LVEF was 29% ± 8% (range: 5%-45%). A pattern of higher N-terminal pro–B-type natriuretic peptide, high-sensitivity C-reactive protein, and interleukin 6 was evident in patients in the lowest LVEF tertile vs the other tertiles. Patients with lower LVEF experienced higher rates of the composite outcome (41.7%, 36.3%, and 33.4% for LVEF ≤24, 25-33, and &gt;33; P &lt; 0.001). There was no significant treatment effect heterogeneity of vericiguat across LVEF groups (adjusted HR from lowest to highest tertiles: 0.79 [95% CI: 0.68-0.94]; 0.95 [95% CI: 0.82-1.11]; 0.94 [95% CI: 0.79-1.11]; P for interaction = 0.222), although the HR was numerically lower in the lowest tertile. There was also no heterogeneity of effect for CVD and HF hospitalization individually (P interaction for CVD = 0.964; HF hospitalization = 0.438). Discontinuation of treatment because of adverse events, symptomatic hypotension, or syncope was consistent across the range of LVEF.Conclusions: Patients with lower LVEF had a distinctive biomarker profile and a higher risk for adverse clinical outcomes vs those with a higher LVEF. There was no significant interaction for the benefit of vericiguat across LVEF tertiles, although the largest signal for benefit in both the primary outcome and HF hospitalizations was noted in tertile 1 (LVEF ≤24%).</p

Effect of varying skin surface electrode position on electroretinogram responses recorded using a handheld stimulating and recording system

Purpose A handheld device (the RETeval system, LKC Technologies) aims to increase the ease of electroretinogram (ERG) recording by using specially designed skin electrodes, rather than corneal electrodes. We explored effects of electrode position on response parameters recorded using this device. Methods Healthy adult twins were recruited from the TwinsUK cohort and underwent recording of light-adapted flicker ERGs (corresponding to international standard stimuli). In Group 1, skin electrodes were placed in a “comfortable” position, which was up to 20 mm below the lid margin. For subsequent participants (Group 2), the electrode was positioned 2 mm from the lid margin as recommended by the manufacturer. Amplitudes and peak times (averaged from both eyes) were compared between groups after age-matching and inclusion of only one twin per pair. Light-adapted flicker and flash ERGs were recorded for an additional 10 healthy subjects in two consecutive recording sessions: in the test eye, electrode position was varied from 2 to 10–20 mm below the lid margin between sessions; in the fellow (control) eye, the electrode was 2 mm below the lid margin throughout. Amplitudes and peak times (test eye normalised to control eye) were compared for the two sessions. Results Including one twin per pair, and age-matching yielded 28 individuals per group. Flicker ERG amplitudes were significantly lower for Group 1 than Group 2 participants (p = 0.0024). However, mean peak times did not differ between groups (p = 0.54). For the subjects in whom electrode position was changed between recording sessions, flash and flicker amplitudes were significantly lower when positioned further from the lid margin (p  0.5). Conclusions Moving the skin electrodes further from the lid margin significantly reduces response amplitudes, highlighting the importance of consistent electrode positioning. However, this does not significantly affect peak times. Thus, it may be feasible to adopt a more comfortable position in participants who cannot tolerate the recommended position if analysis is restricted to peak time parameters

Impacts of meeting minimum access on critical earth systems amidst the Great Inequality

The Sustainable Development Goals aim to improve access to resources and services, reduce environmental degradation, eradicate poverty and reduce inequality. However, the magnitude of the environmental burden that would arise from meeting the needs of the poorest is under debate—especially when compared to much larger burdens from the rich. We show that the ‘Great Acceleration’ of human impacts was characterized by a ‘Great Inequality’ in using and damaging the environment. We then operationalize ‘just access’ to minimum energy, water, food and infrastructure. We show that achieving just access in 2018, with existing inequalities, technologies and behaviours, would have produced 2–26% additional impacts on the Earth’s natural systems of climate, water, land and nutrients—thus further crossing planetary boundaries. These hypothetical impacts, caused by about a third of humanity, equalled those caused by the wealthiest 1–4%. Technological and behavioural changes thus far, while important, did not deliver just access within a stable Earth system. Achieving these goals therefore calls for a radical redistribution of resources

Short Duration Repetitive Transcranial Electrical Stimulation During Sleep Enhances Declarative Memory of Facts

Transcranial electrical stimulation (tES) during sleep has been shown to successfully modulate memory consolidation. Here, we tested the effect of short duration repetitive tES (SDR-tES) during a daytime nap on the consolidation of declarative memory of facts in healthy individuals. We use a previously described approach to deliver the stimulation at regular intervals during non-rapid eye movement (NREM) sleep, specifically stage NREM2 and NREM3. Similar to previous studies using tES, we find enhanced memory performance compared to sham both after sleep and 48 h later. We also observed an increase in the proportion of time spent in NREM3 sleep and SDR-tES boosted the overall rate of slow oscillations (SOs) during NREM2/NREM3 sleep. Retrospective investigation of brain activity immediately preceding stimulation suggests that increases in the SO rate are more likely when stimulation is delivered during quiescent and asynchronous periods of activity in contrast to other closed-loop approaches which target phasic stimulation during ongoing SOs