Neuropsychological outcomes following paediatric temporal lobe surgery for epilepsy: evidence from a systematic review

The objective of this thesis was to present evidence from a systematic review of the literature to assess wider neuropsychological outcomes for temporal lobe resections for epilepsy in children. Neuropsychological outcome domains included intellectual, memory, language, quality of life, psychological wellbeing, educational, vocational, social and behavioural outcome. A systematic literature search was conducted firstly for all studies reporting any outcomes of any resective paediatric epilepsy surgery, yielding 8189, of which 1259 met criteria. After a brief exploration of these broader epilepsy surgery studies, more focussed eligibility criteria were applied. The final review included only those 73 studies that reported neuropsychological outcome of paediatric temporal lobe surgery for epilepsy. Core findings of the review were that for each neuropsychological outcome domain, the majority of participants remained stable after surgery; some declined and some improved. There was some evidence for increased material-specific memory deficits after temporal lobe surgery based on resection side, and more positive cognitive outcome for those with lower pre-surgical ability level. No quantitative analysis of the factors predicting neuropsychological outcome could be performed due to limitations in methodological and reporting quality of the included studies. However, it is this appraisal of the evidence that is of most interest, as it highlights the need for changes in methodology and reporting. Appropriately designed prospective multicentre trials should be conducted, with adequate follow-up for long-term outcomes to be measured. Surgical centres should continue to publish routine clinical case series, but ensure that they report individual participant data, according to established reporting standards. Core outcome measures should be agreed between centres and researchers should collaborate by making their data available for open reviews, in order to build a higher quality evidence base, so that clinicians, young people and their families can make better informed decisions about whether or not to proceed with surgery

Oral treatment with Eubacterium hallii improves insulin sensitivity in db/db mice

F.B. is supported by Swedish Research Council, Swedish Diabetes Foundation, Swedish Heart Lung Foundation, Swedish Foundation for Strategic Research, Knut and Alice Wallenberg foundation, Göran Gustafsson Foundation, Ingbritt and Arne Lundberg’s foundation, Swedish Heart Lung Foundation, Torsten Söderberg’s Foundation, Ragnar Söderberg’s Foundation, NovoNordisk Foundation, AFA insurances, and LUA-ALF grants from Västra Götalandsregionen and Stockholm County Council. F.B. is a recipient of ERC Consolidator Grant (European Research Council, Consolidator grant 615362—METABASE). W.M.d.V. is supported by the Finland Academy of Sciences (grants 137389, 141140 and 1272870 ), the Netherlands Organization for Scientific Research (Spinoza Award and SIAM Gravity Grant 024.002.002) and the European Research Council (ERC Advanced Grant 250172 MicrobesInside). M.N. is supported by a ZONMW-VIDI grant 2013 (016.146.327).Peer reviewedPublisher PD

True interindividual variability exists in postprandial appetite responses in healthy men but is not moderated by the FTO genotype

Background: After meal ingestion, a series of coordinated hormone responses occur concomitantly with changes in perceived appetite. It is not known whether interindividual variability in appetite exists in response to a meal. Objectives: This study aimed to 1) assess the reproducibility of appetite responses to a meal; 2) quantify individual differences in responses; and 3) explore any moderating influence of the fat mass and obesity associated (FTO) gene. Methods: Using a replicated crossover design, 18 healthy men (mean ± SD 28.5 ± 9.8 years, 27.0 ± 5.0 kg·m-2 ) recruited according to FTO genotype (9 AA, 9 TT) completed two identical control and two identical standardized meal conditions (5025 kJ) in randomized sequences. Perceived appetite and plasma acylated ghrelin, total peptide YY (PYY), insulin and glucose concentrations were measured before and after interventions as primary outcomes. Interindividual differences were explored using Pearson’s product-moment correlations between the first and second replicate of the control-adjusted meal response. Within-participant covariate-adjusted linear mixed models were used to quantify participant by-condition and genotype-by-condition interactions. Results: The meal suppressed acylated ghrelin and appetite perceptions (standardized effect sizes (ES): 0.18-4.26) and elevated total PYY, insulin and glucose (ES: 1.96-21.60). For all variables, SD of change scores was greater in the meal versus control conditions. Moderate-to-large positive correlations were observed between the two replicates of control-adjusted meal responses for all variables (r=0.44-0.86, P≤0.070). Participant-by-condition interactions were present for all variables (P≤0.056). FTO genotype-by-condition interactions were not significant (P≥0.19) and treatment effect differences between genotype groups were small (ES≤0.27) for all appetite parameters. Conclusions: Reproducibility of postprandial appetite responses is generally good. True interindividual variability is present beyond any random within-subject variation in healthy men but is not moderated by the FTO genotype. These findings highlight the 3 importance of exploring individual differences in appetite for the prevention and/or treatment of obesity. Clinical trial registry number: NCT03771690 (ClinicalTrials.gov)

Individual variation in hunger, energy intake and ghrelin responses to acute exercise

Purpose This study aimed to characterize the immediate and extended effect of acute exercise on hunger, energy intake, and circulating acylated ghrelin concentrations using a large data set of homogenous experimental trials and to describe the variation in responses between individuals. Methods Data from 17 of our group's experimental crossover trials were aggregated yielding a total sample of 192 young, healthy males. In these studies, single bouts of moderate to high-intensity aerobic exercise (69% ± 5% V˙O2 peak; mean ± SD) were completed with detailed participant assessments occurring during and for several hours postexercise. Mean hunger ratings were determined during (n = 178) and after (n = 118) exercise from visual analog scales completed at 30-min intervals, whereas ad libitum energy intake was measured within the first hour after exercise (n = 60) and at multiple meals (n = 128) during the remainder of trials. Venous concentrations of acylated ghrelin were determined at strategic time points during (n = 118) and after (n = 89) exercise. Results At group level, exercise transiently suppressed hunger (P < 0.010, Cohen's d = 0.77) but did not affect energy intake. Acylated ghrelin was suppressed during exercise (P < 0.001, Cohen's d = 0.10) and remained significantly lower than control (no exercise) afterward (P < 0.024, Cohen's d = 0.61). Between participants, there were notable differences in responses; however, a large proportion of this spread lay within the boundaries of normal variation associated with biological and technical assessment error. Conclusion In young men, acute exercise suppresses hunger and circulating acylated ghrelin concentrations with notable diversity between individuals. Care must be taken to distinguish true interindividual variation from random differences within normal limits

An acute bout of swimming increases post-exercise energy intake in young healthy men and women

Single bouts of land-based exercise (for example, walking, running, cycling) do not typically alter post-exercise energy intake on the day of exercise. However, anecdotal and preliminary empirical evidence suggests that swimming may increase appetite and energy intake. This study compared the acute effects of swimming on appetite, energy intake, and food preference and reward, versus exertion-matched cycling and a resting control. Thirty-two men (n=17; mean ± SD age 24 ± 2 years, body mass index [BMI] 25.0 ± 2.6 kg/m2) and women (n=15; age 22 ± 3 years, BMI 22.8 ± 2.3 kg/m2) completed three experimental trials (swimming, cycling, control) in a randomised, crossover design. The exercise trials involved 60-min of ‘hard’ exercise (self-selected rating of perceived exertion: 15) performed 90-min after a standardised breakfast. Food preference and reward were assessed via the Leeds Food Preference Questionnaire 15-min after exercise, whilst ad libitum energy intake was determined 30-min after exercise. The control trial involved identical procedures except no exercise was performed. Compared with control (3259 ± 1265 kJ), swimming increased ad libitum energy intake (3857 ± 1611 kJ; ES=0.47, 95% CI of the mean difference between trials 185, 1010 kJ, P=0.005); the magnitude of increase was smaller after cycling (3652 ± 1619 kJ; ES=0.31, 95% CI -21, 805 kJ, P=0.062). Ad libitum energy intake was similar between swimming and cycling (ES=0.16, 95% CI -207, 618 kJ, P=0.324). This effect was consistent across sexes and unrelated to food preference and reward which were similar after swimming and cycling compared with control. This study has identified an orexigenic effect of swimming. Further research is needed to identify the responsible mechanism(s), including the relevance of water immersion and water temperature per se

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Model sensitivities and stratosphere - troposphere interactions

In recent years it has been shown that the troposphere is affected by changes in the climate of the stratosphere as well as vice versa. Investigating the downward influence has implications for understanding not only past climate but also for predicting future climate. A simplified, Newtonian-forced general circulation model is used to investigate the impact of changes in the stratosphere on the tropospheric circulation. First the sensitivity of tropospheric climate, tropospheric climate variability and response to stratospheric forcing to the surface temperature relaxation timescale are investigated. Changes to this parameter are shown to have significant impact on the model’s climatology, influencing both the thermal structure of the lower troposphere and the position of the eddy driven mid-latitude jet. The change in mean tropospheric climate influences the annular variability, including its timescale. A strong relationship between this timescale and the magnitude of response to forcing is found, which is consistent with the fluctuation – dissipation theorem. The tropospheric response for both the surface parameter experiments and stratospheric temperature forcings is shown to be remarkably similar. This indicates that the same dynamical feedbacks are triggered, and thus resulting in the same annular mode-like response. Further, the impact of an improved representation of the stratosphere (in a model of greater vertical extent) and its effect on the response to a range of stratospheric heating perturbations is investigated. The extent of the heating perturbations, both in latitude and altitude, are shown to have a significant impact on the tropospheric response. These experiments further reveal an influence of the tropospheric eddy response back onto the stratospheric forcing region which modifies the direct stratospheric response to the heating. This suggests a strong two way coupling between the lower stratosphere and the tropospheric jets and storm track eddies

Model sensitivities and stratosphere-troposphere interactions

In recent years it has been shown that the troposphere is affected by changes in the climate of the stratosphere as well as vice versa. Investigating the downward influence has implications for understanding not only past climate but also for predicting future climate. A simplified, Newtonian-forced general circulation model is used to investigate the impact of changes in the stratosphere on the tropospheric circulation. First the sensitivity of tropospheric climate, tropospheric climate variability and response to stratospheric forcing to the surface temperature relaxation timescale are investigated. Changes to this parameter are shown to have significant impact on the model’s climatology, influencing both the thermal structure of the lower troposphere and the position of the eddy driven mid-latitude jet. The change in mean tropospheric climate influences the annular variability, including its timescale. A strong relationship between this timescale and the magnitude of response to forcing is found, which is consistent with the fluctuation – dissipation theorem. The tropospheric response for both the surface parameter experiments and stratospheric temperature forcings is shown to be remarkably similar. This indicates that the same dynamical feedbacks are triggered, and thus resulting in the same annular mode-like response. Further, the impact of an improved representation of the stratosphere (in a model of greater vertical extent) and its effect on the response to a range of stratospheric heating perturbations is investigated. The extent of the heating perturbations, both in latitude and altitude, are shown to have a significant impact on the tropospheric response. These experiments further reveal an influence of the tropospheric eddy response back onto the stratospheric forcing region which modifies the direct stratospheric response to the heating. This suggests a strong two way coupling between the lower stratosphere and the tropospheric jets and storm track eddies.EThOS - Electronic Theses Online ServiceGBUnited Kingdo