Novel ketone diet enhances physical and cognitive performance.

Ketone bodies are the most energy-efficient fuel and yield more ATP per mole of substrate than pyruvate and increase the free energy released from ATP hydrolysis. Elevation of circulating ketones via high-fat, low-carbohydrate diets has been used for the treatment of drug-refractory epilepsy and for neurodegenerative diseases, such as Parkinson's disease. Ketones may also be beneficial for muscle and brain in times of stress, such as endurance exercise. The challenge has been to raise circulating ketone levels by using a palatable diet without altering lipid levels. We found that blood ketone levels can be increased and cholesterol and triglycerides decreased by feeding rats a novel ketone ester diet: chow that is supplemented with (R)-3-hydroxybutyl (R)-3-hydroxybutyrate as 30% of calories. For 5 d, rats on the ketone diet ran 32% further on a treadmill than did control rats that ate an isocaloric diet that was supplemented with either corn starch or palm oil (P < 0.05). Ketone-fed rats completed an 8-arm radial maze test 38% faster than did those on the other diets, making more correct decisions before making a mistake (P < 0.05). Isolated, perfused hearts from rats that were fed the ketone diet had greater free energy available from ATP hydrolysis during increased work than did hearts from rats on the other diets as shown by using [31P]-NMR spectroscopy. The novel ketone diet, therefore, improved physical performance and cognitive function in rats, and its energy-sparing properties suggest that it may help to treat a range of human conditions with metabolic abnormalities.-Murray, A. J., Knight, N. S., Cole, M. A., Cochlin, L. E., Carter, E., Tchabanenko, K., Pichulik, T., Gulston, M. K., Atherton, H. J., Schroeder, M. A., Deacon, R. M. J., Kashiwaya, Y., King, M. T., Pawlosky, R., Rawlins, J. N. P., Tyler, D. J., Griffin, J. L., Robertson, J., Veech, R. L., Clarke, K. Novel ketone diet enhances physical and cognitive performance.A.J.M. thanks the Research Councils UK for supporting his Academic Fellowship. This work was supported by the Defense Advanced Research Projects Agency.This is the final version of the article. It first appeared from FASEB at https://doi.org/10.1096/fj.201600773R

True 99th centile of high sensitivity cardiac troponin for hospital patients: prospective, observational cohort study?

OBJECTIVE To determine the distribution, and specifically the true 99th centile, of high sensitivity cardiac troponin I (hs-cTnI) for a whole hospital population by applying the hs-cTnI assay currently used routinely at a large teaching hospital. DESIGN Prospective, observational cohort study. SETTING University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom, between 29 June 2017 and 24 August 2017. PARTICIPANTS 20000 consecutive inpatients and outpatients undergoing blood tests for any clinical reason. Hs-cTnI concentrations were measured in all study participants and nested for analysis except when the supervising doctor had requested hs-cTnI for clinical reasons. MAIN OUTCOME MEASURES Distribution of hs-cTnI concentrations of all study participants and specifically the 99th centile. RESULTS The 99th centile of hs-cTnI for the whole population was 296 ng/L compared with the manufacturer’s quoted level of 40 ng/L (currently used clinically as the upper limit of normal; ULN). Hs-cTnI concentrations were greater than 40 ng/L in one in 20 (5.4%, n=1080) of the total population. After excluding participants diagnosed as having acute myocardial infarction (n=122) and those in whom hs-cTnI was requested for clinical reasons (n=1707), the 99th centile was 189 ng/L for the remainder (n=18171). The 99th centile was 563 ng/L for inpatients (n=4759) and 65 ng/L for outpatients (n=9280). Patients from the emergency department (n=3706) had a 99th centile of 215 ng/L, with 6.07% (n=225) greater than the recommended ULN. 39.02% (n=48) of all patients from the critical care units (n=123) and 14.16% (n=67) of all medical inpatients had an hs-cTnI concentration greater than the recommended ULN. CONCLUSIONS Of 20000 consecutive patients undergoing a blood test for any clinical reason at our hospital, one in 20 had an hs-cTnI greater than the recommended ULN. These data highlight the need for clinical staff to interpret hs-cTnI concentrations carefully, particularly when applying the recommended ULN to diagnose acute myocardial infarction, in order to avoid misdiagnosis in the absence of an appropriate clinical presentation. TRIAL REGISTRATION Clinicaltrials.gov NCT0304778

The use of economic evaluation in CAM: an introductory framework

Background For CAM to feature prominently in health care decision-making there is a need to expand the evidence-base and to further incorporate economic evaluation into research priorities. In a world of scarce health care resources and an emphasis on efficiency and clinical efficacy, CAM, as indeed do all other treatments, requires rigorous evaluation to be considered in budget decision-making. Methods Economic evaluation provides the tools to measure the costs and health consequences of CAM interventions and thereby inform decision making. This article offers CAM researchers an introductory framework for understanding, undertaking and disseminating economic evaluation. The types of economic evaluation available for the study of CAM are discussed, and decision modelling is introduced as a method for economic evaluation with much potential for use in CAM. Two types of decision models are introduced, decision trees and Markov models, along with a worked example of how each method is used to examine costs and health consequences. This is followed by a discussion of how this information is used by decision makers. Conclusions Undoubtedly, economic evaluation methods form an important part of health care decision making. Without formal training it can seem a daunting task to consider economic evaluation, however, multidisciplinary teams provide an opportunity for health economists, CAM practitioners and other interested researchers, to work together to further develop the economic evaluation of CAM

What Is the Optimal Therapy for Patients with H5N1 Influenza?

Nicholas White discusses optimal dosing of oseltamivir, Robert Webster and Elena Govorkova discuss combination antiviral therapy, and Timothy Uyeki discusses clinical care of patients with H5N1

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Background Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.Methods The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 µg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 µg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (antispike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.Findings Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group).Interpretation Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose