Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease.

The kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing, and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8+ T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)-6. These late immunometabolic and immune defects may have clinical implications.

Acute cognitive performance and mood effects of coffee berry and apple extracts: A randomised, double blind, placebo controlled crossover study in healthy humans.

Background: Polyphenols from coffee berry (chlorogenic acid) and apple (flavanol) have been shown to improve mood and increase cerebral blood flow in healthy humans. These effects may underpin the cognitive effects of polyphenols seen previously.Objective: The aim of the present paper was to extend previous research by investigating the effects of coffee berry at high and low doses when combined with apple extract on cognitive performance and mood.Design: This randomised, double-blind, placebo controlled, crossover trial included 46 healthy males and females,18-49 years of age (mean age 23 years),consuming: 1100 mg coffee berry extract, 1100 mg coffee berry extract plus 275 mg apple extract, 100 mg coffee berry extract plus 275 mg apple extract or placebo on 4 separate occasions, completing cognitive and mood assessments pre-dose and then again at 1-, 3- and 6 hrs post-dose.Results: Analysis revealed a consistent pattern of alerting effects following 1100 mg coffee berry extract. Limited effects on cognitive function were observed. Specifically, faster peg and ball performance (executive function) was observed following 1100 mg coffee berry plus apple extract and accuracy on the Rapid Visual Information Processing (RVIP) task increased on the third of four repetitions following 1100 mg coffee berry alone. Interestingly, more false alarms on RVIP were observed following the same intervention.Conclusions: In line with previous findings, 1100 mg coffee berry engendered increased arousal. The absence of effects on mood when an apple extract was added, and the potential for the low dose of caffeine within the coffee berry to act synergistically with polyphenols, raise interesting future avenues of research.Abbreviations: Cognitive demand battery (CDB), Profile Of Mood States (POMS), Visual Analogue Scale (VAS), Rapid Visual Information Processing (RVIP).

Challenges and opportunities for conducting a vaccine trial during the COVID-19 pandemic in the United Kingdom.

The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency.

Valuing conservation benefits of disease control in wildlife: A choice experiment approach to bovine tuberculosis management in New Zealand's native forests.

We assess the non-monetary environmental benefits that accrue incidentally in New Zealand (NZ) from pest management conducted primarily to control an animal disease, bovine tuberculosis (TB). TB is an infectious disease that is one of the world's most serious animal health problems and, in many parts of the developing world, still a major mortality risk for humans. The incidence of TB in New Zealand (NZ) farmed livestock has been reduced progressively over the last 20 years, largely due to extensive and sustained population control of the main wildlife reservoir of disease, the introduced brushtail possum. Possums are also major pests that threaten indigenous forest biodiversity, and so extensive possum control for TB mitigation also incidental benefits conservation, but the extent and public value of this benefit has yet to be quantified. We conducted a choice experiment survey of the NZ public in an effort to value the native forest biodiversity benefits of TB-related possum control. We find strong public support for conservation outcomes consequent to TB-possum control in public native forests. The public place substantial value on the most observable biodiversity benefits of TB possum control, such as improved forest canopies and presence of native birds. The benefits, costs and values of TB-possum control are discussed in relation to the future directives of NZ's TB control programme, which is headed toward first regional and then national level disease eradication.

Addition of Orange Pomace to Orange Juice Attenuates the Increases in Peak Glucose and Insulin Concentrations after Sequential Meal Ingestion in Men with Elevated Cardiometabolic Risk.

BACKGROUND: Prospective cohort studies show that higher dietary fiber intake is associated with reduced cardiovascular disease risk, yet the impact on postprandial glucose and insulin responses is unclear. OBJECTIVE: This study aims to evaluate the effects of orange beverages with differing fiber concentrations on postprandial glycemic responses (secondary outcome measure) after a sequential breakfast and lunch challenge in men with increased cardiometabolic risk. METHODS: Thirty-six men (aged 30-65 y; body mass index 25-30 kg/m(2): fasting triacylglycerol or total cholesterol concentrations: 0.8-2.2 or 6.0-8.0 mmol/L, respectively) were provided with a high-fat mixed breakfast and were randomly assigned to consume 240 mL Tropicana (PepsiCo, Inc.) pure premium orange juice without pulp (OJ), OJ with 5.5 g added orange pomace fiber (OPF), juice made from lightly blended whole orange, or an isocaloric sugar-matched control (Control) on 4 occasions separated by 2 wk. A medium-fat mixed lunch was provided at 330 min. Blood samples were collected before breakfast and on 11 subsequent occasions for 420 min (3 time points postlunch) to determine postprandial glucose, insulin, lipid, and inflammatory biomarker responses. Repeated-measures ANOVA was used for data analysis. RESULTS: OPF significantly (P < 0.05) reduced the maximal change in glucose concentrations (1.9 ± 0.21 mmol/L) reached after breakfast compared with other treatments (2.3-2.4 mmol/L) and after lunch (3.0 ± 0.05 mmol/L) compared with OJ (3.6 ± 0.05 mmol/L). The maximal change in insulin concentration (313 ± 25 pmol/L) was also lower compared with Control (387 ± 30 pmol/L) and OJ (418 ± 39 pmol/L) after breakfast. OPF significantly delayed the time to reach the peak glucose concentration compared with Control and OJ, and of insulin compared with Control after breakfast. CONCLUSION: OPF consumed with breakfast may lower postprandial glycemic and insulinemic responses to typical meal ingestion in men with increased cardiometabolic risk. This trial is registered at clinicaltrials.gov as NCT01963416.

Flavanone-rich citrus beverages counteract the transient decline in postprandial endothelial function in humans: a randomised, controlled, double-masked, cross-over intervention study.

Specific flavonoid-rich foods/beverages are reported to exert positive effects on vascular function; however, data relating to effects in the postprandial state are limited. The present study investigated the postprandial, time-dependent (0-7 h) impact of citrus flavanone intake on vascular function. An acute, randomised, controlled, double-masked, cross-over intervention study was conducted by including middle-aged healthy men (30-65 years, n 28) to assess the impact of flavanone intake (orange juice: 128·9 mg; flavanone-rich orange juice: 272·1 mg; homogenised whole orange: 452·8 mg; isoenergetic control: 0 mg flavanones) on postprandial (double meal delivering a total of 81 g of fat) endothelial function. Endothelial function was assessed by flow-mediated dilatation (FMD) of the brachial artery at 0, 2, 5 and 7 h. Plasma levels of naringenin/hesperetin metabolites (sulphates and glucuronides) and nitric oxide species were also measured. All flavanone interventions were effective at attenuating transient impairments in FMD induced by the double meal (7 h post intake; P<0·05), but no dose-response effects were observed. The effects on FMD coincided with the peak of naringenin/hesperetin metabolites in circulation (7 h) and sustained levels of plasma nitrite. In summary, citrus flavanones are effective at counteracting the negative impact of a sequential double meal on human vascular function, potentially through the actions of flavanone metabolites on nitric oxide.

Examining techniques for measuring the effects of nutrients on mental performance and mood state.

PURPOSE: Intake of specific nutrients has been linked to mental states and various indices of cognitive performance although the effects are often subtle and difficult to interpret. Measurement of so-called objective variables (e.g. reaction times) is often considered to be the gold standard for assessing outcomes in this field of research. It can, however, be argued that data on subjective experience (e.g. mood) are also important and may enrich existing objective data. The aim of this review is to evaluate methods for measuring mental performance and mood, considering the definition of subjective mood and the validity of measures of subjective experience. METHODS: A multi-stakeholder expert group was invited by ILSI Europe to come to a consensus around the utility of objective and subjective measurement in this field, which forms the basis of the paper. Therefore, the present review reflects a succinct overview of the science but is not intended to be a systematic review. RESULTS: The proposed approach extends the traditional methodology using standard 'objective' measurements to also include the consumers' subjective experiences in relation to food. Specific recommendations include 1) using contemporary methods to capture transient mood states; 2) using sufficiently sensitive measures to capture effects of nutritional intervention; 3) considering the possibility that subjective and objective responses will occur over different time frames; and 4) recognition of the importance of expectancy and placebo effects for subjective measures. CONCLUSIONS: The consensus reached was that the most informative approach should involve collection and consideration of both objective and subjective data.

Flavonoid-rich orange juice is associated with acute improvements in cognitive function in healthy middle-aged males.

PURPOSE: Epidemiological evidence suggests that chronic consumption of fruit-based flavonoids is associated with cognitive benefits; however, the acute effects of flavonoid-rich (FR) drinks on cognitive function in the immediate postprandial period require examination. The objective was to investigate whether consumption of FR orange juice is associated with acute cognitive benefits over 6 h in healthy middle-aged adults. METHODS: Males aged 30-65 consumed a 240-ml FR orange juice (272 mg) and a calorie-matched placebo in a randomized, double-blind, counterbalanced order on 2 days separated by a 2-week washout. Cognitive function and subjective mood were assessed at baseline (prior to drink consumption) and 2 and 6 h post consumption. The cognitive battery included eight individual cognitive tests. A standardized breakfast was consumed prior to the baseline measures, and a standardized lunch was consumed 3 h post-drink consumption. RESULTS: Change from baseline analysis revealed that performance on tests of executive function and psychomotor speed was significantly better following the FR drink compared to the placebo. The effects of objective cognitive function were supported by significant benefits for subjective alertness following the FR drink relative to the placebo. CONCLUSIONS: These data demonstrate that consumption of FR orange juice can acutely enhance objective and subjective cognition over the course of 6 h in healthy middle-aged adults.

Orange pomace fibre increases a composite scoring of subjective ratings of hunger and fullness in healthy adults.

Dietary fibre has been shown to increase subjective satiating ratings. However data from human trials has produced mixed results, possibly due to different types of fibre which have diverse physicochemical properties and gastrointestinal transit behaviour. The aim of study 1 was to investigate whether orange juice (OJ) with 5.5 g of added orange pomace fibre (OPF) was as satiating as whole orange (WO, chopped and blended to a puree/liquid) compared with OJ. Study 2 was to evaluate the dose-dependent satiating effect of OPF delivered in an orange-flavoured beverage. Both studies were randomized, controlled, double blind, cross over in design with 4 intervention arms in study 1 including OJ, OPF, WO, and water, and 3 arms in study 2: orange-flavoured beverage with low (2.5 g) and high (5.5 g) dose of OPF (LD-OPF and HD-OPF), and orange-flavoured beverage without fibre (Control). Volunteers were asked to response to 8 questions relating to hunger, fullness, desire to eat, thirst and discomfort by visual analogue scale (VAS) for each question. Differences were detected in least squares mean estimates of composite satiety scores and each individual question with statistical modelling to adjust for differences in baseline scores. Addition of 5.5 g OPF either to OJ or to orange-flavoured beverage significantly increased the composite satiety scores compared with OJ (P < 0.0001) or Control (P < 0.0001), and the effect was comparative to WO. LD-OPF showed some satiating effect (less desire to eat) compared with Control (P = 0.038), though less effective than HD-OPF (P = 0.043). In conclusion, the addition of OPF to OJ was as effective at increasing satiety as WO consumption compared with OJ; and there was a trend of dose-dependent effect of OPF on satiety compared with the control.

Do consumers of manufactured cigarettes respond differently to price changes compared with their Roll-Your-Own counterparts? Evidence from New Zealand.

BACKGROUND: Price-based mechanisms are an important tobacco cessation policy tool in New Zealand (NZ) and so measurement of smokers' reaction to price changes is crucial in determining efficacy of this approach. Although approximately two-thirds of NZ tobacco demand is for manufactured cigarettes (MC) and one-third is for Roll-Your-Own (RYO) tobacco, previous price elasticity estimates have ignored differences between RYO tobacco and MC consumers. METHODS: We employ a seemingly unrelated regression econometric approach applied to quarterly data over the period 1991-2011 to estimate price elasticities of demand separately for MC and RYO tobacco. RESULTS: Estimate of price elasticity of demand for MC is -1.033, and -0.441 for RYO tobacco. RYO tobacco is an inferior good; a 1% increase in average weekly income is associated with a 0.8% reduction in demand. RYO tobacco is a substitute for MC; a 1% increase in the price of MC is associated with a 0.867% increase in demand for RYO tobacco. CONCLUSIONS: There is significantly different price responsiveness across the two tobacco product types. MC smokers react far more strongly to price increases compared with RYO tobacco smokers. These findings suggest that pricing mechanisms may be more effective for reducing MC demand than for RYO tobacco. However, substitution between products means that this pricing effect is muted by the uptake of RYO tobacco use. Cessation policy specific to RYO use should be designed to target this growing group.

Developing good practice for clinical research nurses.

This article outlines the role of clinical research in the UK government's strategy for economic growth and the role of clinical research nurses in that research. The diverse skills and knowledge required by clinical research nurses to support a range of research studies in a number of research environments are described. The development and aim of the UK Clinical Research Facility Network is discussed, with particular focus on the role of the UK Clinical Research Facility Network Education Group in supporting clinical research nurses and research teams to acquire and maintain relevant research skills. The outcomes delivered by the UK Clinical Research Facility Network Education Group are outlined along with ongoing and future work. Recommendations to ensure that the workforce will be skilled appropriately to support future clinical research are provided.

Stability of gut microbiome after COVID-19 vaccination in healthy and immuno-compromised individuals.

Bidirectional interactions between the immune system and the gut microbiota are key contributors to various physiological functions. Immune-associated diseases such as cancer and autoimmunity, and efficacy of immunomodulatory therapies, have been linked to microbiome variation. Although COVID-19 infection has been shown to cause microbial dysbiosis, it remains understudied whether the inflammatory response associated with vaccination also impacts the microbiota. Here, we investigate the temporal impact of COVID-19 vaccination on the gut microbiome in healthy and immuno-compromised individuals; the latter included patients with primary immunodeficiency and cancer patients on immunomodulating therapies. We find that the gut microbiome remained remarkably stable post-vaccination irrespective of diverse immune status, vaccine response, and microbial composition spanned by the cohort. The stability is evident at all evaluated levels including diversity, phylum, species, and functional capacity. Our results indicate the resilience of the gut microbiome to host immune changes triggered by COVID-19 vaccination and suggest minimal, if any, impact on microbiome-mediated processes. These findings encourage vaccine acceptance, particularly when contrasted with the significant microbiome shifts observed during COVID-19 infection.

Age-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade.

Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response. Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator (AIRE). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2. ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination.

Meat insights: Uruguayan consumers´ mental associations and motives underlying consumption changes.

A telephone survey (n = 601) was conducted in Uruguay to explore participants' mental associations with meat and the underlying reasons changes in the quantity and type of meat consumed. Participants mentioned mostly positive associations with meat's culinary and cultural aspects and its nutritional value as source of high-quality protein. Other associations were related to meat production, specific types of meat and cuts, meat consumption and pleasure, while price was perceived negatively. Animal welfare concerns emerged as a relevant association, but minor references were made to the effects of meat production on the environment. Changes in the amount and type of meat consumed (higher pork, chicken and cheaper cuts and beef) in the last year were mainly due to price followed by health reasons. Results emphasize the strong meat culture among Uruguayans and reveal that changes in the amount and type of meat consumed last year relate to external (price) or egoistic (health) rather than altruistic motives (ethical or environmental concerns).

A Randomized, Crossover Study of the Acute Cognitive and Cerebral Blood Flow Effects of Phenolic, Nitrate and Botanical Beverages in Young, Healthy Humans.

BACKGROUND: In whole foods, polyphenols exist alongside a wide array of other potentially bioactive phytochemicals. Yet, investigations of the effects of combinations of polyphenols with other phytochemicals are limited. OBJECTIVE: The current study investigated the effects of combining extracts of beetroot, ginseng and sage with phenolic-rich apple, blueberry and coffee berry extracts. DESIGN: This randomized, double-blind, placebo-controlled crossover design investigated three active beverages in 32 healthy adults aged 18-49 years. Each investigational beverage comprised extracts of beetroot, ginseng and sage. Each also contained a phenolic-rich extract derived from apple (containing 234 mg flavanols), blueberry (300 mg anthocyanins) or coffee berry (440 mg chlorogenic acid). Cognition, mood and CBF parameters were assessed at baseline and then again at 60, 180 and 360 min post-drink. RESULTS: Robust effects on mood and CBF were seen for the apple and coffee berry beverages, with increased subjective energetic arousal and hemodynamic responses being observed. Fewer effects were seen with the blueberry extract beverage. CONCLUSIONS: Either the combination of beetroot, ginseng and sage was enhanced by the synergistic addition of the apple and coffee berry extract (and to a lesser extent the blueberry extract) or the former two phenolic-rich extracts were capable of evincing the robust mood and CBF effects alone.

'A group of totally awesome people who do stuff' - a qualitative descriptive study of a children and young people's patient and public involvement endeavour.

BACKGROUND: In 2013, the Cambridge Clinical Research Facility (CCRF) set up a Children's Non-Executive Research Board to advise on service and facility development and research involving children and young people (CYP). In 2015, the Children's Experiences of Engaging in Research study (CHEER) was conceived to explore the Children's Board as a patient and public involvement initiative. AIM: To explore the views of CYP, staff and parents involved in the Children's Board with the view to describe their experiences of the selected mechanism of involvement (Children's Board) within the context of operation (CCRF). METHODS: A qualitative descriptive methodology involving qualitative content analysis of semi-structured interviews was used to derive descriptive summaries of the interview data. SETTING AND PARTICIPANTS: Interviews were carried out with staff (n = 5), children (n = 2) and parents (n = 2) who participated in the first or second Children's Board meetings. RESULTS: Twelve descriptive summaries emerged: (1) CCRF 'role' perspective (2) purpose, remit and future direction (3) aspirations (4) learning as reciprocation (5) regular meetings, contact and feedback (6) expectation setting and ground rules (7) culture of PPI (8) surprise, underestimation and self-selection (9) reciprocity, incentivisation and participation (10) practicalities, timing and barriers (11) parental roles (12) event structure. These highlighted the importance of selecting the right mechanism of involvement in relation to context for involvement and the reductive biases adults and healthcare providers may unconsciously hold. Both of these aspects may affect the efficacy of PPI endeavours with CYP. DISCUSSION AND CONCLUSIONS: Mechanisms by which CYP are involved in research should be considered from the outset; taking into consideration both the setting and contextual features. Contextual and process factors important in the adult PPI realm were generally observed in this PPI initiative with CYP; however further research is required to explore unconscious biases and reductive perceptions in adult facilitators.

Urine collection in infants and children.

June Rogers and Caroline Saunders review current evidence and best practice regarding obtaining a urine specimen from children.

High-flavonoid intake induces cognitive improvements linked to changes in serum brain-derived neurotrophic factor: Two randomised, controlled trials.

BACKGROUND: Recent clinical studies have indicated the beneficial impact of dietary flavonoid intake on human cognitive performance. Although the mechanisms that mediate such improvements are currently unclear, animal and human trial data suggest that changes in neurotrophin expression, and related signalling apparatus, may be involved. OBJECTIVE: To investigate the link between changes in serum brain-derived neurotrophic factor (BDNF) and changes in human cognitive performance following flavonoid intake. METHODS: The relationship between serum levels of BDNF and age, gender, BMI, waist circumference, blood pressure and cognition at baseline, and following flavonoid intake, was investigated in two distinct randomised, controlled clinical trials. Trial 1 was conducted in men and women (aged 26-70 y; consuming an average of 3 portions of fruit and vegetables per day) and delivered high-flavonoid (>15 mg/100 g) or low-flavonoid (<5 mg/100 g) fruit and vegetables and increased intake by 2 portions every 6 weeks. The control arm was habitual diet over the same time frame. Trial 2 was conducted in an older males and female cohort (aged 62-75 y) intervening with a high-flavanol cocoa drink (494 mg total flavanols) and a low-flavanol cocoa drink (23 mg total flavanols) for 12 weeks. RESULTS: Serum BDNF levels increased linearly to the age of 65, after which BDNF levels were found to decrease markedly. All other physiological and anthropometric measurements proved to not be significantly associated with serum BDNF levels (p > 0.05), although higher levels in males compared to females almost achieved significance (p = 0.056). At baseline, higher serum BDNF levels were associated with significantly better global cognition scores, relative to individuals with lower serum levels. In addition, following intervention for 18 weeks, high-flavonoid, but not low-flavonoid, fruit and vegetable intake induced significant improvements in cognitive performance and increases in serum BDNF levels (p = <0.001). Flavanol intervention for 12 weeks also resulted in significant increases in serum BDNF (p = <0.001), and such increases were correlated with improvements in global cognitive performance. CONCLUSION: Increases in global cognition induced by high flavonoid fruit and vegetables, and cocoa flavanols were paralleled by concurrent changes in serum BDNF levels, suggesting a role for BDNF in flavonoid-induced cognitive improvements. Furthermore, we provide further data suggesting that serum BDNF levels may represent a biomarker of cognitive function.