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Background: ANDHI was done to assess the efficacy of benralizumab, including onset of effect and impact on health-related quality of life (HRQOL), exacerbation rate, lung function, and nasal polyposis symptoms. Methods: This phase 3b, randomised, double-blind, parallel-group, placebo-controlled ANDHI study was completed in adults (aged 18–75 years) with severe eosinophilic asthma with at least 2 exacerbations in the previous year, despite high-dose inhaled corticosteroid plus additional controllers, screening blood eosinophil counts of at least 150 cells per μL, and an Asthma Control Questionnaire 6 (ACQ-6) score of 1·5 or more. Patients who met eligibility criteria were randomly assigned (2:1; stratified by previous exacerbation count [two, or three or more], maintenance oral corticosteroid use, and region), using an integrated web-based response system, to receive benralizumab at 30 mg every 8 weeks (first three doses given 4 weeks apart) or matched placebo for 24 weeks. Primary efficacy measure was annualised asthma exacerbation rate, with rate ratio (RR) calculated over the approximate 24-week follow-up. Secondary efficacy measures included change from baseline to end of treatment (week 24) in St George's Respiratory Questionnaire (SGRQ) total score (key secondary endpoint), FEV1, peak expiratory flow (PEF), ACQ-6, Predominant Symptom and Impairment Assessment (PSIA), Clinician Global Impression of Change (CGI-C), Patient Global Impression of Change (PGI-C), and Sino-Nasal Outcome Test-22 (SNOT-22). All efficacy analyses, except for SNOT-22, were summarised and analysed using the full analysis set on an intention-to-treat population (all randomly assigned patients receiving investigational product, regardless of protocol adherence or continued participation in the study). SNOT-22 was summarised for the subgroup of patients with physician-diagnosed nasal polyposis with informed consent. This study is registered with ClinicalTrials.gov, NCT03170271. Findings: Between July 7, 2017, and Sept 25, 2019, 656 patients received benralizumab (n=427) or placebo (n=229). Baseline characteristics were consistent with severe eosinophilic asthma. Benralizumab significantly reduced exacerbation risk by 49% compared with placebo (RR estimate 0·51, 95% CI 0·39–0·65; p5%) were nasopharyngitis (30 [7%]), headache (37 [9%]), sinusitis (28 [7%]), bronchitis (22 [5%]), and pyrexia (26 [6%]). Fewer serious adverse events were reported for benralizumab (23 [5%]) versus placebo (25 [11%]), and the only common serious adverse event (experienced by >1% of patients) was worsening of asthma, which was reported for nine (2%) patients in the benralizumab group and nine (4%) patients in the placebo group. Interpretation: Our results extend the efficacy profile of benralizumab for patients with severe eosinophilic asthma, showing early clinical benefits in patient-reported outcomes, HRQOL, lung function, and nasal polyposis symptoms. Funding: AstraZeneca.

This experimental study evaluated the differential effects of ‘giving’ and ‘receiving’ massage on wellbeing in healthy but stressed couples. Forty-two volunteers started the study and of these, 38 (i.e. 19 couples) completed a 3-week massage course. Emotional stress and mental clarity were assessed before and after mutual massage between each pair of adults belonging to a couple at home. While massage benefitted both parties’ wellbeing within a session, critically we found no differences in wellbeing between those ‘giving’ and ‘receiving’ massage. These novel findings suggest that home-based massage may be advocated to couples as a ‘selves-care’, health-promoting behaviour.

Background The internet continues to offer new forms of support for health decision making. Government, charity, and commercial websites increasingly offer a platform for shared personal health experiences, and these are just some of the opportunities that have arisen in a largely unregulated arena. Understanding how people trust and act on this information has always been an important issue and remains so, particularly as the design practices of health websites continue to evolve and raise further concerns regarding their trustworthiness. Objective The aim of this study was to identify the key factors influencing US and UK citizens’ trust and intention to act on advice found on health websites and to understand the role of patient experiences. Methods A total of 1123 users took part in an online survey (625 from the United States and 498 from the United Kingdom). They were asked to recall their previous visit to a health website. The online survey consisted of an updated general Web trust questionnaire to account for personal experiences plus questions assessing key factors associated with trust in health websites (information corroboration and coping perception) and intention to act. We performed principal component analysis (PCA), then explored the relationship between the factor structure and outcomes by testing the fit to the sampled data using structural equation modeling (SEM). We also explored the model fit across US and UK populations. Results PCA of the general Web trust questionnaire revealed 4 trust factors: (1) personal experiences, (2) credibility and impartiality, (3) privacy, and (4) familiarity. In the final SEM model, trust was found to have a significant direct effect on intention to act (beta=.59; P Conclusions Credibility and impartiality continue to be key predictors of trust in eHealth websites. Websites with patient experiences can positively influence trust but only if users first corroborate the information through other sources. The need for corroboration was weaker in the United Kingdom, where website familiarity reduced the need to check information elsewhere. These findings are discussed in relation to existing trust models, patient experiences, and health literacy.

Benralizumab is an interleukin-5 receptor α-directed cytolytic monoclonal antibody that has been shown to safely reduce exacerbations and improve lung function for patients with asthma. We assessed the long-term safety and efficacy of benralizumab for patients with severe, uncontrolled eosinophilic asthma.We conducted a randomised, double-blind, parallel-group, phase 3 extension study at 447 sites in 24 countries. Eligible patients had to have completed the SIROCCO or CALIMA trials and remained on subcutaneous benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W). Patients who had received placebo in those trials were re-randomised in a 1:1 ratio, using an interactive web-based system, to benralizumab 30 mg either Q4W or Q8W (first three doses 4 weeks apart). Treatment lasted for 56 weeks for adult patients (age ≥18 years) and 108 weeks for adolescent patients (age 12-17 years). The primary endpoint was the safety and tolerability of the two dosing regimens of benralizumab up to 68 weeks for adult patients (including the follow-up visit post-treatment) and up to 56 weeks for adolescent patients. This endpoint was assessed in the full analysis set, which included all patients from the SIROCCO and CALIMA predecessor studies who received at least one dose of study treatment in BORA and did not continue into another trial. This study is registered with ClinicalTrials.gov (NCT02258542).Between Nov 19, 2014, and July 6, 2016, we enrolled 1926 patients, of whom 633 had received benralizumab Q4W and 639 had received benralizumab Q8W in SIROCCO or CALIMA. The remaining 654 patients had received placebo in those trials and were randomly re-assigned in this trial to receive benralizumab Q4W (n=320) or Q8W (n=334). 1576 patients, including 783 who received benralizumab Q4W (265 newly assigned) and 793 who received benralizumab Q8W (281 newly assigned), were included in the full analysis set. The most common adverse events in all groups were viral upper respiratory tract infection (14-16%) and worsening asthma (7-10%). The most common serious adverse events were worsening asthma (3-4%), pneumonia (1% to 1%), and pneumonia caused by bacterial infection (0-1%). The percentages of patients who had any on-treatment adverse event, any serious adverse event, or any adverse event leading to treatment discontinuation during BORA were similar between patients originally assigned benralizumab and those originally assigned placebo and between benralizumab treatment regimens. The percentage of patients who had any adverse event was similar between SIROCCO or CALIMA (71-75%; benralizumab group only) and BORA (65-71%), as was the percentage of patients who had an adverse event that led to treatment discontinuation (2% in SIROCCO and CALIMA vs 2-3% in BORA).The 2 years of safety results validate that observations observed in the first year of benralizumab continued through a second year of treatment. No new consequences of long-term eosinophil depletion occurred, and the incidence of other adverse events, including opportunistic infections, were similar during the second year.AstraZeneca and Kyowa Hakko Kirin.

Background: The use of herbal extracts and supplements to enhance health and wellbeing is increasing in western society. Aims: This study investigated the impact of the acute ingestion of a commercially available water containing an extract and hydrolat of rosemary ( Rosmarinus officinalis L. syn. Salvia rosmarinus Schleid.). Aspects of cognitive functioning, mood and cerebrovascular response measured by near-infrared spectroscopy provided the dependent variables. Methods: Eighty healthy adults were randomly allocated to consume either 250 mL of rosemary water or plain mineral water. They then completed a series of computerised cognitive tasks, followed by subjective measures of alertness and fatigue. Near-infrared spectroscopy monitored levels of total, oxygenated and deoxygenated haemoglobin at baseline and throughout the cognitive testing procedure. Results: Analysis of the data revealed a number of statistically significant, small, beneficial effects of rosemary water on cognition, consistent with those found previously for the inhalation of the aroma of rosemary essential oil. Of particular interest here are the cerebrovascular effects noted for deoxygenated haemoglobin levels during cognitive task performance that were significantly higher in the rosemary water condition. This represents a novel finding in this area, and may indicate a facilitation of oxygen extraction at times of cognitive demand. Conclusion: Taken together the data suggest potential beneficial properties of acute consumption of rosemary water. The findings are discussed in terms of putative metabolic and cholinergic mechanisms.

This study provides further evidence for the impact of the aromas of plant essential oils on aspects of cognition and mood in healthy participants. One hundred and forty-four volunteers were randomly assigned to conditions of ylang-ylang aroma, peppermint aroma, or no aroma control. Cognitive performance was assessed using the Cognitive Drug Research computerized assessment battery, with mood scales completed before and after cognitive testing. The analysis of the data revealed significant differences between conditions on a number of the factors underpinning the tests that constitute the battery. Peppermint was found to enhance memory whereas ylang-ylang impaired it, and lengthened processing speed. In terms of subjective mood peppermint increased alertness and ylang-ylang decreased it, but significantly increased calmness. These results provide support for the contention that the aromas of essential oils can produce significant and idiosyncratic effects on both subjective and objective assessments of aspects of human behavior. They are discussed with reference to possible pharmacological and psychological modes of influence.

Objectives To compare the effects of nitrous oxide and midazolam on cognition and mood. Design A three-way, counterbalanced, cross-over study, using patients receiving conscious sedation for routine dental treatment. Methods On each of three separate visits, patients performed a computerised test battery to determine baseline cognitive performance. Then, following administration of either midazolam, nitrous oxide, or no drug, patients re-performed the test battery. Finally, patients completed visual analogue scales assessing their subjective mood state. Results Relative to baseline performance, midazolam administration produced significantly slower reaction times compared with nitrous oxide and no-drug conditions. Furthermore, patients receiving midazolam were impaired in accuracy relative to the other conditions on many of the cognitive tasks, particularly those assessing the recall of information. Patient performance in nitrous oxide and control conditions did not significantly differ. These results could not be explained by differences in mood between the conditions, as subjective mood ratings during midazolam or nitrous oxide administration were very similar. Conclusions It is important for clinicians to be aware that peri-operative recall of information is reduced in patients who have undergone midazolam sedation. This is an advantage for patients who are anxious, and do not wish to be aware of the operative treatment being performed. However, as the cognitive impairment is enduring, an adult escort and written post-operative instructions should be mandatory for midazolam sedation patients. In contrast, the use of nitrous oxide sedation does not significantly impair higher cognitive tasks and thus patients receiving nitrous oxide sedation can resume normal activities in the post-operative period.

It was recently established that supplemental oxygen administration significantly enhances memory formation in healthy young adults. In the present study, a double-blind, placebo-controled design was employed to assess the cognitive and physiological effects of subjects' inspiration of oxygen or air (control) prior to undergoing simple memory and reaction-time tasks. Arterial blood oxygen saturation and heart rate were monitored during each of six phases of the experiment, corresponding to baseline, gas inhalation, word presentation, reaction time, distractor and word recall, respectively. The results confirm that oxygen administration significantly enhances cognitive performance above that seen in the air inhalation condition. Subjects who received oxygen recalled more words and had faster reaction times. Moreover, compared to participants who inhaled air, they exhibited significant hyperoxia during gas administration, word presentation, and the reaction-time task, but not at other phases of the experiment. Compared to baseline, heart rate was significantly elevated during the word presentation, reaction-time, and distractor tasks in both the air and oxygen groups. In the oxygen group, significant correlations were found between changes in oxygen saturation and cognitive performance. In the air group, greater changes in heart rate were associated with more improved cognitive performance. These results are discussed in the context of cognitive demand and metabolic supply. It is suggested that under periods of cognitive demand a number of physiological responses are brought into play that serve to increase the delivery of metabolic substrates to active neural tissue. These mechanisms can be supplemented by increased availability of circulating blood oxygen, resulting in an augmentation of cognitive performance. Heart rate reactivity and the capacity for increased blood oxygen appear to be important physiological individual differences mediating these phenomena.

Elevated psychological distress and concomitant dysregulation of the hypothalamic pituitary-adrenal (HPA) axis has been implicated as one pathway that links the stress of caregiving with adverse health outcomes. This study assessed whether perceived social support might mitigate the psychological, endocrine and health consequences of caregiver stress in parents of children with autism and attention deficit hyperactivity disorder (ADHD). Parental caregivers completed measures of psychological distress, perceived availability of social support and physical health complaints. To capture important parameters of the basal diurnal cortisol pattern, caregivers collected salivary cortisol at waking, 30 minutes post waking, 1200h and 2200h on two consecutive weekdays. Psychological distress and self reported physical health complaints were inversely related to scores on all support subscales: tangible, belonging, self esteem and appraisal. Results further revealed a significant, positive association between magnitude of the cortisol awakening response (CAR) and caregivers' self esteem. As a buffer between the stress of caregiving and adverse physical health outcomes, social support acts to reduce stress appraisals and mitigate disturbances of the HPA axis. Moving forward, intervention programmes might seek to increase caregivers' perceived availability of social resources

Research that has assessed the psychophysiological consequences of caregiver stress in young and middle aged caregivers, that is, in populations not contending with age associated decline of the endocrine and immune systems, has been scarce and yielded inconsistent findings. To extend work in this area, this study assessed the psychosocial, endocrine and immune consequences of caregiver stress in a cross sectional sample of young and middle aged caregivers of children with autism and attention deficit hyperactivity disorder (ADHD) compared against parents of typically developing children. Caregivers (n=56) and parent controls (n=22) completed measures of psychological distress (perceived stress, anxiety/depression), social support and physical health complaints. To capture important indices of the diurnal cortisol pattern, cortisol was measured at waking, 30 min post waking, 1200 h and 2200 h on two consecutive weekdays. Venous blood was taken to assess systemic concentrations of proinflammatory biomarkers, interleukin-6 (IL-6) and C-reactive protein (CRP). Caregivers scored markedly higher on all measures of psychological distress; scores on social support subscales, however, were significantly lower in this group. Diurnal patterns of cortisol secretion did not differentiate between the groups; however, caregivers displayed elevated systemic concentrations of the proinflammatory biomarker, CRP and reported more frequent episodes of physical ill health. The stress of caregiving exacts a significant psychophysiological toll, that is, even in the absence of HPA dysregulation, caregivers demonstrated elevated concentrations of proinflammatory biomarkers and, therefore, might be at greater risk for diseases fostered by disinhibition of the inflammatory response.

Background Smokers, previous smokers and a never smoked group were compared on self-reported and real world prospective memory (PM – the cognitive ability of remembering to carry out particular actions at some future point in time). Methods Twenty-seven current smokers, 24 people who had never smoked and 18 previous smokers were compared using an existing groups design. Scores on the long and short term PM subscales of the Prospective and Retrospective Memory Questionnaire (PRMQ) and scores on a Real World Prospective Memory Task (RWPMT) constituted the dependent measures. Smoking and other drug use were assessed by a Recreational Drug Use Questionnaire. The Hospital Anxiety and Depression Scale gauged levels of anxiety and depression. The National Adult Reading Test measured IQ, and retrospective memory was measured using the PRMQ. Gender, age, anxiety and depression, IQ, alcohol use and the retrospective memory scores, were measured as covariates and controlled for in the analysis. Results A series of univariate ANCOVAs were applied to the main PM data across the three groups, controlling for variations in age, gender, mood, IQ, alcohol use and retrospective memory scores. These revealed no significant between-group differences on self-reported PM; however smokers recalled significantly fewer action–location combinations than the never smoked and previous smoker groups on the objective RWPMT. Conclusions Existing smokers showed reduced performance on RWPMT when compared to the never smoked group and previous smokers. Real-world PM impairments should be added to a growing list of neuropsychological sequelae associated with persistent smoking.

This study investigated the potential for the aromas of the essential oils of Salvia species to affect cognition and mood in healthy adults. Research has demonstrated that orally administered Salvia officinalis and Salvia lavandulaefolia are capable of modulating cognition and mood. The active compounds in the herbal products might also be present in the aromas and so produce similar effects. In an independent groups design, three conditions, S. officinalis aroma, S. lavandulaefolia aroma and no aroma were employed. One hundred and thirty-five healthy volunteers acted as participants, with 45 in each condition. Cognitive performance was assessed via the Cognitive Drug Research (CDR) System. Bond-Lader mood scales measured the participants' mood on three dimensions before and after the cognitive tasks. Data analysis revealed that the S. officinalis aroma group performed significantly better than the control group on the quality of memory and secondary memory primary outcome factors from the test battery. The Alert mood measure displayed significant differences between both aromas and the control condition. These findings suggest that the aromas of essential oils of Salvia species reproduce some but not all of the effects found following oral herb administration, and that interesting dissociations occur between subjective and objective responses.

Aims: To examine whether persistent smoking leads to impairments in self-reported and objective measures of prospective memory (PM: the cognitive ability to remember to carry out activities at some future point in time). Methods: An opportunity sample of 18 existing smokers and 22 who had never smoked were compared. An existing-groups design was utilised, comparing a smoking group with a never-smoked control group as the independent factor. Scores on the sub-scales of the Prospective and Retrospective Memory Questionnaire (PRMQ) and scores on the Cambridge Prospective Memory Test (CAMPROMPT) constituted the dependent factors. Age, mood, other drug use, strategy scores and IQ were also measured. Each participant was tested in a laboratory setting. Self-reported PM lapses were measured using the PRMQ. The CAMPROMPT was used as an objective measure of PM. Alcohol and other drug use were assessed by a Recreational Drug Use Questionnaire. The Hospital Anxiety and Depression Scale gauged levels of anxiety and depression. A strategy scale measured the number of strategies used to aid memory. The National Adult Reading Test measured IQ. Results: After observing no between-group differences on age, mood, alcohol use, strategy use, and IQ, smokers and the never-smoked did not differ on the self-reported lapses measured on the PRMQ. However, smokers recalled significantly fewer items on the CAMPROMPT than the never-smoked group. Conclusion: The results of the present study suggest that persistent smoking leads to impairments in everyday PM.

Previous research has revealed that natural and synthetic pheromones can enhance ratings of opposite sex attractiveness. The present study investigated the effects of exposure to male axillary secretions on female ratings of the sexual attractiveness of male stimuli. Thirty-two female undergraduates, half of whom were contraceptive pill users, rated male vignette characters and photographs of male faces on aspects of attractiveness. On two separate study days, corresponding to different phases of their menstrual cycle, stimuli were presented while exposed to male axillary pheromones and under a control condition (no pheromone). The order of testing was balanced with respect to pheromone/control condition and menstrual cycle phase. Pheromone exposure resulted in significantly higher attractiveness ratings of vignette characters and faces. Use of the contraceptive pill or menstrual cycle phase had equivocal effects on some vignette items and neither had any influence on female ratings of male facial attractiveness. The results of this study suggest that exposure to natural male axillary pheromones can significantly enhance female perceptions of various aspects of male attractiveness.

Chronic alcohol abuse has a detrimental effect on retrospective memory. Less is known about its putative effects on everyday memory. This study looked at self-ratings of prospective memory (PM) (memory for future events). After controlling for other drug and strategy use, chronic heavy alcohol users showed global impairments in PM, when compared to matched controls. The underlying mechanisms are discussed.

It was recently demonstrated that oxygen administration can improve performance on a simple word recall task in healthy young adults. This study was aimed at determining the impact of various dura- tions of oxygen administration on a wider range of cog- nitive measures. This was achieved using the Cognitive Drug Research computerised test battery, and employ- ing a double-blind, placebo-controlled crossover design. Over a period of 7 weeks, 20 participants were trained and subsequently assessed on the test battery under several durations of oxygen inhalation; air administered in an identical fashion served as a con- trol. The results provided support for our earlier work in that increases were found in both immediate and delayed word recall. In addition, oxygen administra- tion significantly improved performance on several measures of attention and vigilance. Simple reaction time, choice reaction time, digit vigilance reaction time and picture recognition reaction time were improved in a manner which depended on the duration of oxy- gen inspired. With the exception of word recall, no significant improvements were found for any measure of accuracy, nor were word recognition, digit memory scanning, or spatial memory improved. These results are discussed in the context of stages of information processing and are consistent with the hypothesis that cognitive performance is ifuel-limitedi and can be di⁄erentially augmented by increasing the availability of the brainis metabolic resources.

Despite numerous studies indicating that transient cerebral oxygen depletion has a detrimental effect on cognition, surprisingly little research has examined the possibility of cognitive enhancement following elevated oxygen levels in healthy adults. Here, we present evidence demonstrating that oxygen administration improves memory formation. Inhalation of oxygen immediately prior to learning a word list resulted in a significant increase in mean number of words recalled 10 min later, compared to subjects who inhaled oxygen immediately prior to recall or to controls who underwent no intervention. In a second experiment, the learning-test interval was increased to 24 h and, again, only pre-learning (but not pre-test) oxygen administration resulted in significant memory facilitation. In experiment 3, inhalation of oxygen prior to learning was compared to inhalation of compressed air, oxygen (but not compressed air) resulted in a significant increase in word recall 24 h later. In no experiment did oxygen have a significant effect on any mood item measured. We interpret these data as indicating that increased availability of cerebral oxygen facilitates cognition, including memory consolidation. The implications for the psychopharmacology of cognitive enhancement are considered in the context of cholinergic systems and neural metabolism.

Objectives To assess the possible effects of flumazenil on cognitive processing, physiology, and mood. Design A double-blind, placebo controlled, four-way cross-over study, using healthy volunteers. Methods On each of 4 separate visits, 16 participants received 0.5mg, 2.5mg, 5.0mg of flumazenil, or normal saline. They then performed a computerised test battery assessing cognitive function. Measures of pulse rate, arterial oxygen saturation and mean arterial pressure were also taken. Finally, participants completed visual analogue scales assessing their subjective mood state. Results The majority of cognitive tasks showed dose-dependent declines in performance. Mean arterial pressure was significantly reduced, as was pulse rate. Subjective alertness showed a similar decline. Conclusions Flumazenil has been clinically described as an agent with few intrinsic properties, whose primary effect lies in its ability to reverse benzodiazepine-induced states. This study has shown that flumazenil does possess intrinsic activity which have a significant effect on cognition, cardiovascular physiology and mood. Clinicians need to be aware of these effects.