Diurnal variation in anxiety and activity is influenced by chronotype and probable anxiety-related disorder status.

Anxiety symptoms vary moment-to-moment within a day. One factor that may influence these variations is chronotype. Evening chronotypes prefer to engage in activities (e.g., sleep, physical and social activity) later in the day, and evening chronotype is implicated in psychopathology, including anxiety-related disorders. However, it is unknown whether chronotype influences diurnal variation in anxiety symptoms and whether these effects are amplified in individuals with a probable anxiety-related disorder. We examined the diurnal variation in anxiety symptoms and daily activities in morning and evening chronotypes with and without probable generalized anxiety disorder (GAD) or obsessive-compulsive disorder (OCD) in a community sample of adults (N = 410). Evening chronotypes reported higher anxiety symptoms, particularly in the evening hours, and lower engagement in daily activities, predominantly in the morning hours. Evening chronotypes with probable GAD or OCD reported worse anxiety symptoms in the evening. Our findings indicate that anxiety symptoms and engagement in daily activities fluctuate considerably across the day, and these patterns differ depending on chronotype. Evening chronotypes have more anxiety symptoms in the evening, despite preferring this time of day. Personalized treatment approaches that consider chronotype and target certain times of day may be efficient in alleviating peaks in anxiety symptoms.

Fmo induction as a tool to screen for pro-longevity drugs.

Dietary restriction (DR) and hypoxia (low oxygen) extend lifespan in Caenorhabditis elegans through the induction of a convergent downstream longevity gene, fmo-2. Flavin-containing monooxygenases (FMOs) are highly conserved xenobiotic-metabolizing enzymes with a clear role in promoting longevity in nematodes and a plausible similar role in mammals. This makes them an attractive potential target of small molecule drugs to stimulate the health-promoting effects of longevity pathways. Here, we utilize an fmo-2 fluorescent transcriptional reporter in C. elegans to screen a set of 80 compounds previously shown to improve stress resistance in mouse fibroblasts. Our data show that 19 compounds significantly induce fmo-2, and 10 of the compounds induce fmo-2 more than twofold. Interestingly, 9 of the 10 high fmo-2 inducers also extend lifespan in C. elegans. Two of these drugs, mitochondrial respiration chain complex inhibitors, interact with the hypoxia pathway to induce fmo-2, whereas two dopamine receptor type 2 (DRD2) antagonists interact with the DR pathway to induce fmo-2, indicating that dopamine signaling is involved in DR-mediated fmo-2 induction. Together, our data identify nine drugs that each (1) increase stress resistance in mouse fibroblasts, (2) induce fmo-2 in C. elegans, and (3) extend nematode lifespan, some through known longevity pathways. These results define fmo-2 induction as a viable approach to identifying and understanding mechanisms of putative longevity compounds.

A diet of oxidative stress-adapted bacteria improves stress resistance and lifespan in C. elegans via p38-MAPK.

Organisms across taxa face stresses including variable temperature, redox imbalance, and xenobiotics. Successfully responding to stress and restoring homeostasis are crucial for survival. Aging is associated with a decreased stress response and alterations in the microbiome, which contribute to disease development. Animals and their microbiota share their environment; however, microbes have short generation time and can rapidly evolve and potentially affect host physiology during stress. Here, we leverage Caenorhabditis elegans and its simplified bacterial diet to demonstrate how microbial adaptation to oxidative stress affects the host's lifespan and stress response. We find that worms fed stress-evolved bacteria exhibit enhanced stress resistance and an extended lifespan. Through comprehensive genetic and metabolic analysis, we find that iron in stress-evolved bacteria enhances worm stress resistance and lifespan via activation of the mitogen-activated protein kinase pathway. In conclusion, our study provides evidence that understanding microbial stress-mediated adaptations could be used to slow aging and alleviate age-related health decline.

Unravelling influenza correlates of protection: lessons from human A/H1N1 Challenge.

Mucosal immunity is important in protecting from upper respiratory tract influenza infection. Human challenge provides a unique model to define correlates of protection with baseline immune responses being correlated to the quantity and length of viral shedding and clinical outcomes. Here, we discuss recent work on mucosal and systemic correlates of protection (R. Bean, L. T. Giurgea, A. Han, L. Czajkowski, et al., mBio 15:e02372-23, 2024, https://doi.org/10.1128/mbio.02372-23) and place it in the context of previous work on mucosal immunity. We also discuss the importance of standardized assays to allow global comparison of relevant immune responses in defining correlates of protection. Correlates of protection are important for designing next-generation broadly protective influenza vaccines.

Unique and interactive effects of emotion regulation difficulties and perceived stress on COVID-19 traumatic stress, anxiety, and safety behavior use: A four-year prospective study.

Given that emotion regulation difficulties confer risk for poor responses to stress, they may predict who is at risk for adverse psychological reactions to major, chronic stressors such as the COVID-19 pandemic. Specific adverse reactions to the pandemic may include more severe traumatic stress, anxiety, and excessive safety behavior use (i.e., hand washing). While emotion regulation difficulties may be a diathesis for adverse reactions to chronic stressors, the context(s) by which they may confer elevated risk is unclear. Accordingly, the present longitudinal study examined the interaction between pre-pandemic emotion regulation difficulties and early pandemic perceived stress in predicting subsequent COVID-related traumatic stress, anxiety, and safety behavior use over 32 weeks of the pandemic. Community adults (N = 145) who completed a measure of emotion regulation in 2016 as part of a larger study were recontacted at the start of the pandemic (March 2020) and assessed every two weeks for 32 weeks. Consistent with a diathesis-stress model, the interaction between difficulties in emotion regulation and perceived stress was significant in predicting COVID-19 anxiety (p = 0.003, d = 0.52) such that at high, but not low, levels of perceived stress, difficulties in emotion regulation in 2016 significantly predicted higher COVID-19 anxiety in 2020. The interaction between difficulties in emotion regulation in 2016 and perceived stress early in 2020 approached significance in predicting COVID-19 traumatic stress (p = 0.073, d = 0.31) and safety behavior use (p = 0.069, d = 0.31). These findings highlight that current perceived stress is an important context that potentiates the effects of preexisting emotion regulation difficulties on the emergence of anxiety-related symptoms during COVID-19, which has important implications for diathesis-stress models of adverse reactions to chronic stressors.

Symptom trajectories of post-COVID sequelae in patients with acute Delta or Omicron infection in Bergen, Norway.

Introduction: A substantial proportion of the over 700 million COVID-19 cases world-wide experience long-term symptoms. The objectives of this study were to compare symptom trajectories and risk factors for post-COVID-19 condition after Delta and Omicron infection. Methods: This study consecutively recruited patients with SARS-CoV-2 infection from November 2021 to March 2022. We recorded demographics, comorbidities, vaccination status, sick leave, and 18 symptoms during acute infection and after 4 months. The primary outcome measures were symptoms during acute infection and after 4 months. Secondary outcome measures were work and school absenteeism. Results: We followed a cohort of 1,374 non-hospitalized COVID-19 patients in Bergen, Norway, at three time points. The median age was 39.8 years and 11% were children <16 years. Common acute upper respiratory symptoms waned during follow-up. Fatigue remained common from acute infection (40%) until after 4 months (37%). Four months post-infection, patients reported increased frequencies of dyspnea (from 15% during acute illness to 25% at 4 months, p < 0.001), cognitive symptoms (from 9 to 32%, p < 0.001) and depression (from 1 to 17%, p < 0.001). Patients infected with Omicron reported less dyspnea (22% versus 27%, p = 0.046) and smell/taste problems (5% versus 19%, p < 0.001) at 4 months follow-up than those with Delta infection. Comorbidities and female sex were risk factors for persistent dyspnea and cognitive symptoms. Ten percent reported sick leave after acute illness, and vaccination reduced the risk of absenteeism (adjusted risk ratio: 0.36, 95% confidence interval: 0.15, 0.72, p = 0.008). Conclusion: At 4 months, home-isolated patients infected with Omicron reported overall comparable symptom burden, but less dyspnea and smell/taste problems than Delta infected patients. Several acute symptoms waned during follow-up. It is worrying that dyspnea, neurocognitive symptoms, and particularly depression, increased significantly during the first 4 months after acute infection. Previous vaccination was protective against prolonged sick leave.

Regulatory workshop on challenge strain development and GMP manufacture - A stakeholder meeting report.

Within the Innovative Health Initiative (IHI) Inno4Vac CHIMICHURRI project, a regulatory workshop was organised on the development and manufacture of challenge agent strains for Controlled Human Infection Model (CHIM) studies. Developers are often uncertain about which GMP requirements or regulatory guidelines apply but should be guided by the 2022 technical white paper "Considerations on the Principles of Development and Manufacturing Qualities of Challenge Agents for Use in Human Infection Models" (published by hVIVO, Wellcome Trust, HIC-Vac consortium members). Where those recommendations cannot be met, regulators advise following the "Principles of GMP" until definitive guidelines are available. Sourcing wild-type virus isolates is a significant challenge for developers. Still, it is preferred over reverse genetics challenge strains for several reasons, including implications and regulations around genetically modified organisms (GMOs). Official informed consent guidelines for collecting isolates are needed, and the characterisation of these isolates still presents risks and uncertainty. Workshop topics included ethics, liability, standardised clinical endpoints, selection criteria, sharing of challenge agents, and addressing population heterogeneity concerning vaccine response and clinical course. The organisers are confident that the workshop discussions will contribute to advancing ethical, safe, and high-quality CHIM studies of influenza, RSV and C. difficile, including adequate regulatory frameworks.

Impact of ageing on homologous and human-coronavirus-reactive antibodies after SARS-CoV-2 vaccination or infection.

The endemic human coronaviruses (HCoVs) circulate worldwide yet remain understudied and unmitigated. The observation of elevated levels of HCoV reactive antibodies in COVID-19 patients highlights the urgent necessity of better understanding of HCoV specific immunity. Here, we characterized in-depth the de novo SARS-CoV-2 specific antibody responses and the boosting of HCoV-reactive antibodies after SARS-CoV-2 vaccination or infection in individuals up to 98 years old. All the vaccinees were home-dwelling with no documented SARS-CoV-2 infection before receiving the COVID-19 mRNA vaccine (BNT162b2). The first two vaccine doses elicited potent SARS-CoV-2 spike binding antibodies in individuals up to 80 years. The third dose largely boosted the previously low S2 domain binding and neutralizing antibodies in elderly 80-90 years old, but less so in those above 90 years. The endemic betacoronavirus (HKU1 and OC43) reactive antibodies were boosted in all vaccinees, although to a lesser extent in those above 80 years old. COVID-19 patients had potent elevation of alpha- and betacoronavirus (229E, NL63, HKU1 and OC43) reactive antibodies. In both patients and vaccinees, S2 domain specific antibody increases correlated with SARS-CoV-2 neutralizing and HCoV-reactive antibody responses in all ages, indicating S2 domain as a candidate for future universal coronavirus vaccine design.

Chronotype and Affective Response to Sleep Restriction and Subsequent Sleep Deprivation.

Prior research indicates that sleep restriction, sleep deprivation, and circadian misalignment diminish positive affect, whereas effects on negative affect are inconsistent. One potential factor that may influence an individual's affective response to sleep restriction, sleep deprivation, and circadian misalignment is chronotype. Later chronotypes generally report higher negative affect and lower positive affect under typical sleep conditions; however, there is mixed evidence for an influence of chronotype on affective responses to sleep restriction and sleep deprivation. The present study examined the effect of chronotype on positive and negative affect during sleep restriction and subsequent total sleep deprivation. Sixteen healthy adults (Mage = 28.2 years, SDage = 11.6 years) were classified as earlier or later chronotypes using multiple chronotype definitions: morningness-eveningness (MEQ), mid-sleep on free days corrected (MSFsc), habitual mid-sleep timing, dim light melatonin onset (DLMO), and phase relationship between DLMO and bedtime. Participants completed a 10-day protocol with one night of sleep restriction and subsequent 28 h total sleep deprivation. Affect was assessed hourly during scheduled wakefulness with the Positive and Negative Affect Schedule (PANAS). Data were analyzed with mixed-model analyses of variance (ANOVAs). During sleep restriction and subsequent sleep deprivation, positive affect decreased and negative affect increased. Across all chronotype measures, relatively later chronotypes demonstrated vulnerability to increased negative affect during sleep loss. The influence of chronotype on positive affect during sleep loss varied by chronotype measure. These findings suggest later chronotypes are more vulnerable to affective impairments during sleep loss and circadian misalignment, even when late chronotype is not extreme.

Optical Coherence Tomography-Derived Measurements of the Optic Nerve Head Structure of Aboriginal and Torres Strait Islander Children.

PRCIS: This study demonstrated significant differences in optic nerve head characteristics in Aboriginal and Torres Strait Islander children compared with non-Indigenous children, which has implications for glaucoma risk and diagnosis in Aboriginal and Torres Strait Islander populations. PURPOSE: The purpose of this study was to examine the optic nerve head (ONH) characteristics of visually normal Aboriginal and Torres Strait Islander children and non-Indigenous Australian children. MATERIALS AND METHODS: Spectral domain optical coherence tomography imaging was performed on the right eye of 95 Aboriginal and Torres Strait Islander children and 149 non-Indigenous Australian children (5-18 years). Horizontal and vertical line scans, centered on the ONH, were analyzed to determine the dimensions of the ONH (Bruch membrane opening diameter), optic cup diameter, Bruch membrane opening minimum rim width, and the peripapillary retinal nerve fiber layer thickness. RESULTS: The vertical but not horizontal Bruch membrane opening diameter of Aboriginal and Torres Strait Islander children was significantly larger than non-Indigenous children (mean difference: 0.09 mm, P = 0.001). The horizontal (mean difference: 0.12 mm, P = 0.003) and vertical cup diameter (mean difference: 0.16 mm, P < 0.001) were also significantly larger in Aboriginal and Torres Strait Islander children, as were the horizontal and vertical cup-to-disc ratios (both P < 0.01). Aboriginal and Torres Strait Islander children also had a significantly thinner Bruch membrane opening minimum rim width in the superior, nasal, and temporal meridians (all P < 0.001). Peripapillary retinal nerve fiber layer thickness did not differ between groups. CONCLUSIONS: Differences exist in the ONH structure between Aboriginal and Torres Strait Islander children and non-Indigenous children, which may have implications for the detection and monitoring of ocular disease in this population and highlights the need to extend this research to the adult population.

Distribution of dim light melatonin offset (DLMOff) and phase relationship to waketime in healthy adults and associations with chronotype.

OBJECTIVES: Dim light melatonin onset, or the rise in melatonin levels representing the beginning of the biological night, is the gold standard indicator of circadian phase. Considerably less is known about dim light melatonin offset, or the decrease in melatonin to low daytime levels representing the end of the biological night. In the context of insufficient sleep, morning circadian misalignment, or energy intake after waketime but before dim light melatonin offset, is linked to impaired insulin sensitivity, suggesting the need to characterize dim light melatonin offset and identify risk for morning circadian misalignment. METHODS: We examined the distributions of dim light melatonin offset clock hour and the phase relationship between dim light melatonin offset and waketime, and associations between dim light melatonin offset, phase relationship, and chronotype in healthy adults (N = 62) who completed baseline protocols measuring components of the circadian melatonin rhythm and chronotype. RESULTS: 74.4% demonstrated dim light melatonin offset after waketime, indicating most healthy adults wake up before the end of biological night. Later chronotype (morningness-eveningness, mid-sleep on free days corrected, and average mid-sleep) was associated with later dim light melatonin offset clock hour. Later chronotype was also associated with a larger, positive phase relationship between dim light melatonin offset and waketime, except for morningness-eveningness. CONCLUSIONS: These findings suggest morning circadian misalignment risk among healthy adults, which would not be detected if only dim light melatonin onset were assessed. Chronotype measured by sleep timing may better predict this risk in healthy adults keeping a consistent sleep schedule than morningness-eveningness preferences. Additional research is needed to develop circadian biomarkers to predict dim light melatonin offset and evaluate appropriate dim light melatonin offset timing to promote health.

Hyperopia in schoolchildren: Investigating the impact on vision and determining appropriate methods for screening.

INTRODUCTION: Hyperopia is associated with reduced vision and educational outcomes in schoolchildren. This study explored the impact of clinically significant hyperopia (≥+2.00 D) on visual function in schoolchildren and compared the ability of different screening tests (alone and in combination) to detect this level of hyperopia. METHODS: Vision testing including monocular logMAR visual acuity (VA) measured to threshold (distance [DVA], near [NVA] and DVA through a plus lens [+2.50 D]), stereoacuity and cycloplegic autorefraction (tropicamide 1%) were undertaken on 263 schoolchildren (mean age: 11.76 years ± 3.38) in Queensland, Australia. Vision measures were compared between children with clinically significant hyperopia in at least one meridian (≥+2.00 D) and emmetropia/low hyperopia (>0.00 and <+2.00 D). Receiver operating curve (ROC) analysis was performed to identify optimal pass/fail criteria for each test and the diagnostic accuracy of individual and combinations of tests. RESULTS: Thirty-two children had clinically significant hyperopia and 225 had emmetropia/low hyperopia. DVA and NVA were worse (p < 0.01), while the difference in DVA through a plus lens was less in children with clinically significant hyperopia (p < 0.01). ROC analysis for individual tests resulted in areas under the curve (AUCs) ranging from 0.65 to 0.85. Combining screening tests revealed that failing one or more of the following tests was most effective for detecting hyperopia: DVA, NVA and difference in DVA through a plus lens, resulting in a sensitivity and specificity of 72% and 81%, respectively. CONCLUSION: Significant differences in visual function existed between schoolchildren with clinically significant hyperopia and emmetropia/low hyperopia. Combining measures of DVA and NVA and the difference in DVA through a plus lens demonstrated good discriminative ability for detecting clinically significant hyperopia in this population.

The Challenges of Vaccine Trial Participation among Underserved and Hard-to-Reach Communities: An Internal Expert Consultation of the VACCELERATE Consortium.

Underserved and hard-to-reach population groups are under-represented in vaccine trials. Thus, we aimed to identify the challenges of vaccine trial participation of these groups in member countries of the VACCELERATE network. Seventeen National Coordinators (NC), each representing their respective country (15 European countries, Israel, and Turkey), completed an online survey. From 15 eligible groups, those that were more frequently declared underserved/hard-to-reach in vaccine research were ethnic minorities (76.5%), persons experiencing homelessness (70.6%), illegal workers and refugees (64.7%, each). When prioritization for education on vaccine trials was considered, ethnic groups, migrants, and immigrants (5/17, 29.4%) were the groups most frequently identified by the NC as top targets. The most prominent barriers in vaccine trial participation affecting all groups were low levels of health literacy, reluctance to participate in trials due to engagement level, and low levels of trust in vaccines/vaccinations. This study highlighted population groups considered underserved/hard-to-reach in countries contained within the European region, and the respective barriers these groups face when participating in clinical studies. Our findings aid with the design of tailored interventions (within-and across-countries of the European region) and with the development of strategies to overcome major barriers in phase 2 and phase 3 vaccine trial participation.

Distinct receptor binding domain IgG thresholds predict protective host immunity across SARS-CoV-2 variants and time.

SARS-CoV-2 neutralising antibodies provide protection against COVID-19. Evidence from early vaccine trials suggested binding antibody thresholds could serve as surrogate markers of neutralising capacity, but whether these thresholds predict sufficient neutralising capacity against variants of concern (VOCs), and whether this is impacted by vaccine or infection history remains unclear. Here we analyse individuals recovered from, vaccinated or with hybrid immunity against SARS-CoV-2. An NT50 ≥ 100 IU confers protection in vaccine trials, however, as VOC induce a reduction in NT50, we use NT50 ≥ 1000 IU as a cut off for WT NT50 that would retain neutralisation against VOC. In unvaccinated convalescent participants, a receptor binding domain (RBD) IgG of 456 BAU/mL predicts an NT50 against WT of 1000 IU with an accuracy of 80% (95%CI 73-86%). This threshold maintains accuracy in determining loss of protective immunity against VOC in two vaccinated cohorts. It predicts an NT50 < 100 IU against Beta with an accuracy of 80% (95%CI 67-89%) in 2 vaccine dose recipients. In booster vaccine recipients with a history of COVID-19 (hybrid immunity), accuracy is 87% (95%CI 77-94%) in determining an NT50 of <100 IU against BA.5. This analysis provides a discrete threshold that could be used in future clinical studies.

Proficiency tests to evaluate the impact on assay outcomes of harmonized influenza-specific Intracellular Cytokine Staining (ICS) and IFN-É£ Enzyme-Linked ImmunoSpot (ELISpot) protocols.

The magnitude and quality of cell-mediated immune responses elicited by natural infection or vaccination are commonly measured by Interferon-É£ (IFN-É£) Enzyme-Linked ImmunoSpot (ELISpot) and Intracellular Cytokine Staining (ICS). To date, laboratories apply a variety of in-house procedures which leads to diverging results, complicates interlaboratory comparisons and hampers vaccine evaluations. During the FLUCOP project, efforts have been made to develop harmonized Standard Operating Procedures (SOPs) for influenza-specific IFN-É£ ELISpot and ICS assays. Exploratory pilot studies provided information about the interlaboratory variation before harmonization efforts were initiated. Here we report the results of two proficiency tests organized to evaluate the impact of the harmonization effort on assay results and the performance of participating FLUCOP partners. The introduction of the IFN-É£ ELISpot SOP reduced variation of both background and stimulated responses. Post-harmonization background responses were all lower than an arbitrary threshold of 50 SFU/million cells. When stimulated with A/California and B/Phuket, a statistically significant reduction in variation (p < 0.0001) was observed and CV values were strongly reduced, from 148% to 77% for A/California and from 126% to 73% for B/Phuket. The harmonizing effect of applying an ICS SOP was also confirmed by an increased homogeneity of data obtained by the individual labs. The application of acceptance criteria on cell viability and background responses further enhanced the data homogeneity. Finally, as the same set of samples was analyzed by both the IFN-É£ ELISpot and the ICS assays, a method comparison was performed. A clear correlation between the two methods was observed, but they cannot be considered interchangeable. In conclusion, proficiency tests show that a limited harmonization effort consisting of the introduction of SOPs and the use of the same in vitro stimulating antigens leads to a reduction of the interlaboratory variation of IFN-É£ ELISpot data and demonstrate that substantial improvements for the ICS assay are achieved as comparable laboratory datasets could be generated. Additional steps to further reduce the interlaboratory variation of ICS data can consist of standardized gating templates and detailed data reporting instructions as well as further efforts to harmonize reagent and instrument use.

SARS-CoV-2 specific immune responses in overweight and obese COVID-19 patients.

Obesity is a known risk factor for severe respiratory tract infections. In this prospective study, we assessed the impact of being obese or overweight on longitudinal SARS-CoV-2 humoral and cellular responses up to 18 months after infection. 274 patients provided blood samples at regular time intervals up to 18 months including obese (BMI ≥30, n=32), overweight (BMI 25-29.9, n=103) and normal body weight (BMI 18.5-24.9, n=134) SARS-CoV-2 patients. We determined SARS-CoV-2 spike-specific IgG, IgA, IgM levels by ELISA and neutralising antibody titres by neutralisation assay. RBD- and spike-specific memory B cells were investigated by ELISpot, spike- and non-spike-specific IFN-γ, IL-2 and IFN-γ/IL-2 secreting T cells by FluoroSpot and T cell receptor (TCR) sequencing was performed. Higher BMI correlated with increased COVID-19 severity. Humoral and cellular responses were stronger in overweight and obese patients than normal weight patients and associated with higher spike-specific IgG binding titres relative to neutralising antibody titres. Linear regression models demonstrated that BMI, age and COVID-19 severity correlated independently with higher SARS-CoV-2 immune responses. We found an increased proportion of unique SARS-CoV-2 specific T cell clonotypes after infection in overweight and obese patients. COVID-19 vaccination boosted humoral and cellular responses irrespective of BMI, although stronger immune boosting was observed in normal weight patients. Overall, our results highlight more severe disease and an over-reactivity of the immune system in overweight and obese patients after SARS-CoV-2 infection, underscoring the importance of recognizing overweight/obese individuals as a risk group for prioritisation for COVID-19 vaccination.

Prolonging the delivery of influenza virus vaccine improves the quantity and quality of the induced immune responses in mice.

Introduction: Influenza vaccines play a vital role in protecting individuals from influenza virus infection and severe illness. However, current influenza vaccines have suboptimal efficacy, which is further reduced in cases where the vaccine strains do not match the circulating strains. One strategy to enhance the efficacy of influenza vaccines is by extended antigen delivery, thereby mimicking the antigen kinetics of a natural infection. Prolonging antigen availability was shown to quantitatively enhance influenza virus-specific immune responses but how it affects the quality of the induced immune response is unknown. Therefore, the current study aimed to investigate whether prolongation of the delivery of influenza vaccine improves the quality of the induced immune responses over that induced by prime-boost immunization. Methods: Mice were given daily doses of whole inactivated influenza virus vaccine for periods of 14, 21, or 28 days; the control group received prime-boost immunization with a 28 days interval. Results: Our data show that the highest levels of cellular and humoral immune responses were induced by 28 days of extended antigen delivery, followed by 21, and 14 days of delivery, and prime-boost immunization. Moreover, prolonging vaccine delivery also improved the quality of the induced antibody response, as indicated by higher level of high avidity antibodies, a balanced IgG subclass profile, and a higher level of cross-reactive antibodies. Conclusions: Our findings contribute to a better understanding of the immune response to influenza vaccination and have important implications for the design and development of future slow-release influenza vaccines.

Psychometric properties of a daily obsessive-compulsive symptom scale for ecological momentary assessment.

Despite growing interest in ecological momentary assessment (EMA) in psychopathology and clinical observation of day-to-day fluctuations in obsessive-compulsive disorder (OCD) symptoms, there is not a standardized EMA measure of such symptoms that can guide systematic research. In the absence of such a measure, prior EMA research in OCD has utilized heterogeneous approaches to sampling momentary and daily OCD symptoms, which limits the ability to compare results between studies. The present study sought to examine the psychometric properties of a daily OCD symptom (d-OCS) measure that assesses common OCD symptom themes (e.g., contamination, checking, intrusive thoughts) in a sample of adults with OCD (n = 20), psychiatric controls (n = 27), and healthy controls (n = 27). Participants completed the d-OCS 3 times per day for 1 week. The d-OCS distinguished those with OCD from psychiatric controls and healthy controls. The d-OCS demonstrated good internal consistency, adequate test-retest reliability, and good convergent validity. These findings offer initial psychometric support for the use of the d-OCS in EMA research examining day-to-day fluctuations in symptoms of OCD. Additional investigation is needed to examine the discriminant validity of the d-OCS and generalize these findings to more diverse samples.

Factors that impact on recruitment to vaccine trials in the context of a pandemic or epidemic: a qualitative evidence synthesis.

BACKGROUND: The World Health Organization declared the COVID-19 pandemic on 11 March 2020. Vaccine development and deployment were swiftly prioritised as a method to manage and control disease spread. The development of an effective vaccine relies on people's participation in randomised trials. Recruitment to vaccine trials is particularly challenging as it involves healthy volunteers who may have concerns around the potential risks and benefits associated with rapidly developed vaccines. OBJECTIVES: To explore the factors that influence a person's decision to participate in a vaccine trial in the context of a pandemic or epidemic. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was June 2021. SELECTION CRITERIA: We included qualitative studies and mixed-methods studies with an identifiable qualitative component. We included studies that explored the perspectives of adults aged 18 years or older who were invited to take part in vaccine trials in the context of a pandemic or epidemic. DATA COLLECTION AND ANALYSIS: We assessed the title, abstracts and full texts identified by the search. We used a sampling frame to identify data-rich studies that represented a range of diseases and geographical spread. We used QSR NVivo to manage extracted data. We assessed methodological limitations using an adapted version of the Critical Skills Appraisal Programme (CASP) tool for qualitative studies. We used the 'best-fit framework approach' to analyse and synthesise the evidence from our included studies. We then used the Confidence in the Evidence from Reviews of Qualitative research (GRADE-CERQual) assessment to assess our confidence in each finding and develop implications for practice. MAIN RESULTS: We included 34 studies in our review. Most studies related to HIV vaccine trials. The other studies related to Ebola virus, tuberculosis, Zika virus and COVID-19. We developed 20 key findings, under three broad themes (with seven subthemes), that described the factors that people consider when deciding whether to take part in a vaccine trial for a pandemic or epidemic disease. Our GRADE-CERQual confidence was high in nine of the key findings, moderate in 10 key findings and low in one key finding. The main reason for downgrading review findings were concerns regarding the relevance and adequacy of the underlying data. As a result of the over-representation of HIV studies, our GRADE-CERQual assessment of some findings was downgraded in terms of relevance because the views described may not reflect those of people regarding vaccine trials for other pandemic or epidemic diseases. Adequacy relates to the degree of richness and quantity of data supporting a review finding. Moderate concerns about adequacy resulted in a downgrading of some review findings. Some factors were considered to be under the control of the trial team. These included how trial information was communicated and the inclusion of people in the community to help with trial information dissemination. Aspects of trial design were also considered under control of the trial team and included convenience of participation, provision of financial incentives and access to additional support services for those taking part in the trial. Other factors influencing people's decision to take part could be personal, from family, friends or wider society. From a personal perceptive, people had concerns about vaccine side effects, vaccine efficacy and possible impact on their daily lives (carer responsibilities, work, etc.). People were also influenced by their families, and the impact participation may have on relationships. The fear of stigma from society influenced the decision to take part. Also, from a societal perspective, the level of trust in governments' involvement in research and trial may influence a person's decision. Finally, the perceived rewards, both personal and societal, were influencing factors on the decision to participate. Personal rewards included access to a vaccine, improved health and improved disease knowledge, and a return to normality in the context of a pandemic or epidemic. Potential societal rewards included helping the community and contributing to science, often motivated by the memories of family and friends who had died from the disease. AUTHORS' CONCLUSIONS: This review identifies many of the factors that influence a person's decision to take part in a vaccine trial, and these reflect findings from reviews that examine trials more broadly. However, we also recognise some factors that become more important in connection with a vaccine trial in the context of a pandemic or epidemic. These factors include the potential stigma of taking part, the possible adverse effects of a vaccine, the added motivation for helping society, the role of community leaders in trial dissemination, and the level of trust placed in governments and companies developing vaccines. These specific influences need to be considered by trial teams when designing, and communicating about, vaccine trials in the context of a pandemic or epidemic.