Reboot coaching programme: a mixed-methods evaluation assessing resilience, confidence, burnout and depression in medical students.

BACKGROUND: Poor mental health in medical students is a global concern. Effective interventions are required, which are tailored towards the training-related stressors medical students experience. The Reboot coaching programme is an online, tailored intervention based on cognitive-behavioural principles. AIMS: To evaluate whether the Reboot coaching programme tailored for medical students was feasible and associated with improvements in mental health outcome indicators. METHODS: Medical students participated in two group online workshops and a one-to-one coaching call with a Reboot-trained licensed psychological therapist. Participants provided data at: baseline (T1), post-workshops (T2), post-coaching call (T3) and 4-month follow-up (T4). Outcome measures included resilience, confidence, burnout and depression. Feedback was provided regarding the workshops at T2. RESULTS: 115 participants (93/80.9% women; mage = 23.9; SD = 2.8) were recruited, 83 (72.2%) completed all intervention elements and 82 (71.3%) provided T4 data, surpassing recruitment and retention targets. There were significant improvements following baseline in resilience (ps < .001), confidence (ps < .001), burnout (ps < .001) and depression (ps ≤ .001). Most participants agreed the workshops imparted useful skills (n = 92; 99%) and would recommend Reboot to others (n = 89; 95.6%). CONCLUSIONS: Existing interventions have produced mixed results regarding their effectiveness in improving medical students' mental health. Reboot is a feasible intervention in this group which is associated with improvements in resilience, confidence, burnout and depression. Further controlled studies of Reboot are now needed.

Critical care nursing workforce in crisis: A discussion paper examining contributing factors, the impact of the COVID-19 pandemic and potential solutions.

AIMS AND OBJECTIVES: The critical care nursing workforce is in crisis, with one-third of critical care nurses worldwide intending to leave their roles. This paper aimed to examine the problem from a wellbeing perspective, offering implications for research, and potential solutions for organisations. DESIGN: Discursive/Position paper. METHOD: The discussion is based on the nursing and wellbeing literature. It is guided by the authors' collaborative expertise as both clinicians and researchers. Data were drawn from nursing and wellbeing peer-reviewed literature, such as reviews and empirical studies, national surveys and government and thinktank publications/reports. RESULTS: Critical care nurses have been disproportionately affected by the COVID-19 pandemic with studies consistently showing critical care nurses to have the worst psychological outcomes on wellbeing measures, including depression, burnout and post-traumatic stress disorder (PTSD). These findings are not only concerning for the mental wellbeing of critical care nurses, they also raise significant issues for healthcare systems/organisations: poor wellbeing, increased burnout and PTSD are directly linked with critical care nurses intending to leave the profession. Thus, the wellbeing of critical care nurses must urgently be supported. Resilience has been identified as a protective mechanism against the development of PTSD and burnout, thus offering evidence-based interventions that address resilience and turnover have much to offer in tackling the workforce crisis. However, turnover data must be collected by studies evaluating resilience interventions, to further support their evidence base. Organisations cannot solely rely on the efficacy of these interventions to address their workforce crisis but must concomitantly engage in organisational change. CONCLUSIONS: We conclude that critical care nurses are in urgent need of preventative, evidence-based wellbeing interventions, and make suggestions for research and practice.

Prevention of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination.

BACKGROUND: Recent Mycobacterium tuberculosis infection confers a predisposition to the development of tuberculosis disease, the leading killer among global infectious diseases. H4:IC31, a candidate subunit vaccine, has shown protection against tuberculosis disease in preclinical models, and observational studies have indicated that primary bacille Calmette-Guérin (BCG) vaccination may offer partial protection against infection. METHODS: In this phase 2 trial, we randomly assigned 990 adolescents in a high-risk setting who had undergone neonatal BCG vaccination to receive the H4:IC31 vaccine, BCG revaccination, or placebo. All the participants had negative results on testing for M. tuberculosis infection on the QuantiFERON-TB Gold In-tube assay (QFT) and for the human immunodeficiency virus. The primary outcomes were safety and acquisition of M. tuberculosis infection, as defined by initial conversion on QFT that was performed every 6 months during a 2-year period. Secondary outcomes were immunogenicity and sustained QFT conversion to a positive test without reversion to negative status at 3 months and 6 months after conversion. Estimates of vaccine efficacy are based on hazard ratios from Cox regression models and compare each vaccine with placebo. RESULTS: Both the BCG and H4:IC31 vaccines were immunogenic. QFT conversion occurred in 44 of 308 participants (14.3%) in the H4:IC31 group and in 41 of 312 participants (13.1%) in the BCG group, as compared with 49 of 310 participants (15.8%) in the placebo group; the rate of sustained conversion was 8.1% in the H4:IC31 group and 6.7% in the BCG group, as compared with 11.6% in the placebo group. Neither the H4:IC31 vaccine nor the BCG vaccine prevented initial QFT conversion, with efficacy point estimates of 9.4% (P=0.63) and 20.1% (P=0.29), respectively. However, the BCG vaccine reduced the rate of sustained QFT conversion, with an efficacy of 45.4% (P=0.03); the efficacy of the H4:IC31 vaccine was 30.5% (P=0.16). There were no clinically significant between-group differences in the rates of serious adverse events, although mild-to-moderate injection-site reactions were more common with BCG revaccination. CONCLUSIONS: In this trial, the rate of sustained QFT conversion, which may reflect sustained M. tuberculosis infection, was reduced by vaccination in a high-transmission setting. This finding may inform clinical development of new vaccine candidates. (Funded by Aeras and others; C-040-404 ClinicalTrials.gov number, NCT02075203 .).

Evidence that an intervention weakens the relationship between adolescent electronic cigarette use and tobacco smoking: a 24-month prospective study.

BACKGROUND: The electronic cigarette (e-cigarette) use to subsequent smoking relationship in adolescents has received much attention. Whether an intervention to reduce smoking initiation attenuated this relationship was assessed. METHOD: Data were from 3994 adolescent never smokers (aged 13-14 years at baseline) as part of a cluster randomised controlled trial. Self-report measures of smoking, e-cigarette use and covariates were assessed and used to predict ever smoked cigarettes, any recent tobacco smoking and regularly smoked cigarettes at 24-month follow-up. RESULTS: Baseline ever use of e-cigarettes was associated with ever smoked cigarettes (OR=4.03, 95% CI 3.33 to 4.88; controlling for covariates, OR=2.78, 95% CI 2.20 to 3.51), any recent tobacco smoking (OR=3.38, 95% CI 2.72 to 4.21; controlling for covariates, OR=2.17, 95% CI 1.76 to 2.69) and regularly smoked cigarettes (OR=3.60, 95% CI 2.35 to 5.51; controlling for covariates, OR=1.27, 95% CI 1.17 to 1.39) at follow-up. For ever smoked cigarettes only, the impact of e-cigarette use was attenuated in the intervention (OR=1.83) compared with control (OR=4.53) condition. For ever smoked cigarettes and any recent tobacco smoking, the impact of e-cigarette use was attenuated among those with friends who smoked (OR=2.05 (ever smoked); 1·53 (any tobacco use)) compared with those without friends who smoked (OR=3.32 (ever smoked); 2·17 (any tobacco use)). CONCLUSIONS: This is one of the first studies to show that e-cigarette use was robustly associated with measures of smoking over 24 months and the first to show an intervention to attenuate the relationship. Further research with a broader age range of adolescents is required.

Can we prepare healthcare professionals and students for involvement in stressful healthcare events? A mixed-methods evaluation of a resilience training intervention.

BACKGROUND: Healthcare professionals are experiencing unprecedented levels of occupational stress and burnout. Higher stress and burnout in health professionals is linked with the delivery of poorer quality, less safe patient care across healthcare settings. In order to understand how we can better support healthcare professionals in the workplace, this study evaluated a tailored resilience coaching intervention comprising a workshop and one-to-one coaching session addressing the intrinsic challenges of healthcare work in health professionals and students. METHODS: The evaluation used an uncontrolled before-and-after design with four data-collection time points: baseline (T1); after the workshop (T2); after the coaching session (T3) and four-to-six weeks post-baseline (T4). Quantitative outcome measures were Confidence in Coping with Adverse Events ('Confidence'), a Knowledge assessment ('Knowledge') and Resilience. At T4, qualitative interviews were also conducted with a subset of participants exploring participant experiences and perceptions of the intervention. RESULTS: We recruited 66 participants, retaining 62 (93.9%) at T2, 47 (71.2%) at T3, and 33 (50%) at T4. Compared with baseline, Confidence was significantly higher post-intervention: T2 (unadj. ß = 2.43, 95% CI 2.08-2.79, d = 1.55, p < .001), T3 (unadj. ß = 2.81, 95% CI 2.42-3.21, d = 1.71, p < .001) and T4 (unadj. ß = 2.75, 95% CI 2.31-3.19, d = 1.52, p < .001). Knowledge increased significantly post-intervention (T2 unadj. ß = 1.14, 95% CI 0.82-1.46, d = 0.86, p < .001). Compared with baseline, resilience was also higher post-intervention (T3 unadj. ß = 2.77, 95% CI 1.82-3.73, d = 0.90, p < .001 and T4 unadj. ß = 2.54, 95% CI 1.45-3.62, d = 0.65, p < .001). The qualitative findings identified four themes. The first addressed the 'tension between mandatory and voluntary delivery', suggesting that resilience is a mandatory skillset but it may not be effective to make the training a mandatory requirement. The second, the 'importance of experience and reference points for learning', suggested the intervention was more appropriate for qualified staff than students. The third suggested participants valued the 'peer learning and engagement' they gained in the interactive group workshop. The fourth, 'opportunities to tailor learning', suggested the coaching session was an opportunity to personalise the workshop material. CONCLUSIONS: We found preliminary evidence that the intervention was well received and effective, but further research using a randomised controlled design will be necessary to confirm this.

Diagnostic Accuracy of Early Secretory Antigenic Target-6-Free Interferon-gamma Release Assay Compared to QuantiFERON-TB Gold In-tube.

BACKGROUND: Early secretory antigenic target-6 (ESAT-6) is an immunodominant Mycobacterium tuberculosis (M.tb) antigen included in novel vaccines against tuberculosis (TB) and in interferon-gamma (IFN-γ) release assays (IGRAs). Therefore, the availability of an ESAT-6-free IGRA is essential to determine M.tb infection status following vaccination with ESAT-6-containing vaccines. We aimed to qualify a recently developed ESAT-6-free IGRA and to assess its diagnostic performance in comparison to QuantiFERON-TB Gold In-tube (QFT). METHODS: Participants with different levels of M.tb exposure and TB disease were enrolled to determine the ESAT-6-free IGRA cutoff, test assay performance in independent cohorts compared to standard QFT, and perform a technical qualification of antigen-coated blood collection tubes. RESULTS: ESAT-6-free IGRA antigen recognition was evaluated in QFT-positive and QFT-negative South African adolescents. The ESAT-6-free IGRA cutoff was established at 0.61 IU/mL, based on receiver operating characteristic analysis in M.tb-unexposed controls and microbiologically confirmed pulmonary TB patients. In an independent cohort of healthy adolescents, levels of IFN-γ released in QFT and ESAT-6-free IGRA were highly correlated (P < .0001, r = 0.83) and yielded comparable positivity rates, 41.5% and 43.5%, respectively, with 91% concordance between the tests (kappa = 0.82; 95% confidence interval, 0.74-0.90; McNemar test P = .48). ESAT-6-free IGRA blood collection tubes had acceptable lot-to-lot variability, precision, and stability. CONCLUSIONS: The novel ESAT-6-free IGRA had diagnostic accuracy comparable to QFT and is suitable for use in clinical trials to assess efficacy of candidate TB vaccines to prevent established M.tb infection.

Optimization and Interpretation of Serial QuantiFERON Testing to Measure Acquisition of Mycobacterium tuberculosis Infection.

RATIONALE: Conversion from a negative to positive QuantiFERON-TB test is indicative of Mycobacterium tuberculosis (Mtb) infection, which predisposes individuals to tuberculosis disease. Interpretation of serial tests is confounded by immunological and technical variability. OBJECTIVES: To improve the consistency of serial QuantiFERON-TB testing algorithms and provide a data-driven definition of conversion. METHODS: Sources of QuantiFERON-TB variability were assessed, and optimal procedures were identified. Distributions of IFN-γ response levels were analyzed in healthy adolescents, Mtb-unexposed control subjects, and patients with pulmonary tuberculosis. MEASUREMENTS AND MAIN RESULTS: Individuals with no known Mtb exposure had IFN-γ values less than 0.2 IU/ml. Among individuals with IFN-γ values less than 0.2 IU/ml, 0.2-0.34 IU/ml, 0.35-0.7 IU/ml, and greater than 0.7 IU/ml, tuberculin skin test positivity results were 15%, 53%, 66%, and 91% (P < 0.005), respectively. Together, these findings suggest that values less than 0.2 IU/ml were true negatives. In short-term serial testing, "uncertain" conversions, with at least one value within the uncertainty zone (0.2-0.7 IU/ml), were partly explained by technical assay variability. Individuals who had a change in QuantiFERON-TB IFN-γ values from less than 0.2 to greater than 0.7 IU/ml had 10-fold higher tuberculosis incidence rates than those who maintained values less than 0.2 IU/ml over 2 years (P = 0.0003). By contrast, "uncertain" converters were not at higher risk than nonconverters (P = 0.229). Eighty-seven percent of patients with active tuberculosis had IFN-γ values greater than 0.7 IU/ml, suggesting that these values are consistent with established Mtb infection. CONCLUSIONS: Implementation of optimized procedures and a more rigorous QuantiFERON-TB conversion definition (an increase from IFN-γ <0.2 to >0.7 IU/ml) would allow more definitive detection of recent Mtb infection and potentially improve identification of those more likely to develop disease.

Do electronic cigarettes increase cigarette smoking in UK adolescents? Evidence from a 12-month prospective study.

BACKGROUND: In cross-sectional surveys, increasing numbers of adolescents report using both electronic cigarettes (e-cigarettes) and cigarettes. This study assessed whether adolescent e-cigarette use was associated prospectively with initiation or escalation of cigarette use. METHODS: Data were from 2836 adolescents (aged 13-14 years at baseline) in 20 schools in England. At baseline, breath carbon monoxide levels, self-reported e-cigarette and cigarette use, sex, age, friends and family smoking, beliefs about cigarette use and percentage receiving free school meals (measure of socioeconomic status) were assessed. At 12-month follow-up, self-reported cigarette use was assessed and validated by breath carbon monoxide levels. RESULTS: At baseline, 34.2% of adolescents reported ever using e-cigarettes (16.0% used only e-cigarettes). Baseline ever use of e-cigarettes was strongly associated with subsequent initiation (n=1726; OR 5.38, 95% CI 4.02 to 7.22; controlling for covariates, OR 4.06, 95% CI 2.94 to 5.60) and escalation (n=318; OR 1.91, 95% CI 1.14 to 3.21; controlling for covariates, this effect became non-significant, OR 1.39, 95% CI 0.97 to 1.82) of cigarette use. CONCLUSIONS: This is the first study to report prospective relationships between ever use of e-cigarettes and initiation and escalation of cigarette use among UK adolescents. Ever use of e-cigarettes was robustly associated with initiation but more modestly related to escalation of cigarette use. Further research with longer follow-up in a broader age range of adolescents is required.

Combining viral vectored and protein-in-adjuvant vaccines against the blood-stage malaria antigen AMA1: report on a phase 1a clinical trial.

The development of effective vaccines against difficult disease targets will require the identification of new subunit vaccination strategies that can induce and maintain effective immune responses in humans. Here we report on a phase 1a clinical trial using the AMA1 antigen from the blood-stage Plasmodium falciparum malaria parasite delivered either as recombinant protein formulated with Alhydrogel adjuvant with and without CPG 7909, or using recombinant vectored vaccines--chimpanzee adenovirus ChAd63 and the orthopoxvirus MVA. A variety of promising "mixed-modality" regimens were tested. All volunteers were primed with ChAd63, and then subsequently boosted with MVA and/or protein-in-adjuvant using either an 8- or 16-week prime-boost interval. We report on the safety of these regimens, as well as the T cell, B cell, and serum antibody responses. Notably, IgG antibody responses primed by ChAd63 were comparably boosted by AMA1 protein vaccine, irrespective of whether CPG 7909 was included in the Alhydrogel adjuvant. The ability to improve the potency of a relatively weak aluminium-based adjuvant in humans, by previously priming with an adenoviral vaccine vector encoding the same antigen, thus offers a novel vaccination strategy for difficult or neglected disease targets when access to more potent adjuvants is not possible.

Managing nurse redeployment during the Covid-19 pandemic, lessons for future redeployment: A qualitative study.

BACKGROUND: The mass redeployment of nurses was critical across countries necessitated by the acute health impact of Covid-19. Knowledge was limited regarding how to manage nurse redeployment or the impact that redeployment might have. Redeployment continues, particularly in response to the current staffing crisis and surges such as winter pressures. This study aims to address these gaps in evidence to inform guidance on how best to manage nurse redeployment in practice. OBJECTIVES: First, to understand the processes and underpinning decisions made by managers when managing nurse redeployment prior to and during the Covid-19 pandemic. Second, to identify the lessons that can be learned to improve the management of on-going nurse redeployment. DESIGN: Qualitative study utilising semi-structured interviews and focus groups with nurse managers (ISRCTN: 18172749). SETTING(S): Three acute National Health Service (NHS) Trusts in England with geographical and ethnic diversity, and different Covid-19 contexts. PARTICIPANTS: Thirty-two nurse managers and four Human Resource advisors responsible for redeploying nurses or receiving and supporting redeployed nurses. METHODS: Participants took part in face-to-face or virtual semi-structured interviews from February 2021 to November 2021 and virtual focus groups from July to December 2021. Qualitative data were analysed using reflexive thematic analysis. RESULTS: Four themes were evident in the data, capturing four distinctive phases of the redeployment process. There was a fundamental mismatch between how different parts of the nursing and managerial workforce conceived of their decision-making responsibilities across different phases. This led to managers taking inconsistent and sometimes contradictory approaches when redeploying nurses, and a disconnect between nursing staff at all levels of the chain of command. Furthermore, in conjunction with limited guidance in operationalising redeployment and the distressing experiences vocalised by nurses, nurse managers found nurse redeployment logistically and emotionally challenging; and felt 'caught in the middle' of meeting both their managerial and mentoring responsibilities. This became increasingly challenging during subsequent phases of redeployment and remained challenging once the pandemic waned. CONCLUSIONS: The approach to nurse redeployment in response to the Covid-19 pandemic prioritised nurse staffing numbers over personal well-being. Key principles of good practice relating to nurse redeployment during the Covid-19 pandemic can be applied to improve future redeployment of nurses and support positive outcomes. Having a planned approach for staff redeployment during normal service delivery comprising operational guidance for those tasked with implementing redeployment, that is scalable in a crisis setting, would be beneficial for the nursing workforce.

Study protocol: A cluster randomised controlled trial of implementation intentions to reduce smoking initiation in adolescents.

BACKGROUND: The current literature suggests that forming implementation intentions (simple 'if-then' plans) about how to refuse the offer of a cigarette may be an effective intervention to reduce smoking initiation in adolescents. This study is a pragmatic trial to test the effectiveness and cost-effectiveness of such an intervention in reducing smoking initiation in a sample of UK adolescents. METHODS/DESIGN: A cluster randomised controlled trial with at least 36 schools randomised to receive an implementation intention intervention targeting reducing smoking initiation (intervention group) or increasing homework (control group). Interventions will be conducted at the classroom level and be repeated every six months for four years (eight interventions). Objectively assessed (carbon monoxide monitor) and self-reported smoking plus smoking related cognitions (e.g., smoking intentions, attitudes, norms and self-efficacy) will be assessed at baseline and 12, 24, 36 and 48 months post baseline. Objectively assessed smoking at 48 months post baseline will be the primary outcome variable. Health economic analyses will assess life years gained. DISCUSSION: The results of the trial will provide information on the impact of a repeated implementation intention for refusing offers of cigarettes on rates of smoking initiation in adolescents. TRIAL REGISTRATION: ISRCTN27596806.

Evaluation of the reboot coaching workshops among urology trainees: A mixed method approach.

Background: Urology trainees experience high burnout, and there is an urgent need for acceptable and effective interventions. The current study evaluated Reboot coaching workshops (Reboot-C), a tailored intervention based on cognitive-behavioural principles, with urology trainees. Objective: Our primary objective was to evaluate the acceptability of Reboot-C among urology trainees. In addition, this study aimed to investigate whether there were changes in confidence, resilience, depression and burnout levels. Materials and method: A single-arm design was used, including pre- and post-online questionnaires and semi-structured interviews. Result: Twenty-one urology trainees replied to the survey, attended both Reboot-C workshops and responded to the post-intervention questionnaire. Thirteen of 21 (61%) urology trainees participated in the interview. Participating in Reboot-C was associated with significant improvements in resilience and confidence and a significant reduction in burnout. However, there was no significant reduction in depression. Qualitative data indicated that Reboot was acceptable and helped participants develop useful skills. Conclusion: These findings pave the way for more conclusive studies on the efficacy of Reboot-C for surgeons.

Multiple meanings of resilience: Health professionals' experiences of a dual element training intervention designed to help them prepare for coping with error.

RATIONALE, AIMS AND OBJECTIVES: Consistent data demonstrates negative psychological effects of caregiving on front-line health professionals. Evidence that psychological resilience factors can help minimize distress and the potential for low-cost interventions have created interest in resilience-based development programmes; yet evidence of perceived value amongst health professionals is lacking. This study explored health professionals' experiences and perceptions of a novel, resilience-based intervention designed to pro-actively prepare staff for coping with error; to investigate their perceptions of what resilience meant to them, the relevance of the intervention, and impact of participation on ability to cope with error. METHODS: Semi-structured interviews 4-6 weeks post intervention with 23 randomly selected participants from seven cohorts (midwives, paediatricians, obstetricians/gynaecologists, paramedics) and trainees (physician associates, mammographers, sonographers). Thematic analysis of interview data. FINDINGS: Participants reported various interpretations of, and a shift in perception regarding what the concept of psychological resilience meant to them and their practice. These included for example, resilience as a positive or negative concept and their awareness and response to a range of personal, organizational and system factors influencing personal resilience. They valued the prophylactic, clinically relevant, interactive and applied nature of the intervention; having developed and applied valuable skills beyond the context of involvement in error, noting that individuals needed to be willing to explore their own coping mechanisms and human fallibility to gain maximum benefit. There was also consensus that whilst proactively developing individual level psychological resilience is important, so too is addressing the organizational and system factors that affect staff resilience which are outside individual staff control. CONCLUSION: Enhancing resilience appears to be considered useful in supporting staff to prepare for coping with error and the wider emotional burden of clinical work, but such interventions require integration into wider system approaches to reduce the burden of clinical work for health professionals.

Patient and Family Involvement in Serious Incident Investigations From the Perspectives of Key Stakeholders: A Review of the Qualitative Evidence.

OBJECTIVES: Investigations of healthcare harm often overlook the valuable insights of patients and families. Our review aimed to explore the perspectives of key stakeholders when patients and families were involved in serious incident investigations. METHODS: The authors searched three databases (Medline, PsycInfo, and CINAHL) and Connected Papers software for qualitative studies in which patients and families were involved in serious incident investigations until no new articles were found. RESULTS: Twenty-seven papers were eligible. The perspectives of patients and families, healthcare professionals, nonclinical staff, and legal staff were sought across acute, mental health and maternity settings. Most patients and families valued being involved; however, it was important that investigations were flexible and sensitive to both clinical and emotional aspects of care to avoid compounding harm. This included the following: early active listening with empathy for trauma, sincere and timely apology, fostering trust and transparency, making realistic timelines clear, and establishing effective nonadversarial communication. Most staff perceived that patient and family involvement could improve investigation quality, promote an open culture, and help ensure future safety. However, it was made difficult when multidisciplinary input was absent, workload and staff turnover were high, training and support needs were unmet, and fears surrounded litigation. Potential solutions included enhancing the clarity of roles and responsibilities, adequately training staff, and providing long and short-term support to stakeholders. CONCLUSIONS: Our review provides insights to ensure patient and family involvement in serious incident investigations considers both clinical and emotional aspects of care, is meaningful for all key stakeholders, and avoids compounding harm. However, significant gaps in the literature remain.

Anaemia in a phase 2 study of a blood stage falciparum malaria vaccine.

BACKGROUND: A Phase 1-2b study of the blood stage malaria vaccine AMA1-C1/Alhydrogel was conducted in 336 children in Donéguébougou and Bancoumana, Mali. In the Phase 2 portion of the study (n = 300), no impact on parasite density or clinical malaria was seen; however, children who received the study vaccine had a higher frequency of anaemia (defined as haemoglobin < 8.5 g/dL) compared to those who received the comparator vaccine (Hiberix). This effect was one of many tested and was not significant after adjusting for multiple comparisons. METHODS: To further investigate the possible impact of vaccination on anaemia, additional analyses were conducted including patients from the Phase 1 portion of the study and controlling for baseline haemoglobin, haemoglobin types S or C, alpha-thalassaemia, G6PD deficiency, and age. A multiplicative intensity model was used, which generalizes Cox regression to allow for multiple events. Frailty effects for each subject were used to account for correlation of multiple anaemia events within the same subject. Intensity rates were calculated with reference to calendar time instead of time after randomization in order to account for staggered enrollment and seasonal effects of malaria incidence. Associations of anaemia with anti-AMA1 antibody were further explored using a similar analysis. RESULTS: A strong effect of vaccine on the incidence of anaemia (risk ratio [AMA1-C1 to comparator (Hiberix)]= 2.01, 95% confidence interval [1.26,3.20]) was demonstrated even after adjusting for baseline haemoglobin, haemoglobinopathies, and age, and using more sophisticated statistical models. Anti-AMA1 antibody levels were not associated with this effect. CONCLUSIONS: While these additional analyses show a robust effect of vaccination on anaemia, this is an intensive exploration of secondary results and should, therefore, be interpreted with caution. Possible mechanisms of the apparent adverse effect on haemoglobin of vaccination with AMA1-C1/Alhydrogel and implications for blood stage vaccine development are discussed. The potential impact on malaria-associated anaemia should be closely evaluated in clinical trials of AMA1 and other blood stage vaccines in malaria-exposed populations.

The TLR9 ligand CpG promotes the acquisition of Plasmodium falciparum-specific memory B cells in malaria-naive individuals.

Despite the central role of memory B cells (MBC) in protective immune responses, little is understood about how they are acquired in naive individuals in response to Ag exposure, and how this process is influenced by concurrent activation of the innate immune system's TLR. In this longitudinal study of malaria-naive individuals, we examined the MBC response to two candidate malaria vaccines administered with or without CpG, a TLR9 ligand. We show that the acquisition of MBC is a dynamic process in which the vaccine-specific MBC pool rapidly expands and then contracts, and that CpG enhances the kinetics, magnitude, and longevity of this response. We observed that the percentage of vaccine-specific MBC present at the time of reimmunization predicts vaccine-specific Ab levels 14 days later; and that at steady-state, there is a positive correlation between vaccine-specific MBC and Ab levels. An examination of the total circulating MBC and plasma cell pools also suggests that MBC differentiate into plasma cells through polyclonal activation, independent of Ag specificity. These results provide important insights into the human MBC response, which can inform the development of vaccines against malaria and other pathogens that disrupt immunological memory.

Association between age at first reported e-cigarette use and subsequent regular e-cigarette, ever cigarette and regular cigarette use.

BACKGROUND AND AIMS: Association of electronic cigarette use and subsequent smoking has received considerable attention, although age of first use has not. This study tested differences in regular (e-cigarettes, cigarettes) and ever (cigarettes) use between e-cigarette user groups: early versus never users, late versus never users, early versus late users and effects of controlling for covariates. DESIGN: Prospective study with 12- and 24-month follow-up of e-cigarette/cigarette ever/regular use with data from an intervention. SETTING: Forty-five schools in England (Staffordshire and Yorkshire). PARTICIPANTS: Never smokers (3289 13-14-year-olds) who were part of a cluster randomized controlled trial. MEASUREMENTS: The sample was divided into groups of e-cigarette users: early users (at 13-14 years), late users (at 14-15 years) and never users (at 13-14 and 14-15 years). Dependent variables were self-reported regular e-cigarette and cigarette use and ever cigarette use at 15-16 years. Covariates were assessed. FINDINGS: Early and late users compared with never users were significantly more likely to be regular e-cigarette users [early: odds ratio (OR) = 9.42, 95% confidence interval (CI) = 5.38, 16.49, P < 0.001; late: OR = 6.89, 95% CI = 4.11, 11.54, P < 0.001], ever cigarette users (early: OR = 7.96, 95% CI = 6.02, 10.53, P < 0.001; late: OR = 5.13, 95% CI = 3.85, 6.84, P < 0.001) and regular cigarette users (early: OR = 7.80, 95% CI = 3.99, 15.27, P < 0.001; late: OR = 4.34, 95% CI = 1.93, 9.77, P < 0.001) at age 15-16 years. Late users compared with early users had significantly lower rates of ever use of cigarettes at 15-16 years (OR = 0.48, 95% CI = 0.35, 0.66, P < 0.001), although this difference was non-significant at 12 months after first use of e-cigarettes (OR = 0.89, 95% CI = 0.64, 1.25, P = 0.498). Controlling for covariates did not change the findings. CONCLUSIONS: Adolescents in England who report using e-cigarettes at age 13-14 years have higher rates of subsequently initiating cigarette use than adolescents who report using e-cigarettes at age 14-15 years, a difference that may be attributable to a longer period of time to initiate cigarette use in former group.

Lack of allele-specific efficacy of a bivalent AMA1 malaria vaccine.

BACKGROUND: Extensive genetic diversity in vaccine antigens may contribute to the lack of efficacy of blood stage malaria vaccines. Apical membrane antigen-1 (AMA1) is a leading blood stage malaria vaccine candidate with extreme diversity, potentially limiting its efficacy against infection and disease caused by Plasmodium falciparum parasites with diverse forms of AMA1. METHODS: Three hundred Malian children participated in a Phase 2 clinical trial of a bivalent malaria vaccine that found no protective efficacy. The vaccine consists of recombinant AMA1 based on the 3D7 and FVO strains of P. falciparum adjuvanted with aluminum hydroxide (AMA1-C1). The gene encoding AMA1 was sequenced from P. falciparum infections experienced before and after immunization with the study vaccine or a control vaccine. Sequences of ama1 from infections in the malaria vaccine and control groups were compared with regard to similarity to the vaccine antigens using several measures of genetic diversity. Time to infection with parasites carrying AMA1 haplotypes similar to the vaccine strains with respect to immunologically important polymorphisms and the risk of infection with vaccine strain haplotypes were compared. RESULTS: Based on 62 polymorphic AMA1 residues, 186 unique ama1 haplotypes were identified among 315 ama1 sequences that were included in the analysis. Eight infections had ama1 sequences identical to 3D7 while none were identical to FVO. Several measures of genetic diversity showed that ama1 sequences in the malaria vaccine and control groups were comparable both at baseline and during follow up period. Pre- and post-immunization ama1 sequences in both groups all had a similar degree of genetic distance from FVO and 3D7 ama1. No differences were found in the time of first clinical episode or risk of infection with an AMA1 haplotype similar to 3D7 or FVO with respect to a limited set of immunologically important polymorphisms found in the cluster 1 loop of domain I of AMA1. CONCLUSION: This Phase 2 trial of a bivalent AMA1 malaria vaccine found no evidence of vaccine selection or strain-specific efficacy, suggesting that the extreme genetic diversity of AMA1 did not account for failure of the vaccine to provide protection.

Blood stage vaccines for Plasmodium falciparum: current status and the way forward.

Since the recent call for a shift from malaria control to eradication, the role of asexual blood stage vaccines for falciparum malaria, which are not expected to prevent infection, has become less clear. However, blood stage antigens remain likely to be a critical component of a highly effective malaria vaccine. The inclusion of a blood stage component in a multistage malaria vaccine would not only prevent disease caused by "leaky" pre-erythrocytic immunity, but would also protect against epidemics in newly vulnerable populations. Recent clinical results of blood stage vaccine candidates have shown strain specific and partial efficacy, although no protection against clinical outcomes has been demonstrated in experimental infection or field trials to date. The current status of Plasmodium falciparum blood stage vaccine development is summarized and the potential role of these vaccines in the changed malaria landscape is discussed. Alternative preclinical and clinical development paths will speed iterative development.

Evaluating a Strategy for Implementation and Sustainability of School-Based Health Centers in 3 Disparate Communities.

BACKGROUND: School-based health centers (SBHCs) increase access to health care and improve academic achievement for underserved students. We report on the test of a strategy to take SBHCs to scale by addressing the issues of community need and support and financial sustainability. METHODS: Using mixed methods, we collected data on student enrollment, utilization, health outcomes, seat time, patient revenues, surveys and key informant interviews from SBHCs located in 3 geographically and demographically different communities over a 2-year period. RESULTS: The 3 health centers were comparable in their capacity to implement their operations and achieve quality outcomes but varied considerably in their abilities to achieve sustainability after 2 years of operation. All participated in a planning phase and were able to achieve community buy in and support which impacted their implementation. Only one of the SBHCs which had the highest patient utilization was able to generate enough revenue from patient billings to become sustainable after the second year. CONCLUSION: Expanding SBHCs requires a period of planning to generate community buy in and support which is required for successful implementation. Sustainability requires sustained high clinic utilization and is enhanced by health centers that are able to receive high Medicaid reimbursements.