Implementing a complex mental health intervention in occupational settings: process evaluation of the MENTUPP pilot study.

BACKGROUND: According to the Medical Research Council (MRC) framework, the theorisation of how multilevel, multicomponent interventions work and the understanding of their interaction with their implementation context are necessary to be able to evaluate them beyond their complexity. More research is needed to provide good examples following this approach in order to produce evidence-based information on implementation practices. OBJECTIVES: This article reports on the results of the process evaluation of a complex mental health intervention in small and medium enterprises (SMEs) tested through a pilot study. The overarching aim is to contribute to the evidence base related to the recruitment, engagement and implementation strategies of applied mental health interventions in the workplace. METHOD: The Mental Health Promotion and Intervention in Occupational Settings (MENTUPP) intervention was pilot tested in 25 SMEs in three work sectors and nine countries. The evaluation strategy of the pilot test relied on a mixed-methods approach combining qualitative and quantitative research methods. The process evaluation was inspired by the RE-AIM framework and the taxonomy of implementation outcomes suggested by Proctor and colleagues and focused on seven dimensions: reach, adoption, implementation, acceptability, appropriateness, feasibility and maintenance. RESULTS: Factors facilitating implementation included the variety of the provided materials, the support provided by the research officers (ROs) and the existence of a structured plan for implementation, among others. Main barriers to implementation were the difficulty of talking about mental health, familiarisation with technology, difficulty in fitting the intervention into the daily routine and restrictions caused by COVID-19. CONCLUSIONS: The results will be used to optimise the MENTUPP intervention and the theoretical framework that we developed to evaluate the causal mechanisms underlying MENTUPP. Conducting this systematic and comprehensive process evaluation contributes to the enhancement of the evidence base related to mental health interventions in the workplace and it can be used as a guide to overcome their contextual complexity. TRIAL REGISTRATION NUMBER: ISRCTN14582090.

Outcome assessment of a complex mental health intervention in the workplace. Results from the MENTUPP pilot study.

OBJECTIVE: Multicomponent interventions are recommendable to achieve the greatest mental health benefits, but are difficult to evaluate due to their complexity. Defining long-term outcomes, arising from a Theory of Change (ToC) and testing them in a pilot phase, is a useful approach to plan a comprehensive and meaningful evaluation later on. This article reports on the pilot results of an outcome evaluation of a complex mental health intervention and examines whether appropriate evaluation measures and indicators have been selected ahead of a clustered randomised control trial (cRCT). METHODS: The MENTUPP pilot is an evidence-based intervention for Small and Medium Enterprises (SMEs) active in three work sectors and nine countries. Based on our ToC, we selected the MENTUPP long-term outcomes, which are reported in this article, are measured with seven validated scales assessing mental wellbeing, burnout, depression, anxiety, stigma towards depression and anxiety, absenteeism and presenteeism. The pilot MENTUPP intervention assessment took place at baseline and at 6 months follow-up. RESULTS: In total, 25 SMEs were recruited in the MENTUPP pilot and 346 participants completed the validated scales at baseline and 96 at follow-up. Three long-term outcomes significantly improved at follow-up (p < 0.05): mental wellbeing, symptoms of anxiety, and personal stigmatising attitudes towards depression and anxiety. CONCLUSIONS: The results of this outcome evaluation suggest that MENTUPP has the potential to strengthen employees' wellbeing and decrease anxiety symptoms and stigmatising attitudes. Additionally, this study demonstrates the utility of conducting pilot workplace interventions to assess whether appropriate measures and indicators have been selected. Based on the results, the intervention and the evaluation strategy have been optimised.

Gaps in the Identification of Child Race and Ethnicity in a Pediatric Emergency Department.

INTRODUCTION: Race and ethnicity are social constructs that are associated with meaningful health inequities. To address health disparities, it is essential to have valid, reliable race and ethnicity data. We compared child race and ethnicity as identified by the parent with that reported in the electronic health record (EHR). METHODS: A convenience sample of parents of pediatric emergency department (PED) patients completed a tablet-based questionnaire (February-May 2021). Parents identified their child's race and ethnicity from options within a single category. We used chi-square to compare concordance between child race and ethnicity reported by the parent with that recorded in the EHR. RESULTS: Of 219 approached parents, 206 (94%) completed questionnaires. Race and/or ethnicity were misidentified in the EHR for 56 children (27%). Misidentifications were most common among children whose parents identified them as multiracial (100% vs 15% of children identified as a single race, P < 0.001) or Hispanic (84% vs 17% of non-Hispanic children, P < 0.001), and children whose race and/or ethnicity differed from that of their parent (79% vs 18% of children with the same race and ethnicity as their parent, P < 0.001). CONCLUSION: In this PED, misidentification of race and ethnicity was common. This study provides the basis for a multifaceted quality improvement effort at our institution. The quality of child race and ethnicity data in the emergency setting warrants further consideration across health equity efforts.

Mental Health Promotion and Intervention in Occupational Settings: Protocol for a Pilot Study of the MENTUPP Intervention.

Depression and anxiety are the most prevalent mental health difficulties in the EU, causing immense suffering and costing the global economy EUR 1 trillion each year in lost productivity. Employees in construction, health and information and communications technology have an elevated risk of mental health difficulties. Most mental health interventions for the workplace have been targeted at larger companies and small and medium-sized enterprises (SMEs) are often overlooked despite most people being employed in SMEs. The MENTUPP intervention aims to improve mental health and wellbeing and reduce depression, anxiety, and suicidal behaviour. The MENTUPP project involves the development, implementation, and evaluation of a multilevel intervention targeting both clinical and non-clinical mental health issues and combating the stigma of mental (ill-)health, with a specific focus on SMEs. The intervention is underpinned by a framework of how to create a mentally healthy workplace by employing an integrated approach and has been informed by several systematic reviews designed to understand organisational mental health interventions and a consultation survey with key experts in the area. The intervention is facilitated through the MENTUPP Hub, an online platform that presents interactive psychoeducational materials, toolkits, and links to additional resources in an accessible and user-friendly manner. This paper presents the pilot study protocol for delivering the MENTUPP intervention in eight European countries and Australia. Each intervention country will aim to recruit at least 23 participants in 1-3 SMEs in one of the three high-risk sectors. The central aim of the pilot study will be to examine the feasibility, acceptability, and uptake of the MENTUPP intervention across the target SMEs. The findings will contribute to devising the protocol for a cluster randomised controlled trial (cRCT) of the MENTUPP intervention. Findings from this study will also be used to inform the optimisation phase of the MENTUPP intervention which will aim to improve the materials and the implementation of the intervention as well as enhancing the evaluation strategy which will be employed for the cRCT.

A Quality Education: A Comprehensive Review of a Combined Longitudinal and Specialty Track Quality Improvement and Patient Safety Medical School Curriculum.

Structured quality improvement and patient safety (QI/PS) education has increased at every level of medical education; however, great variability exists in the content taught. Here, the authors present a longitudinal model for medical student QI/PS education that is currently implemented at the University of Florida College of Medicine. The curriculum is taught with a variety of teaching methods incorporated into each year with increasing levels of clinical implementation. This curriculum is multimodal and introduces students to QI/PS concepts, presents mock scenarios, and eventually encourages clinical application to situations students experience during their own clinical practice. Additionally, a specialized track for students to have further immersion into this field of medicine is described, which involves specialized training, expanded educational opportunities, and a capstone project. Both the curriculum and specialized track contain explicit clinical integration to ensure students are prepared to enter the medical profession to engage in QI/PS endeavors.

Workplace interventions to reduce depression and anxiety in small and medium-sized enterprises: A systematic review.

BACKGROUND: Depression and anxiety are the most prevalent mental health difficulties in the workplace, costing the global economy $1 trillion each year. Evidence indicates that symptoms may be reduced by interventions in the workplace. This paper is the first to systematically review psychosocial interventions for depression, anxiety, and suicidal ideation and behaviours in small-to medium-size enterprises (SMEs). METHODS: A systematic search following PRISMA guidelines, registered in PROSPERO (CRD42020156275), was conducted for psychosocial interventions targeting depression, anxiety, and suicidal ideation/behaviour in SMEs. The PubMed, PsycINFO, Scopus, and two specific occupational health databases were searched, as well as four databases for grey literature, without time limit until 2nd December 2019. RESULTS: In total, 1283 records were identified, 70 were retained for full-text screening, and seven met the inclusion criteria: three randomised controlled trials (RCTs), three before and after designs and one non-randomised trial, comprising 5111 participants. Study quality was low to moderate according to the Quality Assessment Tool for Quantitative Studies. Five studies showed a reduction in depression and anxiety symptoms using techniques based on cognitive behavioural therapy (CBT), two reported no significant change. LIMITATIONS: Low number and high heterogeneity of interventions and outcomes, high attrition and lack of rigorous RCTs. CONCLUSIONS: Preliminary evidence indicates CBT-based interventions can be effective in targeting symptoms of depression and anxiety in SME employees. There may be unique challenges to implementing programmes in SMEs. Further research is needed in this important area.

Transforming the Culture of Peer Review: Implementation Across Three Departments in an Academic Health Center.

OBJECTIVES: Although many health care institutions believe that clinical peer review is vital for identifying and improving quality of care, peer review is perceived by many clinicians as variable and inherently punitive. Successful peer review requires institutional leadership and adoption of a just culture approach to investigating and determining accountability for medical errors that result in harm. METHODS: We describe how an academic medical center implemented and adapted its clinical peer review processes to be consistent with just culture theory and provide a roadmap that other institutions may follow. Specific examples of peer review are highlighted to show how the process improved patient safety in the departments of emergency medicine, internal medicine, and pediatrics. RESULTS: The most significant process improvement was shifting from a tradition of assigning letter grades of "A," "B," or "C" to determine whether preventable adverse events were caused by "human error," "at-risk behavior," or "reckless behavior." This categorization of human behaviors enabled patient safety officers within 3 departments to develop specific interventions to protect patients and enlist physician support for improving clinical systems. CONCLUSIONS: Each department's success was due to recognition of different patient and provider cultures that offer unique challenges. The transformation of peer review was a crucial first step to shift perceptions of peer review from a punitive to a constructive process intended to improve patient safety. Our experience with reengineering clinical peer review shows the importance of focusing on just culture as a key method to prevent patient harm.

Implementation of Targeted Point of Care HIV Testing in a Pediatric Emergency Department.

HIV infection rates are increasing among adolescents. Despite guidelines recommending annual HIV screening among sexually active adolescents, 3.6% of adolescents tested for other sexually transmitted infections (STI) in a pediatric emergency department (PED) were screened for HIV. The aim was to increase HIV screening to 90%. METHODS: Interventions were designed to address 4 key drivers thought to be critical in reliably offering HIV testing. The primary outcome measure was the proportion of adolescents offered HIV testing among those being tested for common STIs. Statistical process control charts were used to measure performance over time and differentiate common versus special cause variation. RESULTS: We instituted point of care (POC) HIV testing in the PED in January 2012. The proportion of STI tested patients offered HIV testing was increased to >87% and sustained this performance. Implementation of a clinical decision support tool had the highest impact. The majority offered testing agreed, and the most common reason for refusal was a recent negative test. We identified eleven HIV positive patients over 5 years. Eight were newly diagnosed, and 3 had prior positive tests but were not connected to care. All 11 were successfully connected to providers with HIV care expertise. CONCLUSIONS: POC HIV testing is feasible, acceptable, and sustainable in a PED setting. The implementation of targeted HIV POC testing in the PED increased the number of HIV tests being offered, the number of high-risk patients being screened, and the number diagnosed and connected to care.

Opportunities for earlier HIV diagnosis in a pediatric ED.

OBJECTIVES: Emergency department (ED) HIV screening is recommended but challenging to implement and of uncertain effectiveness in pediatric EDs (PEDs). We sought to determine whether there were opportunities for earlier HIV diagnosis in the PED for a cohort of young adults diagnosed with HIV. METHODS: This retrospective cohort study reviewed PED records of a group of young adults receiving HIV care in an urban hospital setting. Pediatric ED visits were selected for review if they took place after the patient's estimated time of HIV acquisition and before their eventual diagnosis. Charts were reviewed to determine whether HIV infection was suspected and whether testing was offered. RESULTS: Among a cohort of HIV-positive young adults, only 3 (3.6%; 95% confidence interval, 0.9-10.8) of 84 were seen in the PED during the time they were undiagnosed but likely to be infected with HIV. Among these subjects, there was no documentation that HIV testing was offered or refused nor was there documented suspicion of HIV. CONCLUSIONS: There are opportunities for earlier diagnosis of HIV in PEDs, affirming the importance of HIV screening implementation in these settings. However, PEDs are unlikely to have the same frequency of contact with undiagnosed individuals as do adult EDs. Alternative methods of accessing at-risk adolescent populations must be identified.

Adolescent patient preferences surrounding partner notification and treatment for sexually transmitted infections.

OBJECTIVES: Important barriers to addressing the sexually transmitted infection (STI) epidemic among adolescents are the inadequate partner notification of positive STI results and insufficient rates of partner testing and treatment. However, adolescent attitudes regarding partner notification and treatment are not well understood. The aim was to qualitatively explore the barriers to and preferences for partner notification and treatment among adolescent males and females tested for STIs in an emergency department (ED) setting and to explore the acceptability of ED personnel notifying their sexual partners. METHODS: This was a descriptive, qualitative study in which a convenience sample of 40 adolescents (18 females, 22 males) 14 to 21 years of age who presented to either adult or pediatric EDs with STI-related complaints participated. Individualized, semistructured, confidential interviews were administered to each participant. Interviews were audiotaped and transcribed verbatim by an independent transcriptionist. Data were analyzed using framework analysis. RESULTS: Barriers to partner notification included fear of retaliation or loss of the relationship, lack of understanding of or concern for the consequences associated with an STI, and social stigma and embarrassment. Participants reported two primary barriers to their partners obtaining STI testing and treatment: lack of transportation to the health care site and the partner's fear of STI positive test results. Most participants preferred to notify their main sexual partners of an STI exposure via a face-to-face interaction or a phone call. Most participants were agreeable with a health care provider (HCP) notifying their main sexual partners of STI exposure and preferred that the HCP notify the partner by phone call. CONCLUSIONS: There are several adolescent preferences and barriers for partner notification and treatment. To be most effective, future interventions to prevent adolescent STIs should incorporate these preferences and address the barriers to partner notification. In an ED setting, using HCPs to provide partner notification of STI exposures is acceptable to adolescent patients; however, the feasibility of this type of program needs further exploration.

Sequential Phase 1 and Phase 2 randomized, controlled trials of the safety, immunogenicity and efficacy of combined pre-erythrocytic vaccine antigens RTS,S and TRAP formulated with AS02 Adjuvant System in healthy, malaria naïve adults.

In an attempt to improve the efficacy of the candidate malaria vaccine RTS,S/AS02, two studies were conducted in 1999 in healthy volunteers of RTS,S/AS02 in combination with recombinant Plasmodium falciparum thrombospondin-related anonymous protein (TRAP). In a Phase 1 safety and immunogenicity study, volunteers were randomized to receive TRAP/AS02 (N=10), RTS,S/AS02 (N=10), or RTS,S+TRAP/AS02 (N=20) at 0, 1 and 6-months. In a Phase 2 challenge study, subjects were randomized to receive either RTS,S+TRAP/AS02 (N=25) or TRAP/AS02 (N=10) at 0 and 1-month, or to a challenge control group (N=8). In both studies, the combination vaccine had an acceptable safety profile and was acceptably tolerated. Antigen-specific antibodies, lymphoproliferative responses, and IFN-γ production by ELISPOT assay elicited with the combination vaccine were qualitatively similar to those generated by the single component vaccines. However, post-dose 2 anti-CS antibodies in the RTS,S+TRAP/AS02 vaccine recipients were lower than in the RTS,S/AS02 vaccine recipients. After challenge, 10 of 11 RTS,S+TRAP/AS02 vaccinees, 5 of 5 TRAP/AS02 vaccinees, and 8 of 8 infectivity controls developed parasitemia, with median pre-patent periods of 13.0, 11.0, and 12.0 days, respectively. The absence of any prevention or delay of parasitemia by TRAP/AS02 suggests no apparent added value of TRAP/AS02 as a candidate vaccine. The absence of significant protection or delay of parasitemia in the 11 RTS,S+TRAP/AS02 vaccine recipients contrasts with previous 2 dose studies of RTS,S/AS02. The small sample size did not permit identifying statistically significant differences between the study arms. However, we speculate, within the constraints of the challenge study, that the presence of the TRAP antigen may have interfered with the vaccine efficacy previously observed with this regimen of RTS,S/AS02, and that any future TRAP-based vaccines should consider employing alternative vaccine platforms.

Pediatric emergency department provider perceptions of universal sexually transmitted infection screening.

The purpose of this study was to describe the perceptions of pediatric emergency care providers in relation to implementing a universal sexually transmitted infection screening process for adolescent female patients in a pediatric emergency department. A descriptive qualitative design was used with a convenience sample of pediatric emergency physicians and nurses working in a large urban, pediatric teaching hospital. Participants were individually interviewed using a standard interview guide. Verbatim transcripts were analyzed using a modified constant comparative analysis method. Three overriding themes were identified that describe the perceptions of providers in relation to a universal screening process in a pediatric emergency department: Attitudes, Barriers, and Solutions. Universal sexually transmitted infection screening is one strategy that may help with early identification and treatment of adolescent female patients with undiagnosed sexually transmitted infections, and the pediatric emergency department is a potential site for such screening.

Improving notification of sexually transmitted infections: a quality improvement project and planned experiment.

BACKGROUND AND OBJECTIVE: Inadequate follow-up of positive sexually transmitted infection (STI) test results is a gap in health care quality that contributes to the epidemic of STIs in adolescent women. The goal of this study was to improve our ability to contact adolescent women with positive STI test results after an emergency department visit. METHODS: We conducted an interventional quality improvement project at a pediatric emergency department. Phase 1 included plan-do-study-act cycles to test interventions such as provider education and system changes. Phase 2 was a planned experiment studying 2 interventions (study cell phone and patient activation card), using a 2 × 2 factorial design with 1 background variable and 2 replications. Outcomes were: (1) the proportion of women aged 14 to 21 years with STI testing whose confidential telephone number was documented in the electronic medical record; (2) the proportion of STI positive women successfully contacted within 7 days. RESULTS: Phase 1 interventions increased the proportion of records with a confidential number from 24% to 58% and the proportion contacted from 45% to 65%, and decreased loss to follow-up from 40% to 24%. In phase 2, the proportion contacted decreased after the electronic medical record system changed and recording of the confidential number decreased. Study interventions (patient activation card and study cell phone) had a synergistic effect on successful contact, especially when confidential numbers were less reliably documented. CONCLUSIONS: Feasible and sustainable interventions such as improved documentation of a confidential number worked synergistically to increase our ability to successfully contact adolescent women with their STI test results.

Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya.

OBJECTIVE: The antigen, falciparum malaria protein 1 (FMP1), represents the 42-kDa C-terminal fragment of merozoite surface protein-1 (MSP-1) of the 3D7 clone of P. falciparum. Formulated with AS02 (a proprietary Adjuvant System), it constitutes the FMP1/AS02 candidate malaria vaccine. We evaluated this vaccine's safety, immunogenicity, and efficacy in African children. METHODS: A randomised, double-blind, Phase IIb, comparator-controlled trial.The trial was conducted in 13 field stations of one mile radii within Kombewa Division, Nyanza Province, Western Kenya, an area of holoendemic transmission of P. falciparum. We enrolled 400 children aged 12-47 months in general good health.Children were randomised in a 1ratio1 fashion to receive either FMP1/AS02 (50 microg) or Rabipur(R) rabies vaccine. Vaccinations were administered on a 0, 1, and 2 month schedule. The primary study endpoint was time to first clinical episode of P. falciparum malaria (temperature >/=37.5 degrees C with asexual parasitaemia of >/=50,000 parasites/microL of blood) occurring between 14 days and six months after a third dose. Case detection was both active and passive. Safety and immunogenicity were evaluated for eight months after first immunisations; vaccine efficacy (VE) was measured over a six-month period following third vaccinations. RESULTS: 374 of 400 children received all three doses and completed six months of follow-up. FMP1/AS02 had a good safety profile and was well-tolerated but more reactogenic than the comparator. Geometric mean anti-MSP-1(42) antibody concentrations increased from1.3 microg/mL to 27.3 microg/mL in the FMP1/AS02 recipients, but were unchanged in controls. 97 children in the FMP1/AS02 group and 98 controls had a primary endpoint episode. Overall VE was 5.1% (95% CI: -26% to +28%; p-value = 0.7). CONCLUSIONS: FMP1/AS02 is not a promising candidate for further development as a monovalent malaria vaccine. Future MSP-1(42) vaccine development should focus on other formulations and antigen constructs. TRIAL REGISTRATION: Clinicaltrials.gov NCT00223990.

Phase 2a trial of 0, 1, and 3 month and 0, 7, and 28 day immunization schedules of malaria vaccine RTS,S/AS02 in malaria-naïve adults at the Walter Reed Army Institute of Research.

BACKGROUND: Immunization with RTS,S/AS02 consistently protects some vaccinees against malaria infection in experimental challenges and in field trials. A brief immunization schedule against falciparum malaria would be compatible with the Expanded Programme on Immunization, or in combination with other prevention measures, interrupt epidemic malaria or protect individuals upon sudden travel to an endemic area. METHODS: We conducted an open label, Phase 2a trial of two different full dose schedules of RTS,S/AS02 in 40 healthy malaria-naïve adults. Cohort 1 (n=20) was immunized on a 0, 1, and 3 month schedule and Cohort 2 (n=20) on a 0, 7, and 28 day schedule. Three weeks later, 38 vaccinees and 12 unimmunized infectivity controls underwent malaria challenge. RESULTS: Both regimens had a good safety and tolerability profile. Peak GMCs of antibody to the circumsporozoite protein (CSP) were similar in Cohort 1 (78 microg/mL; 95% CI: 45-134) and Cohort 2 (65 microg/mL; 95% CI: 40-104). Vaccine efficacy for Cohort 1 was 45% (95% CI: 18-62%) and for Cohort 2, 39% (95% CI: 11-56%). Protected volunteers had a higher GMC of anti-CSP antibody (114 microg/mL) than did volunteers with a 2-day delay (70 microg/mL) or no delay (30 microg/mL) in the time to onset of parasitemia (Kruskal-Wallis, p=0.019). A trend was seen for higher CSP-specific IFN-gamma responses in PBMC from protected volunteers only in Cohort 1, but not in Cohort 2, for ex vivo and for cultured ELISPOT assays. CONCLUSION: In malaria-naïve adults, the efficacy of three-dose RTS,S/AS02 regimens on either a 0, 1, and 3 month schedule or an abbreviated 0, 7, and 28 day schedule was not discernibly different from two previously reported trials of two-dose regimens given at 0, 1 month that conferred 47% (95% CI: -19 to 76%) protection and in another trial 42% (95% CI: 5-63%). A strong association of CSP-specific antibody with protection against malaria challenge is observed and confirms similar observations made in other studies. Subsequent trials of adjuvanted RTS,S in African children and infants on a 0, 1, and 2 month schedule have demonstrated a favorable safety and efficacy profile.

Phase 1 randomized double-blind safety and immunogenicity trial of Plasmodium falciparum malaria merozoite surface protein FMP1 vaccine, adjuvanted with AS02A, in adults in western Kenya.

We report the first trial of candidate malaria vaccine antigen FMP1, a 42kDa fragment from the C-terminus of merozoite surface protein-1 (MSP-1) from the 3D7 strain of Plasmodium falciparum, in an endemic area. Forty adult male and female residents of western Kenya were enrolled to receive 3 doses of either FMP1/AS02A or Imovax rabies vaccine by intra-deltoid injection on a 0, 1, 2 month schedule. Thirty-seven volunteers received all three immunizations and 38 completed the 12-month evaluation period. Slightly more recipients of the FMP1/AS02A vaccine experienced any instance of pain at 24 h post-immunization than in the Imovax group (95% versus 65%), but otherwise the two vaccines were equally safe and well-tolerated. Baseline antibody levels were high in both groups and were boosted in the FMP1/AS02A group. Longitudinal models revealed a highly significant difference between groups for both the average post-baseline antibody responses to MSP-1(42) (F1,335=13.16; P<0.001) and the Day 90 responses to MSP-1(42) (F1,335=16.69; P<0.001). The FMP1/AS02A vaccine is safe and immunogenic in adults and should progress to safety testing in children at greatest risk of malaria.

Safety and reactogenicity of an MSP-1 malaria vaccine candidate: a randomized phase Ib dose-escalation trial in Kenyan children.

OBJECTIVE: Our aim was to evaluate the safety, reactogenicity, and immunogenicity of an investigational malaria vaccine. DESIGN: This was an age-stratified phase Ib, double-blind, randomized, controlled, dose-escalation trial. Children were recruited into one of three cohorts (dosage groups) and randomized in 2:1 fashion to receive either the test product or a comparator. SETTING: The study was conducted in a rural population in Kombewa Division, western Kenya. PARTICIPANTS: Subjects were 135 children, aged 12-47 mo. INTERVENTIONS: Subjects received 10, 25, or 50 microg of falciparum malaria protein 1 (FMP1) formulated in 100, 250, and 500 microL, respectively, of AS02A, or they received a comparator (Imovax (rabies vaccine). OUTCOME MEASURES: We performed safety and reactogenicity parameters and assessment of adverse events during solicited (7 d) and unsolicited (30 d) periods after each vaccination. Serious adverse events were monitored for 6 mo after the last vaccination. RESULTS: Both vaccines were safe and well tolerated. FMP1/AS02A recipients experienced significantly more pain and injection-site swelling with a dose-effect relationship. Systemic reactogenicity was low at all dose levels. Hemoglobin levels remained stable and similar across arms. Baseline geometric mean titers were comparable in all groups. Anti-FMP1 antibody titers increased in a dose-dependent manner in subjects receiving FMP1/AS02A; no increase in anti-FMP1 titers occurred in subjects who received the comparator. By study end, subjects who received either 25 or 50 microg of FMP1 had similar antibody levels, which remained significantly higher than that of those who received the comparator or 10 microg of FMP1. A longitudinal mixed effects model showed a statistically significant effect of dosage level on immune response (F(3,1047) = 10.78, or F(3, 995) = 11.22, p < 0.001); however, the comparison of 25 microg and 50 microg recipients indicated no significant difference (F(1,1047) = 0.05; p = 0.82). CONCLUSIONS: The FMP1/AS02A vaccine was safe and immunogenic in malaria-exposed 12- to 47-mo-old children and the magnitude of immune response of the 25 and 50 microg doses was superior to that of the 10 microg dose.

High fidelity medical simulation in the difficult environment of a helicopter: feasibility, self-efficacy and cost.

BACKGROUND: This study assessed the feasibility, self-efficacy and cost of providing a high fidelity medical simulation experience in the difficult environment of an air ambulance helicopter. METHODS: Seven of 12 EM residents in their first postgraduate year participated in an EMS flight simulation as the flight physician. The simulation used the Laerdal SimMantrade mark to present a cardiac and a trauma case in an EMS helicopter while running at flight idle. Before and after the simulation, subjects completed visual analog scales and a semi-structured interview to measure their self-efficacy, i.e. comfort with their ability to treat patients in the helicopter, and recognition of obstacles to care in the helicopter environment. After all 12 residents had completed their first non-simulated flight as the flight physician; they were surveyed about self-assessed comfort and perceived value of the simulation. Continuous data were compared between pre- and post-simulation using a paired samples t-test, and between residents participating in the simulation and those who did not using an independent samples t-test. Categorical data were compared using Fisher's exact test. Cost data for the simulation experience were estimated by the investigators. RESULTS: The simulations functioned correctly 5 out of 7 times; suggesting some refinement is necessary. Cost data indicated a monetary cost of 440 dollars and a time cost of 22 hours of skilled instructor time. The simulation and non-simulation groups were similar in their demographics and pre-hospital experiences. The simulation did not improve residents' self-assessed comfort prior to their first flight (p > 0.234), but did improve understanding of the obstacles to patient care in the helicopter (p = 0.029). Every resident undertaking the simulation agreed it was educational and it should be included in their training. Qualitative data suggested residents would benefit from high fidelity simulation in other environments, including ground transport and for running codes in hospital. CONCLUSION: It is feasible to provide a high fidelity medical simulation experience in the difficult environment of the air ambulance helicopter, although further experience is necessary to eliminate practical problems. Simulation improves recognition of the challenges present and provides an important opportunity for training in challenging environments. However, use of simulation technology is expensive both in terms of monetary outlay and of personnel involvement. The benefits of this technology must be weighed against the cost for each institution.

Heterologous prime-boost immunization in rhesus macaques by two, optimally spaced particle-mediated epidermal deliveries of Plasmodium falciparum circumsporozoite protein-encoding DNA, followed by intramuscular RTS,S/AS02A.

BACKGROUND: RTS,S/AS02A, a recombinant Plasmodium falciparum vaccine based on the circumsporozoite protein (CSP) repeat and C-terminus regions, elicits strong humoral and Th1 cell-mediated immunity. In field studies, RTS,S/AS02A reduced malaria infection, clinical episodes, and disease severity. Heterologous prime-boost immunization regimens, optimally spaced, might improve the protective immunity of RTS,S/AS02A. METHODS: DNA plasmid encoding P. falciparum CSP (3D7) was administered to six experimental groups of rhesus monkeys (N = 5) by gene gun (coded as D), followed by a 1/5th human dose of RTS,S/AS02A (coded as R). Immunization regimens, including a numeral to denote weeks between immunizations, were D-4-R, D-16-R, D-4-D-4-R, D-4-D-16-R, D-16-D-4-R and D-16-D-16-R. A control group (N = 5) received a single 1/5th dose of RTS,S/AS02A. Endpoints were antibody (Ab) to homologous CSP repeat and C-terminus regions and delayed-type hypersensitivity (DTH) to CSP peptides. FINDINGS: Monkeys immunized twice with DNA, 16 weeks apart (D-16-D-4-R and D-16-D-16-R), developed higher levels of anti-C-terminus Abs than control monkeys (p<0.02). No CSP DNA priming regimen increased RTS,S/AS02A-induced Ab to CSP repeats. At 16 months after first immunization, D-R and D-D-R, but not control, monkeys had histologically confirmed DTH reactions against CSP C-terminus, which persisted at repeat testing 12 months later. INTERPRETATION: Two optimally spaced, particle-mediated epidermal deliveries of CSP DNA improved the humoral immunogenicity of a single dose of RTS,S/AS02A. Further, CSP DNA prime followed by one dose of RTS,S/AS02A gave biopsy proven DTH reactions against CSP C-terminus of up to 2 years duration, implying the induction of CD4+ memory T cells. Heterologous prime-boost strategies for malaria involving gene gun delivered DNA or more potent vectors, administered at optimal intervals, warrant further investigation.