Risk of Acute Kidney Injury in Combat-Injured Patients Associated With Concomitant Vancomycin and Extended-Spectrum ß-Lactam Antibiotic Use.

BACKGROUND: Multidrug-resistant infections complicating combat-related trauma necessitate the use of broad-spectrum antimicrobials. Recent literature posits an association between vancomycin (VANC) and piperacillin-tazobactam (VPT) combination therapy and acute kidney injury (AKI). We examined whether therapy with VPT was associated with an increased risk of AKI compared to VANC and other broad-spectrum ß-lactam antibiotics (VBL) following combat-related injuries. METHODS: Patients within the Trauma Infectious Disease Outcomes Study (TIDOS) who received ≥48 hours concomitant VPT or VBL started within 24 hours of each other were assessed. Exclusion criteria were receipt of renal replacement therapy and baseline creatinine >1.5 mg/dL. Acute kidney injury was defined by meeting any of the Risk, Injury, Failure, Loss, End Stage Renal Disease (RIFLE), AKIN, or VANC consensus guidelines criteria 3 to 7 days after therapy initiation. Variables significantly associated with AKI were used in inverse probability treatment weighting to perform univariate and subsequent logistic regression multivariate modeling to determine significant risk factors for AKI. RESULTS: Sixty-one patients who received VPT and 207 who received VBL were included. Both groups had a median age of 24 years and initial median creatinine of 0.7 mg/dL. The VBL patients were more likely to have sustained blast injuries (P = .001) and received nephrotoxic agents (amphotericin [P = .002] and aminoglycosides [P < .001]). In the VBL group, AKI incidence was 9.7% compared to 13.1% in the VPT group (P = .438). Multivariate analysis identified a relative risk of 1.727 (95% CI: 1.027-2.765) for AKI associated with VPT exposure. Acute kidney injury severity generally met RIFLE Risk criteria and was 1 day in duration. Only 1 patient had persistent renal dysfunction 30 days after therapy completion. CONCLUSION: In this young and previously healthy, severely ill combat-injured population, VPT was associated with nearly twice the risk of AKI compared to VBL. Nevertheless, AKI was of low severity, short duration, and had high rates of renal recovery.

An empirical study of how the Dutch healthcare regulator first formulates the concept of trust and then puts it into practice.

BACKGROUND: Responsive regulation assumes that the parties being regulated are trustworthy and motivated by social responsibility. This assumes that regulation based upon trust will improve the regulated organization more effectively than other regulation models. The purpose of our qualitative study was to unravel the most important elements of trust in the inspectee which can support the inspector's work and to develop a model and a framework of trust that can be used by the inspectors to legitimize their trust in the inspectee. METHODS: We conducted an empirical study on trust regarding the regulation of care services to reveal how trust in the inspectee is conceptualized and assessed. Based on literature and empirical research, we synthesized the concept of trust into six elements, five regarding behavior, and a sixth looking at information about its context. We developed a practical framework for the concept to reduce the conceptual ambiguity, strengthen regulatory assessment, and support appropriate tailoring of the regulatory response. RESULTS: Six elements with respect to trust emerged from the data: showing integrity; transparency; ability to learn; accepting feedback; showing actual change in behavior; context information. These five behavioral elements, plus the context information were merged into a Framework of Trust and designed into an interactive PDF document. CONCLUSIONS: This study has sought to address a gap in the empirical knowledge regarding the assessment of trust in the inspectee. The results aim to inform and clarify the regulatory conceptualization and understanding of trust in the inspectee. Other inspectorates may learn from these results for their own practice and explore whether operational deployment of our Framework of Trust effects their assessment and enforcement strategies.

What are the perceived added values and barriers of regulating long-term care in the home environment using a care network perspective: a qualitative study.

BACKGROUND: Changes in Dutch policy towards long-term care led to the Dutch Health and Youth Care Inspectorate testing a regulatory framework focusing on care networks around older adults living independently. This regulatory activity involved all care providers and the older adults themselves. METHODS: Semi-structured interviews with the older adults, and focus groups with care providers and inspectors were used to assess the perceived added value of, and barriers to the framework. RESULTS: The positive elements of this framework were the involvement of the older adults in the regulatory activity, the focus of the framework on care networks and the open character of the conversations with the inspectors. However, applying the framework requires a substantial investment of time. Care providers often did not perceive themselves as being part of a care network around one person and they expressed concerns about financial and privacy issues when thinking in terms of care networks. CONCLUSIONS: The experiences of the client were seen as important in regulating long-term care. Regulating care networks as a whole puts cooperation between care providers involved around one person on the agenda. However, barriers for this form of regulation were also perceived and, therefore, careful consideration when and how to regulate care networks is recommended.

Inspectors' responses to adolescents' assessment of quality of care: a case study on involving adolescents in inspections.

BACKGROUND: Users of care services are increasingly participating in inspections of the quality of care. In practice, incorporating service users' views is difficult, as users may have other views on good care than inspectors and thus give information that does not fit the inspectors' assessment criteria. This study compared the views on good care of young care users (adolescents) and inspectors, seeking to understand what the differences and similarities mean to incorporating the users' views in inspections. METHODS: We conducted a single-case study combining document analysis with a meeting with inspectors. The selected case came from a Dutch inspectorate and involved a thematic inspection of care for children growing up poor. RESULTS: Inspectors and adolescents agree on the importance of timely care, creating opportunities for personal development, and a respectful relationship. The views on quality of care differ with regard to sharing information, creating solutions, and the right moment to offer help. We identified three ways inspectors deal with the differences: 1) prioritize their own views, 2) pass the problem onto others to solve, and 3) separate the differing perspectives. With similar viewpoints, inspectors use the adolescents' views to support their assessments. When viewpoints conflict, information from adolescents does not affect the inspectors' judgments. Explanations are related to the vulnerability of the adolescents involved, the inspectorate's organizational rules and routines and the external regulatory context. CONCLUSIONS: Service user involvement in inspections potentially impacts the quality of care. Yet, conflicts between the views of service users and inspectors are not easily overcome in the regulatory context.

Important factors for effective patient safety governance auditing: a questionnaire survey.

BACKGROUND: Audits are increasingly used for patient safety governance purposes. However, there is little insight into the factors that hinder or stimulate effective governance based on auditing. The aim of this study is to quantify the factors that influence effective auditing for hospital boards and executives. METHODS: A questionnaire of 32 factors was developed using influencing factors found in a qualitative study on effective auditing. Factors were divided into four categories. The questionnaire was sent to the board of directors, chief of medical staff, nursing officer, medical department head and director of the quality and safety department of 89 acute care hospitals in the Netherlands. RESULTS: We approached 522 people, of whom 211 responded. Of the 32 factors in the questionnaire, 30 factors had an agreement percentage higher than 50%. Important factors per category were 'audit as an improvement tool as well as a control tool', 'department is aware of audit purpose', 'quality of auditors' and 'learning culture at department'. We found 14 factors with a significant difference in agreement between stakeholders of at least 20%. Amongst these were 'medical specialist on the audit team', 'soft signals in the audit report', 'patients as auditors' and 'post-audit support'. CONCLUSION: We found 30 factors for effective auditing, which we synthesised into eight recommendations to optimise audits. Hospitals can use these recommendations as a framework for audits that enable boards to become more in control of patient safety in their hospital.

A cross-sectional study into medical students' perceptions of healthcare regulation and self-reported compliance: a study conducted in the City of Al Ain, United Arab Emirates, 2016.

BACKGROUND: Although healthcare regulation is commonplace, there is limited evidence of its impact. Making sure that healthcare professionals comply with the regulatory requirements is a prerequisite to achieving effective regulation. Therefore, investigating factors that influence compliance may provide better insights into how regulators can be more effective. This study aimed to find out if medical students' perceptions of regulation in the United Arab Emirates are associated with self-reported regulatory compliance. METHODS: In the cross-sectional study, we administered a structured questionnaire to students of medicine with different statements concerning their perceptions of healthcare regulation and self-reported compliance. The statements included statement regarding the legitimacy, fairness and regulatory performance, as well as the risk to getting caught and being punished. The association between perceptions and self-reported compliance was analyzed using multiple regression models. RESULTS: One hundred and six Year 3 and 4 pre-clinical medicine students (56.4% response rate) completed the survey. Almost 40% of the students rated their level of awareness and understanding of regulation as Good or Very Good., despite their lack of direct contact with the regulatory authorities (less than 10% reported monthly or more frequent contact). Self-reported compliance was high with almost 85% of the students either agreeing or strongly agreeing with the four compliance statements (mean score 4.1 out of 5). The findings suggest that positive perceptions of the regulator's performance (ß 0.27; 95% CI 0.13-0.41), fairness of the regulatory processes (ß 0.25; 95% CI 0.11-0.38) and its legitimacy (ß 0.23; 95% CI 0.05-0.41), are stronger associated with compliance than the perceived risks of getting caught and being punished (ß 0.10; 95% CI -0.04 - 0.23). CONCLUSIONS: To improve compliant behavior, healthcare regulators should pay more attention to their own perceived performance, as well as the perceived fairness and legitimacy of their regulatory processes rather than focusing on more traditional methods of deterrence, such as perceived risk of getting caught and being published.

Progress and outcomes of health systems reform in the United Arab Emirates: a systematic review.

BACKGROUND: The United Arab Emirates (UAE) government aspires to build a world class health system to improve the quality of healthcare and the health outcomes for its population. To achieve this it has implemented extensive health system reforms in the past 10 years. The nature, extent and success of these reforms has not recently been comprehensively reviewed. In this paper we review the progress and outcomes of health systems reform in the UAE. METHODS: We searched relevant databases and other sources to identify published and unpublished studies and other data available between 01 January 2002 and 31 March 2016. Eligible studies were appraised and data were descriptively and narratively synthesized. RESULTS: Seventeen studies were included covering the following themes: the UAE health system, population health, the burden of disease, healthcare financing, healthcare workforce and the impact of reforms. Few, if any, studies prospectively set out to define and measure outcomes. A central part of the reforms has been the introduction of mandatory private health insurance, the development of the private sector and the separation of planning and regulatory responsibilities from provider functions. The review confirmed the commitment of the UAE to build a world class health system but amongst researchers and commentators opinion is divided on whether the reforms have been successful although patient satisfaction with services appears high and there are some positive indications including increasing coverage of hospital accreditation. The UAE has a rapidly growing population with a unique age and sex distribution, there have been notable successes in improving child and maternal mortality and extending life expectancy but there are high levels of chronic diseases. The relevance of the reforms for public health and their impact on the determinants of chronic diseases have been questioned. CONCLUSIONS: From the existing research literature it is not possible to conclude whether UAE health system reforms are working. We recommend that research should continue in this area but that research questions should be more clearly defined, focusing whenever possible on outcomes rather than processes.

Government supervision on quality of smoking-cessation counselling in midwifery practices: a qualitative exploration.

BACKGROUND: The Dutch Healthcare Inspectorate supervises care providers in order to improve quality of care. Recently the inspectorate assessed and promoted the use of a guideline on smoking-cessation counselling in midwifery practices. The supervision programme consisted of an announcement of the enforcement deadline for the guideline and site visits. The purpose of our qualitative study was to identify factors related to guideline adherence after the supervision programme, and investigate whether the programme had helped improve adherence. METHODS: We conducted semi-structured interviews with inspected and non-inspected midwives. Additionally, we studied documents and observed the inspection process. The sampled midwives all work in primary care midwifery practices providing care to pregnant smokers. The questions included the current provision of smoking-cessation counselling, support to the midwife in counselling, recent changes in provision of counselling, reasons for recent changes, knowledge about the supervision programme, and experiences with supervision by the inspectorate. RESULTS: Our results show that guideline adherence depends on several factors. Awareness and familiarity with the guideline are important, as is outcome expectancy. Additionally, motivation, guideline factors and environment factors were mentioned. Besides these previously documented factors, we found that professional collaboration also determined guideline adherence. Increased collaboration in counselling is associated with greater adherence to the guideline, such as provision of counselling and taking required training. The supervision programme helped improve stop-smoking counselling, by making midwives aware of the counselling and giving them an extrinsic motivation to provide counselling. CONCLUSION: Motivation and environmental aspects were the most important factors related to guideline adherence, and professional environment was added as significant factor. The improved guideline adherence is partly attributable to the supervision programme.

Perspectives on the risks for older adults living independently.

Insight into risks concerning older adults living independently from their own perspective and their care provider's perspective is essential to address issues that may threaten their independent living. The most often mentioned perceived risks by older adults and their care providers in different regions in the Netherlands were: loneliness, falls, budget cuts in Dutch long-term care and not being able to call for help. The different perspectives of the respondents show a wide variety in risks, but also some similarities. The perspective of the frail older adults is required to gain insight into the priority of their perceived risks. An additional finding was the reluctance shown by the older adults to ask others in their social network for help. Results imply that possible preventive measures should not only focus on the medical or physical domain because older adults are likely to have other priorities to maintain self-reliance and live independently.

Patients' perspectives on the role of their complaints in the regulatory process.

BACKGROUND: Governments in several countries are facing problems concerning the accountability of regulators in health care. Questions have been raised about how patients' complaints should be valued in the regulatory process. However, it is not known what patients who made complaints expect to achieve in the process of health-care quality regulation. OBJECTIVE: To assess expectations and experiences of patients who complained to the regulator. DESIGN: Interviews were conducted with 11 people, and a questionnaire was submitted to 343 people who complained to the Dutch Health-care Inspectorate. The Inspectorate handled 92 of those complaints. This decision was based on the idea that the Inspectorate should only deal with complaints that relate to 'structural and severe' problems. RESULTS: The response rate was 54%. Self-reported severity of physical injury of complaints that were not handled was significantly lower than of complaints that were. Most respondents felt that their complaint indicated a structural and severe problem that the Inspectorate should act upon. The desire for penalties or personal satisfaction played a lesser role. Only a minority felt that their complaint had led to improvements in health-care quality. CONCLUSIONS: Patients and the regulator share a common goal: improving health-care quality. However, patients' perceptions of the complaints' relevance differ from the regulator's perceptions. Regulators should favour more responsive approaches, going beyond assessing against exclusively clinical standards to identify the range of social problems associated with complaints about health care. Long-term learning commitment through public participation mechanisms can enhance accountability and improve the detection of problems in health care.

Evaluation of moral case deliberation at the Dutch Health Care Inspectorate: a pilot study.

BACKGROUND: Moral case deliberation (MCD) as a form of clinical ethics support is usually implemented in health care institutions and educational programs. While there is no previous research on the use of clinical ethics support on the level of health care regulation, employees of regulatory bodies are regularly confronted with moral challenges. This pilot study describes and evaluates the use of MCD at the Dutch Health Care Inspectorate (IGZ). The objective of this pilot study is to investigate: 1) the current way of dealing with moral issues at the IGZ; 2) experience with and evaluation of MCD as clinical ethics support, and 3) future preferences and (perceived) needs regarding clinical ethics support for dealing with moral questions at the IGZ. METHODS: We performed an explorative pilot study. The research questions were assessed by means of: 1) interviews with MCD participants during four focus groups; and 2) interviews with six key stakeholders at the IGZ. De qualitative data is illustrated by data from questionnaires on MCD outcomes, perspective taking and MCD evaluation. RESULTS: Professionals do not always recognize moral issues. Employees report a need for regular and structured moral support in health care regulation. The MCD meetings are evaluated positively. The most important outcomes of MCD are feeling secure and learning from others. Additional support is needed to successfully implement MCD at the Inspectorate. CONCLUSION: We conclude that the respondents perceive moral case deliberation as a useful form of clinical ethics support for dealing with moral questions and issues in health care regulation.

Effects of Government Supervision on Quality of Integrated Diabetes Care: A Cluster Randomized Controlled Trial.

OBJECTIVES: The quality of integrated diabetes care is important for reducing the burden of diabetes. Therefore, we have evaluated the effect of a supervision program on the quality of integrated diabetes care in the Netherlands in the 2011-2012 period. METHODS: In this cluster RCT, the supervision program was assigned to randomly selected care groups providing care to diabetes patients. The supervision program included announcements of inspections, site visits, and sending individualized reports. Indicators of effectiveness were derived from the structures, processes, and outcomes of care. These indicators were collected from patients' files, before and after the supervision program. Hierarchical linear and logistic regression models were used to analyze data from 356 patients of 10 intervention and 8 control care groups. RESULTS: Structures and processes of care did not improve more in the intervention groups than in the control care groups. Moreover, health outcomes did not improve more in the intervention groups than in the control care groups. Although structures of care improved over time in the total population of intervention and control care groups, there were no changes in process of care or health outcomes. CONCLUSIONS: In this cluster RCT, we could not demonstrate improvements in quality of integrated diabetes care resulting from the supervision program. Although structures of care did improve over time, other quality-improvement initiatives are necessary to substantially strengthen integrated care for diabetes patients.

Does government supervision improve stop-smoking counseling in midwifery practices?

INTRODUCTION: Smoking-cessation counseling during pregnancy is important to prevent smoking-related harm in pregnant smokers and their children. Therefore we evaluated the effects of an Inspectorate's supervision programme on the provision of smoking-cessation counseling by midwifery practices in the Netherlands. The supervision programme consisted of 3 elements: A) A deadline was announced by which all practices should comply with professional norms on such counseling (2011); B) A set of randomly selected practices were assessed using a questionnaire and a personal feedback report (2010); C) Another set of randomly selected practices were assessed through a site visit and a personal feedback report (2012). METHODS: Programme A was evaluated in a before-after study, Programmes B and C were evaluated in a randomized controlled trial (RCT) with only a post-intervention measurement. Primary outcome was provision of smoking-cessation counseling through a minimal-intervention strategy (V-MIS). Linear and logistic regression models were used to analyze data from 233 primary-care midwifery practices. RESULTS: A) After announcement of the deadline, Dutch midwifery practices reported significantly more provision of smoking-cessation counseling. For example, the use of V-MIS increased substantially from 28% to 80%; B) In practices that were assessed with a questionnaire, the provision of counseling improved partially compared to controls; C) The provision of counseling did not differ between practices that were visited and their controls. While the training participation rate in counseling by midwifery practices did not differ between the intervention and control groups, the rate increased significantly in all practices after the start of the supervision programme. CONCLUSIONS: The provision of smoking-cessation counseling improved spectacularly in Dutch midwifery practices. Despite some limitations of our study, the Inspectorate's supervision programme is likely to have contributed to the improvements in provision of counseling.

Including citizens in institutional reviews: expectations and experiences from the Dutch Healthcare Inspectorate.

BACKGROUND: Recent changes in the structure and policy context of Dutch health care have placed the issue of citizen participation high on the agenda of the Dutch Healthcare Inspectorate (IGZ), which conducts quality and safety reviews in medical practices and health-care institutions. With a few exceptions, the potential role that citizens can play in the regulation of health-care institutions is overlooked in research on patient/citizen participation in health care. OBJECTIVE: This research addressed the following question: What are the (political) expectations for increasing citizen participation in health-care regulation and how do these compare to regulators' expectations and experiences in practice? DESIGN: Because of the largely explorative nature of this study, we used qualitative methods (document and web analysis, focus groups and interviews) to answer this question. RESULTS: Our study shows that inspectors already have experience with participatory formats that lead to important information. There are three areas where the IGZ is currently increasing citizen participation: (i) providing individuals with information about inspectorate processes and activities, (ii) including patients as sources of information, and (iii) formally reviewing how citizen participation is ensured by health-care institutions. In situations where the patient has the clearest overview of the whole care trajectory, intensive methods of participation deliver valuable information. CONCLUSIONS: It is important to target participation activities and to capitalize on existing opportunities and activities, rather than creating participation activities for the sake of participation. In this regard, further research on the effectiveness and efficacy of different participatory strategies is necessary.

The public's voice about healthcare quality regulation policies. A population-based survey.

BACKGROUND: In the wake of various high-profile incidents in a number of countries, regulators of healthcare quality have been criticised for their 'soft' approach. In politics, concerns were expressed about public confidence. It was claimed that there are discrepancies between public opinions related to values and the values guiding regulation policies. Although the general public are final clients of regulators' work, their opinion has only been discussed in research to a limited extent. The aim of this study is to explore possible discrepancies between public values and opinions and current healthcare quality regulation policies. METHODS: A questionnaire was submitted to 1500 members of the Dutch Healthcare Consumer Panel. Questions were developed around central ideas underlying healthcare quality regulation policies. RESULTS: The response rate was 58.3%. The regulator was seen as being more responsible for quality of care than care providers. Patients were rated as having the least responsibility. Similar patterns were observed for the food service industry and the education sector. Complaints by patients' associations were seen as an important source of information for quality regulation, while fewer respondents trusted information delivered by care providers. However, respondents supported the regulator's imposition of lighter measures firstly. CONCLUSIONS: There are discrepancies and similarities between public opinion and regulation policies. The discrepancies correspond to fundamental concepts; decentralisation of responsibilities is not what the public wants. There is little confidence in the regulator's use of information obtained by care providers' internal monitoring, while a larger role is seen for complaints of patient organisations. This discrepancy seems not to exist regarding the regulator's approach of imposing measures. A gradual, and often soft approach, is favoured by the majority of the public in spite of the criticism that is voiced in the media regarding this approach. Our study contributes to the limited knowledge of public opinion on government regulation policies. This knowledge is needed in order to effectively assess different approaches to involve the public in regulation policies.

Guideline adherence and health outcomes in diabetes mellitus type 2 patients: a cross-sectional study.

BACKGROUND: The complex disease of diabetes mellitus type 2 (T2DM) requires a high standard of quality of care. Clinical practice guidelines define norms for diabetes care that ensure regular monitoring of T2DM patients, including annual diagnostic tests. This study aims to quantify guideline adherence in Dutch general practices providing care to T2DM patients and explores the association between guideline adherence and patients' health outcomes. METHODS: In this cross-sectional study, we studied 363 T2DM patients in 32 general practices in 2011 and 2012. Guideline adherence was measured by comparing structure and process indicators of care with recommendations in the national diabetes care guideline. Health outcomes included biomedical measures and health behaviours. Data was extracted from medical records. The association between guideline adherence and health outcomes was analysed using hierarchical linear and logistic regression models. RESULTS: Guideline adherence varied between different recommendations. For example 53% of the practices had a system for collecting patient experience feedback, while 97% had a policy for no-show patients. With regard to process indicators of care, guideline adherence was below 50% for foot, eye and urine albumin examination and high (>85%) for blood pressure, HbA1c and smoking behaviour assessment. Although guideline adherence varied considerably between practices, after adjusting for patient characteristics we found guideline adherence not to be associated with patients' health outcomes. CONCLUSIONS: Guideline adherence in Dutch general practices offering diabetes care was not optimal. Despite considerable variations between general practices, we found no clear relationship between guideline adherence and health outcomes. More research is needed to better understand the relationship between guideline adherence and health outcomes, specifically for guidelines that are based on limited scientific evidence.

Late-presenting Plasmodium falciparum Malaria in a Non-Endemic Setting During COVID-19 Travel Restrictions.

We report a case of febrile Plasmodium falciparum malaria in a 36-year-old male patient occurring 14 years after immigration from and more than 12 months since a return visit to the endemic area. The critical need for awareness regarding late presentations of P. falciparum is discussed.

The development of quality indicators in mental healthcare: a discrete choice experiment.

BACKGROUND: Health care regulatory agencies perform audits or inspections to judge the quality and safety of health care. This judgment is based on the assessment of a large set of health care indicators as accepted by the profession. However, there is a lack of knowledge about the influence of these indicators and whether a smaller number would be sufficient for a quality assessment or audit procedure. METHODS: A discrete choice experiment (DCE) was performed for the assessment of quality of care regarding the management of patients with schizophrenia and drug dependency in psychiatric institutes. Based on multidisciplinary guidelines for the treatment of schizophrenia and a visit of (co)inspectors of the Dutch Healthcare Inspectorate at all 33 integrated mental hospitals a set of 51 indicators were assessed in a subsequent interview. With the analysis of the results, 6 attributes were selected for the DCE as quality indicators. RESULTS: Seventy-six percent of all health services (co)inspectors (n = 33) involved in the inspection of mental health services, participated in the experiment. Respondents considered an operational elaborate treatment plan the most important indicator for the assessment of quality of care in a psychiatric institute, followed by a general care program, treatment outcome measurement, and involvement in treatment of patients and relatives. Pharmacotherapy and governance responsibility were valued as less important indicators. CONCLUSIONS: The results of this DCE show that there is a prioritisation in the six selected quality indicators. This might help health services (co) inspectors to enhance the efficiency and transparency of the quality of care assessment for patients with schizophrenia and/or drug dependency in psychiatric institutes.

First-in-human assessment of safety and immunogenicity of low and high doses of Plasmodium falciparum malaria protein 013 (FMP013) administered intramuscularly with ALFQ adjuvant in healthy malaria-naïve adults.

The global burden of malaria remains substantial. Circumsporozoite protein (CSP) has been demonstrated to be an effective target antigen, however, improvements that offer more efficacious and more durable protection are still needed. In support of research and development of next-generation malaria vaccines, Walter Reed Army Institute of Research (WRAIR) has developed a CSP-based antigen (FMP013) and a novel adjuvant ALFQ (Army Liposome Formulation containing QS-21). We present a single center, open-label, dose-escalation Phase 1 clinical trial to evaluate the safety and immunogenicity of the FMP013/ALFQ malaria vaccine candidate. In this first-in-human evaluation of both the antigen and adjuvant, we enrolled ten subjects; five received 20 µg FMP013 / 0.5 mL ALFQ (Low dose group), and five received 40 µg FMP013 / 1.0 mL ALFQ (High dose group) on study days 1, 29, and 57. Adverse events and immune responses were assessed during the study period. The clinical safety profile was acceptable and there were no serious adverse events. Both groups exhibited robust humoral and cellular immunological responses, and compared favorably with historical responses reported for RTS,S/AS01. Based on a lower reactogenicity profile, the 20 µg FMP013 / 0.5 mL ALFQ (Low dose) was selected for follow-on efficacy testing by controlled human malaria infection (CHMI) with a separate cohort. Trial Registration:Clinicaltrials.gov Identifier NCT04268420 (Registered February 13, 2020).

Recruitment of Gr-1+ monocytes is essential for control of acute toxoplasmosis.

Circulating murine monocytes comprise two largely exclusive subpopulations that are responsible for seeding normal tissues (Gr-1-/CCR2-/CX3CR1high) or responding to sites of inflammation (Gr-1+/CCR2+/CX3CR1lo). Gr-1+ monocytes are recruited to the site of infection during the early stages of immune response to the intracellular pathogen Toxoplasma gondii. A murine model of toxoplasmosis was thus used to examine the importance of Gr-1+ monocytes in the control of disseminated parasitic infection in vivo. The recruitment of Gr-1+ monocytes was intimately associated with the ability to suppress early parasite replication at the site of inoculation. Infection of CCR2-/- and MCP-1-/- mice with typically nonlethal, low doses of T. gondii resulted in the abrogated recruitment of Gr-1+ monocytes. The failure to recruit Gr-1+ monocytes resulted in greatly enhanced mortality despite the induction of normal Th1 cell responses leading to high levels of IL-12, TNF-alpha, and IFN-gamma. The profound susceptibility of CCR2-/- mice establishes Gr-1+ monocytes as necessary effector cells in the resistance to acute toxoplasmosis and suggests that the CCR2-dependent recruitment of Gr-1+ monocytes may be an important general mechanism for resistance to intracellular pathogens.