Pilot Evaluation of S-(3-[18F]Fluoropropyl)-D-Homocysteine and O-(2-[18F]Fluoroethyl)-D-Tyrosine as Bacteria-Specific Radiotracers for PET Imaging of Infection.

PURPOSE: There is currently no ideal radiotracer for imaging bacterial infections. Radiolabelled D-amino acids are promising candidates because they are actively incorporated into the peptidoglycan of the bacterial cell wall, a structural feature which is absent in human cells. This work describes fluorine-18 labelled analogues of D-tyrosine and D-methionine, O-(2-[18F]fluoroethyl)-D-tyrosine (D-[18F]FET) and S-(3-[18F]fluoropropyl)-D-homocysteine (D-[18F]FPHCys), and their pilot evaluation studies as potential radiotracers for imaging bacterial infection. PROCEDURES: D-[18F]FET and D-[18F]FPHCys were prepared in classical fluorination-deprotection reactions, and their uptake in Staphylococcus aureus and Pseudomonas aeruginosa was evaluated over 2 h. Heat killed bacteria were used as controls. A clinically-relevant foreign body model of S. aureus infection was established in Balb/c mice, as well as a sterile foreign body to mimic inflammation. The ex vivo biodistribution of D-[18F]FPHCys in the infected and inflamed mice was evaluated after 1 h, by dissection and gamma counting. The uptake was compared to that of [18F]FDG. RESULTS: In vitro uptake of both D-[18F]FET and D-[18F]FPHCys was specific to live bacteria. Uptake was higher in S. aureus than in P. aeruginosa for both radiotracers, and of the two, higher for D-[18F]FPHCys than D-[18F]FET. Blocking experiments with non-radioactive D-[19F]FPHCys confirmed specificity of uptake. In vivo, D-[18F]FPHCys had greater accumulation in S. aureus infection compared with sterile inflammation, which was statistically significant. As anticipated, [18F]FDG showed no significant difference in uptake between infection and inflammation. CONCLUSIONS: D-[18F]FPHCys uptake was higher in infected tissues than inflammation, and represents a fluorine-18 labelled D-AA with potential to detect a S. aureus reference strain (Xen29) in vivo. Additional studies are needed to evaluate uptake of this radiotracer in clinical isolates.

Automated radiosynthesis and preclinical in vivo evaluation of [18F]Fluoroethylpuromycin as a potential radiotracer for imaging protein synthesis with PET.

PURPOSE: From a series of fluorinated analogues of puromycin, we recently identified [18F]fluoroethylpuromycin (FEPURO) as a potential candidate for imaging the rate of protein synthesis in vivo. Herein, we describe the automation of the radiosynthesis, and evaluation of [18F]FEPURO in vivo. PROCEDURES: [18F]FEPURO was radiosynthesised in an automated module. PET imaging was conducted in Wistar rats under control and blocking conditions using the protein synthesis inhibitor cycloheximide. Biodistribution and metabolite studies at 30, 60 and 120 min were conducted in healthy rats. RESULTS: Automation of the radiosynthesis resulted in reduction of the synthesis time by half from the manual method. A steady increase in the SUV was observed in the time-activity curves for the whole brain as expected for a protein synthesis marker. However, rapid in vivo metabolism of [18F]FEPURO within 15 min in plasma as well as the brain (4 % of parent 30 min p.i.) indicated formation of the [18F]FET radio-metabolite in >90 % thus suggesting that observed increase in the brain uptake was due to the radiometabolite. CONCLUSIONS: [18F]FEPURO is not a suitable PET radiotracer for imaging protein synthesis rates in brain in vivo due to its rapid metabolism. Further structural modifications to prevent in vivo metabolism are underway.

Wheel of Wellbeing (WoW) health promotion program: Australian participants report on their experiences and impacts.

BACKGROUND: Community-based mental health promotion programs focus on improving individual and community wellbeing by strengthening resilience and building capacity to support positive health outcomes. The Wheel of Wellbeing (WoW) is an example of such a program, promoting activities that support social engagement and positive emotions within a holistic framework underpinned by positive psychology. WoW is intended to be flexibly implemented in each community, training community members who implement behaviour change activities in their local community, workplace and educational settings. METHOD: This study aimed to understand the opinions and experiences of a sample of individuals who had participated in a range of WoW training programs; documenting the impact on participant behaviours and professional practices, and how the WoW framework was subsequently employed within their communities. Using Ripple Effects Mapping evaluation processes to guide a focus group, nine WoW training participants collectively reflected on the program impacts, generating consensus themes and a mind map. Mind map qualitative data were entered into XMIND mapping software and reviewed with the focus group transcription and field notes. RESULTS: Thematic analysis identified three themes: increased community involvement and engagement (strengthening community connections); improved health, emotions and behaviour (motivating change to health behaviours); and flexible resources which could be utilised in a range of settings (easily incorporated in the existing organisational cultures). CONCLUSIONS: The results of this study support the premise that the WoW framework can be an effective framework for guiding wellbeing promotion activities, with participants championing a 'ripple effect' across individual, family, friendship, professional and community networks.

200 Years Since the Birth of Nursing Informatics?

It is 200 years since the birth of Florence Nightingale. This keynote paper reviews some of her work relating to health statistics and outlines its continuing legacy to nursing informatics around the world and especially in poorer countries, like South Africa, in the 21st century.

A tolerability and patient acceptability pilot study of a novel antimicrobial urinary catheter for long-term use.

AIMS: We have developed a novel antimicrobial urinary catheter (AUC) impregnated with rifampicin, triclosan, and sparfloxacin and demonstrated that it has long-term (∼84 days) protection against bacterial colonization in vitro. This study aimed to assess the safety and patient acceptability of this device in long-term catheter users. METHODS: Adults who use long term (>28 days) indwelling urinary catheters with capacity to consent were invited to receive the AUC at their next catheter change. The primary outcome measure was adverse events (AE) attributable to antimicrobial impregnation of the catheter. Secondary outcome measures included severity of related AEs, patient acceptability, early removal of the trial catheter, and degree of microbial colonization of trial catheters. Except for the last, outcomes were assessed by telephone interviews. Original and trial catheters were collected, and the lumens and balloons were separated and analyzed for microbiological colonization. RESULTS: Thirty participants were recruited. Eighty four AEs were reported, and only one was rated as "probably" related to antimicrobial impregnation. The AE was mild and resolved within 48 h. A total of 82.14% of participants rated the catheter as no different or better than their usual catheter. Two participants chose to remove the AUC early due to it feeling shorter. There were significantly fewer bacterial isolates attached to the balloons of trial catheters compared to the matched original catheters. CONCLUSIONS: The AUC has an advantageous safety profile and was acceptable to the majority of participants. Information gained from this trial will support a larger randomized controlled study of efficacy.

Hypoxia imaging with [18F]HX4 PET in squamous cell head and neck cancers: a pilot study for integration into treatment planning.

BACKGROUND: Radical chemoradiotherapy is the primary treatment for head and neck cancers in many hospitals. Tumour hypoxia causes radiotherapy resistance and is an indicator of poor prognosis for patients. Identifying hypoxia to select patients for intensified or hypoxia-modified treatment regimens is therefore of high clinical importance. PATIENTS AND METHODS: We evaluated hypoxia in a group of patients with newly diagnosed squamous cell head and neck cancer using the hypoxia-selective radiotracer [F]HX4. Patients underwent a single [F]HX4 PET/computed tomography scan prior to beginning chemoradiotherapy. RESULTS: Three out of eight patients recruited were scanned with [F]HX4. Two out of three had pretreatment [F]FDG PET/computed tomography scans available for review. [F]HX4 tumour uptake varied between patients, with tumour to mediastinal ratios ranging from 1 to 3.5. CONCLUSION: The spectrum of [F]HX4 uptake in this small series of patients exemplifies the difference in oxygenation profiles between histologically similar tumours. Performing an additional PET scan with [F]HX4 prior to chemoradiotherapy treatment was logistically challenging in a routine setting, and therefore validation of its clinical impact should be the focus of future studies [EudraCT number 2013-003563-58].

Synthesis, in Vitro Evaluation, and Radiolabeling of Fluorinated Puromycin Analogues: Potential Candidates for PET Imaging of Protein Synthesis.

There is currently no ideal radiotracer for imaging of protein synthesis rate (PSR) by positron emission tomography (PET). Existing fluorine-18-labeled amino acid-based radiotracers predominantly visualize amino acid transporter processes, and in many cases they are not incorporated into nascent proteins at all. Others are radiolabeled with the short-half-life positron emitter carbon-11, which is rather impractical for many PET centers. Based on the puromycin (6) structural manifold, a series of 10 novel derivatives of 6 was prepared via Williamson ether synthesis from a common intermediate. A bioluminescence assay was employed to study their inhibitory action on protein synthesis, which identified the fluoroethyl analogue 7b as a lead compound. The fluorine-18 analogue was prepared via nucleophilic substitution of the corresponding tosylate precursor in a modest radiochemical yield of 2 ± 0.6% with excellent radiochemical purity (>99%) and showed complete stability over 3 h at ambient temperature.

Health Informatics: Developing a Masters Programme in Rwanda based on the IMIA Educational Recommendations and the IMIA Knowledge Base.

Since 2011, the Regional e-Health Center of Excellence in Rwanda (REHCE) has run an MSc in Health Informatics programme (MSc HI). A programme review was commissioned in February 2014 after 2 cohorts of students completed the post-graduate certificate and diploma courses and most students had started preparatory activity for their master dissertation. The review developed a method for mapping course content on health informatics competences and knowledge units. Also the review identified and measured knowledge gaps and content redundancy. Using this method, we analyzed regulatory and programme documents combined with stakeholder interviews, and demonstrated that the existing MSc HI curriculum did not completely address the needs of the Rwandan health sector. Teaching strategies did not always match students' expectations. Based on a detailed Rwandan health informatics needs assessment, International Medical Informatics Association (IMIA)'s Recommendations on Education in Biomedical and Health Informatics and the IMIA Health Informatics Knowledge Base, a new curriculum was developed and provided a better competences match for the specifics of healthcare in the Central African region. The new approved curriculum will be implemented in the 2014/2015 academic year and options for regional extension of the programme to Eastern DRC (Bukavu) and Burundi (Bujumbura) are being investigated.

Nurses behaviour pre and post the implementation of data capture using tablet computers in a rural clinic in South Africa.

This Time and Motion study was part of a larger Open Source Development Project to evaluate the use of Tablet computers for collecting patient data in rural clinics in the OR Tambo District, Eastern Cape, South Africa. The intention was to determine if there were any differences in the activities and workloads between the two methods of data capture. The main difference between the Phases was that the number of activities undertaken per patient decreased in the second phase. More time was spent on each activity.

Automated radiosynthesis of GMP quality [18F]HX4 for PET imaging of hypoxia.

INTRODUCTION: [(18)F]HX4 is a 2-nitroimidazole based investigational radiotracer for imaging hypoxia. METHODS: A two-step, one-pot synthetic procedure was developed on a GE Tracerlab MX-FDG with a disposable cassette. Nucleophilic substitution of a nosylate group with [(18)F]fluoride was followed by solvent evaporation and acidic removal of the acetyl protecting group. HPLC purification in a bio-compatible solvent mixture was developed. RESULTS AND CONCLUSIONS: Using starting activities of 80-110 GBq [(18)F]fluoride, GMP compliant [(18)F]HX4 was produced in non-decay corrected radiochemical yields of 12 ± 3% (n = 9) in 55 min including HPLC purification. No reformulation steps were required. The mean specific activity of the final product was 2450 GBq/µmol. Modifications to the process and final formulation were included to prevent decomposition of the product, and these changes resulted in an improved stability of the formulated [(18)F]HX4, with a shelf-life of at least 8h post-synthesis. The product consistently passed all required quality control tests to determine that the [(18)F]HX4 was suitable for clinical use. Using a 90 minute target bombardment, and 80-110 GBq starting [(18)F]fluoride, the method produced multiple patient doses.

Problemas y soluciones potenciales en la captura de datos de salud en clínicas rurales de Sudáfrica / Issues and potential solutions when capturing health data in rural clinics in South Africa

This paper highlights the data and information required by various International bodies, including WHO, PEPFAR, World Bank and the South African Government regarding HIV and its associated programmes and comorbidities. It explores the current collection of data in South African rural clinics and reports on the results from in-depth interviews with nurses regarding the burden of data collection and the perceptions and attitudes to electronic solutions including smart phones and tablet computers(AU)

Este artículo destaca los datos y la información requeridos por diversos organismos internacionales, como la OMS, el PEPFAR, el Banco Mundial y el Gobierno de Sudáfrica en relación con el VIH y sus programas asociados y comorbilidades. Explora la colección actual de los datos en las clínicas rurales de Sudáfrica y los informes sobre los resultados de las entrevistas en profundidad con las enfermeras con respecto a la carga de la recopilación de datos y las percepciones y actitudes hacia soluciones electrónicas, incluyendo teléfonos inteligentes y tablet PC(AU)

Issues and potential solutions when capturing health data in rural clinics in South Africa

This paper highlights the data and information required by various International bodies, including WHO, PEPFAR, World Bank and the South African Government regarding HIV and its associated programmes and comorbidities. It explores the current collection of data in South African rural clinics and reports on the results from in-depth interviews with nurses regarding the burden of data collection and the perceptions and attitudes to electronic solutions including smart phones and tablet computers(AU)

Este artículo destaca los datos y la información requeridos por diversos organismos internacionales, como la OMS, el PEPFAR, el Banco Mundial y el Gobierno de Sudáfrica en relación con el VIH y sus programas asociados y comorbilidades. Explora la colección actual de los datos en las clínicas rurales de Sudáfrica y los informes sobre los resultados de las entrevistas en profundidad con las enfermeras con respecto a la carga de la recopilación de datos y las percepciones y actitudes hacia soluciones electrónicas, incluyendo teléfonos inteligentes y tablet PC(AU)

A clinical and economic evaluation of Control of Hyperglycaemia in Paediatric intensive care (CHiP): a randomised controlled trial.

BACKGROUND: Early research in adults admitted to intensive care suggested that tight control of blood glucose during acute illness can be associated with reductions in mortality, length of hospital stay and complications such as infection and renal failure. Prior to our study, it was unclear whether or not children could also benefit from tight control of blood glucose during critical illness. OBJECTIVES: This study aimed to determine if controlling blood glucose using insulin in paediatric intensive care units (PICUs) reduces mortality and morbidity and is cost-effective, whether or not admission follows cardiac surgery. DESIGN: Randomised open two-arm parallel group superiority design with central randomisation with minimisation. Analysis was on an intention-to-treat basis. Following random allocation, care givers and outcome assessors were no longer blind to allocation. SETTING: The setting was 13 English PICUs. PARTICIPANTS: Patients who met the following criteria were eligible for inclusion: ≥ 36 weeks corrected gestational age; ≤ 16 years; in the PICU following injury, following major surgery or with critical illness; anticipated treatment > 12 hours; arterial line; mechanical ventilation; and vasoactive drugs. Exclusion criteria were as follows: diabetes mellitus; inborn error of metabolism; treatment withdrawal considered; in the PICU > 5 consecutive days; and already in CHiP (Control of Hyperglycaemia in Paediatric intensive care). INTERVENTION: The intervention was tight glycaemic control (TGC): insulin by intravenous infusion titrated to maintain blood glucose between 4.0 and 7.0 mmol/l. CONVENTIONAL MANAGEMENT (CM): This consisted of insulin by intravenous infusion only if blood glucose exceeded 12.0 mmol/l on two samples at least 30 minutes apart; insulin was stopped when blood glucose fell below 10.0 mmol/l. MAIN OUTCOME MEASURES: The primary outcome was the number of days alive and free from mechanical ventilation within 30 days of trial entry (VFD-30). The secondary outcomes comprised clinical and economic outcomes at 30 days and 12 months and lifetime cost-effectiveness, which included costs per quality-adjusted life-year. RESULTS: CHiP recruited from May 2008 to September 2011. In total, 19,924 children were screened and 1369 eligible patients were randomised (TGC, 694; CM, 675), 60% of whom were in the cardiac surgery stratum. The randomised groups were comparable at trial entry. More children in the TGC than in the CM arm received insulin (66% vs. 16%). The mean VFD-30 was 23 [mean difference 0.36; 95% confidence interval (CI) -0.42 to 1.14]. The effect did not differ among prespecified subgroups. Hypoglycaemia occurred significantly more often in the TGC than in the CM arm (moderate, 12.5% vs. 3.1%; severe, 7.3% vs. 1.5%). Mean 30-day costs were similar between arms, but mean 12-month costs were lower in the TGC than in CM arm (incremental costs -£3620, 95% CI -£7743 to £502). For the non-cardiac surgery stratum, mean costs were lower in the TGC than in the CM arm (incremental cost -£9865, 95% CI -£18,558 to -£1172), but, in the cardiac surgery stratum, the costs were similar between the arms (incremental cost £133, 95% CI -£3568 to £3833). Lifetime incremental net benefits were positive overall (£3346, 95% CI -£11,203 to £17,894), but close to zero for the cardiac surgery stratum (-£919, 95% CI -£16,661 to £14,823). For the non-cardiac surgery stratum, the incremental net benefits were high (£11,322, 95% CI -£15,791 to £38,615). The probability that TGC is cost-effective is relatively high for the non-cardiac surgery stratum, but, for the cardiac surgery subgroup, the probability that TGC is cost-effective is around 0.5. Sensitivity analyses showed that the results were robust to a range of alternative assumptions. CONCLUSIONS: CHiP found no differences in the clinical or cost-effectiveness of TGC compared with CM overall, or for prespecified subgroups. A higher proportion of the TGC arm had hypoglycaemia. This study did not provide any evidence to suggest that PICUs should stop providing CM for children admitted to PICUs following cardiac surgery. For the subgroup not admitted for cardiac surgery, TGC reduced average costs at 12 months and is likely to be cost-effective. Further research is required to refine the TGC protocol to minimise the risk of hypoglycaemic episodes and assess the long-term health benefits of TGC. TRIAL REGISTRATION: Current Controlled Trials ISRCTN61735247. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 26. See the NIHR Journals Library website for further project information.

2-Bromo-6-[(18) F]fluoropyridine: two-step fluorine-18 radiolabelling via transition metal-mediated chemistry.

Novel radiolabelling methods are important for the development of new tracers for positron emission tomography. Direct nucleophilic fluorination of aromatic rings with [(18) F]fluoride is limited to activated substrates, restricting the application of this approach. Inspired by transition metal-mediated transformations, a fluorine-18 synthon was prepared to supplement the radiolabelling methods available for molecules unsuitable for direct labelling. 2-Bromo-6-[(18) F]fluoropyridine (denoted [(18) F]1) was prepared in high yield, and palladium-mediated cross-coupling reactions were exemplified. High incorporation of fluoride and efficient cross-coupling reactions demonstrate that compound [(18) F]1 holds promise as a new synthon for construction of fluorine-18-labelled molecules via transition metal-mediated reactions.

A functional microsatellite of the macrophage migration inhibitory factor gene associated with meningococcal disease.

Macrophage migration inhibitory factor (MIF) is an abundantly expressed proinflammatory cytokine playing a critical role in innate immunity and sepsis and other inflammatory diseases. We examined whether functional MIF gene polymorphisms (-794 CATT(5-8) microsatellite and -173 G/C SNP) were associated with the occurrence and outcome of meningococcal disease in children. The CATT(5) allele was associated with the probability of death predicted by the Pediatric Index of Mortality 2 (P=0.001), which increased in correlation with the CATT(5) copy number (P=0.04). The CATT(5) allele, but not the -173 G/C alleles, was also associated with the actual mortality from meningoccal sepsis [OR 2.72 (1.2-6.4), P=0.02]. A family-based association test (i.e., transmission disequilibrium test) performed in 240 trios with 1 afflicted offspring indicated that CATT(5) was a protective allele (P=0.02) for the occurrence of meningococcal disease. At baseline and after stimulation with Neisseria meningitidis in THP-1 monocytic cells or in a whole-blood assay, CATT(5) was found to be a low-expression MIF allele (P=0.005 and P=0.04 for transcriptional activity; P=0.09 and P=0.09 for MIF production). Taken together, these data suggest that polymorphisms of the MIF gene affecting MIF expression are associated with the occurrence, severity, and outcome of meningococcal disease in children.

Intestinal injury and endotoxemia in children undergoing surgery for congenital heart disease.

RATIONALE: Children with congenital heart disease are at risk of gut barrier dysfunction and translocation of gut bacterial antigens into the bloodstream. This may contribute to inflammatory activation and organ dysfunction postoperatively. OBJECTIVES: To investigate the role of intestinal injury and endotoxemia in the pathogenesis of organ dysfunction after surgery for congenital heart disease. METHODS: We analyzed blood levels of intestinal fatty acid binding protein and endotoxin (endotoxin activity assay) alongside global transcriptomic profiling and assays of monocyte endotoxin receptor expression in children undergoing surgery for congenital heart disease. MEASUREMENTS AND MAIN RESULTS: Levels of intestinal fatty acid binding protein and endotoxin were greater in children with duct-dependent cardiac lesions. Endotoxemia was associated with severity of vital organ dysfunction and intensive care stay. We identified activation of pathogen-sensing, antigen-processing, and immune-suppressing pathways at the genomic level postoperatively and down-regulation of pathogen-sensing receptors on circulating immune cells. CONCLUSIONS: Children undergoing surgery for congenital heart disease are at increased risk of intestinal mucosal injury and endotoxemia. Endotoxin activity correlates with a number of outcome variables in this population, and may be used to guide the use of gut-protective strategies.

Endotoxemia in pediatric critical illness--a pilot study.

INTRODUCTION: The aim was to investigate the prevalence of endotoxemia in children admitted to pediatric intensive care unit (PICU), and its association with disease severity and outcome. METHODS: We conducted a prospective, observational cohort study of children admitted to PICU at St. Mary's Hospital, London over a 6-month period. One hundred consecutive patients were recruited. Demographic and clinical data were collected. Severity of illness was assessed by the pediatric index of mortality 2 (PIM2) score. The pediatric logistic organ dysfunction (PELOD) score was performed daily for the first 4 days. Patients were categorized according to primary reason for PICU admission. Blood samples were taken within 24 hours of admission and endotoxemia was measured using the endotoxin activity assay (EAA). Patients were stratified according to EAA level (high, EAA > 0.4, low, EAA < 0.4) and categorized as septic, post-surgical, respiratory or other. Data were analyzed using appropriate non-parametric tests. RESULTS: EAA level was significantly lower in PICU controls versus other PICU admissions (P = 0.01). Fifty-five children had endotoxemia on admission. Forty-one (75%) of these were eventually diagnosed with an infectious cause of admission. Nine children without infection had elevated EAA on admission. An infectious cause of admission was significantly associated with endotoxemia (P < 0.005). Of 15 children with gram-negative infection, only 9 (60%) had endotoxemia on admission. Endotoxemia on admission was not associated with shock or death. However, there was a tendency for increased PELOD score and length of stay in endotoxemic children. CONCLUSIONS: Endotoxemia is common in children admitted to intensive care. Understanding the implications of endotoxemia and potential anti-endotoxin strategies may have the potential to reduce severity of illness and length of PICU stay in critically ill children.

Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease.

Meningococcal disease is an infection caused by Neisseria meningitidis. Genetic factors contribute to host susceptibility and progression to disease, but the genes responsible for disease development are largely unknown. We report here a genome-wide association study for host susceptibility to meningococcal disease using 475 individuals with meningococcal disease (cases) and 4,703 population controls from the UK. We performed, in Western European and South European cohorts (consisting of 968 cases and 1,376 controls), two replication studies for the most significant SNPs. A cluster of complement factor SNPs replicated independently in both cohorts, including SNPs within complement factor H (CFH) (rs1065489 (p.936D

Control of hyperglycaemia in paediatric intensive care (CHiP): study protocol.

BACKGROUND: There is increasing evidence that tight blood glucose (BG) control improves outcomes in critically ill adults. Children show similar hyperglycaemic responses to surgery or critical illness. However it is not known whether tight control will benefit children given maturational differences and different disease spectrum. METHODS/DESIGN: The study is an randomised open trial with two parallel groups to assess whether, for children undergoing intensive care in the UK aged

Polymorphisms in PARP, IL1B, IL4, IL10, C1INH, DEFB1, and DEFA4 in meningococcal disease in three populations.

The pathogenesis of meningococcal infections involves activation of the complement system, proinflammatory and anti-inflammatory mediators, antimicrobial peptides, and apoptosis. We hypothesized that variations in genes encoding these products are involved in the susceptibility to and severity of pediatric meningococcal infections. Polymorphisms in poly (adenosine diphosphate-ribose) polymerase (PARP), serine protease C1 inhibitor (C1INH), IL4, IL10 and IL1B, alpha-defensin 4, and beta-defensin 1 (DEFB1) were analyzed in two independent Caucasian case control cohorts from the United Kingdom and the Netherlands and in a family-based transmission disequilibrium test cohort from the UK. In the UK case control cohort, the DEFB1 -44 G/G homozygous genotype was overrepresented in patients with meningococcal disease compared with the G/C and C/C genotypes when combined (odds ratio, 1.57; 95% confidence interval, 1.12-2.20). The transmission disequilibrium test analysis did not confirm this, but did find an association and linkage of the IL4 -524 and the C1INH 480 polymorphisms with susceptibility to meningococcal infection. Hematological failure was present more often in UK patients with the DEFB1 -44 G/G genotype compared with the C allele carriers (odds ratio, 2.17; 95% confidence interval, 1.22-3.85). Additional studies are necessary to elucidate the conflicting results obtained for the DEFB1, IL4, and C1INH polymorphisms and their role in susceptibility to and severity of meningococcal disease.