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IFN-γ–driven responses to malaria have been shown to modulate the development and function of T follicular helper (TFH) cells and memory B cells (MBCs), with conflicting evidence of their involvement in the induction of antibody responses required to achieve clinical immunity and their association with disease outcomes. Using high-dimensional single-cell mass cytometry, we identified distinct populations of TH1-polarized CD4+ T cells and MBCs expressing the TH1-defining transcription factor T-bet, associated with either increased or reduced risk of Plasmodium vivax (P. vivax) malaria, demonstrating that inflammatory responses to malaria are not universally detrimental for infection. Furthermore, we found that, whereas class-switched but not IgM+ MBCs were associated with a reduced risk of symptomatic malaria, populations of TH1 cells with a stem central memory phenotype, TH17 cells, and T regulatory cells were associated with protection from asymptomatic infection, suggesting that activation of cell-mediated immunity might also be required to control persistent P. vivax infection with low parasite burden.

Summary: Despite the key role that antibodies play in protection, the cellular processes mediating the acquisition of humoral immunity against malaria are not fully understood. Using an infection model of severe malaria, we find that germinal center (GC) B cells upregulate the transcription factor T-bet during infection. Molecular and cellular analyses reveal that T-bet in B cells is required not only for IgG2c switching but also favors commitment of B cells to the dark zone of the GC. T-bet was found to regulate the expression of Rgs13 and CXCR3, both of which contribute to the impaired GC polarization observed in the absence of T-bet, resulting in reduced IghV gene mutations and lower antibody avidity. These results demonstrate that T-bet modulates GC dynamics, thereby promoting the differentiation of B cells with increased affinity for antigen. : Antibody responses play a pivotal role in clinical immunity to malaria. Ly et al. report that that germinal center (GC) B cells upregulate the transcription factor T-bet during infection. T-bet favors commitment of B cells to the GC dark zone, thereby augmenting immunoglobulin gene mutation rates and antibody affinity maturation. Keywords: malaria, T-bet, B cells, germinal center, antibodies, affinity maturation

A single exposure to many viral and bacterial pathogens typically induces life-long immunity, however, the development of the protective immunity to Plasmodium parasites is strikingly less efficient and achieves only partial protection, with adults residing in endemic areas often experiencing asymptomatic infections. Although naturally acquired immunity to malaria requires both cell-mediated and humoral immune responses, antibodies govern the control of malarial disease caused by the blood-stage form of the parasites. A large body of epidemiological evidence described that antibodies to Plasmodium antigens are inefficiently generated and rapidly lost without continued parasite exposure, suggesting that malaria is accompanied by defects in the development of immunological B cell memory. This topic has been of focus of recent studies of malaria infection in humans and mice. This review examines the main findings to date on the processes that modulate the acquisition of memory B cell responses to malaria, and highlights the importance of closing outstanding gaps of knowledge in the field for the rational design of next generation therapeutics against malaria.

Naturally acquired immunity to malaria develops only after years of repeated exposure to Plasmodium parasites. Despite the key role antibodies play in protection, the cellular processes underlying the slow acquisition of immunity remain unknown. Using mouse models, we show that severe malaria infection inhibits the establishment of germinal centers (GCs) in the spleen. We demonstrate that infection induces high frequencies of T follicular helper (Tfh) cell precursors but results in impaired Tfh cell differentiation. Despite high expression of Bcl-6 and IL-21, precursor Tfh cells induced during infection displayed low levels of PD-1 and CXCR5 and co-expressed Th1-associated molecules such as T-bet and CXCR3. Blockade of the inflammatory cytokines TNF and IFN-γ or T-bet deletion restored Tfh cell differentiation and GC responses to infection. Thus, this study demonstrates that the same pro-inflammatory mediators that drive severe malaria pathology have detrimental effects on the induction of protective B cell responses.

BackgroundThe Natural Killer Complex (NKC) is a genetic region of highly linked genes encoding several receptors involved in the control of NK cell function. The NKC is highly polymorphic and allelic variability of various NKC loci has been demonstrated in inbred mice, providing evidence for NKC haplotypes. Using BALB.B6-Cmv1r congenic mice, in which NKC genes from C57BL/6 mice were introduced into the BALB/c background, we have previously shown that the NKC is a genetic determinant of malarial pathogenesis. C57BL/6 alleles are associated with increased disease-susceptibility as BALB.B6-Cmv1r congenic mice had increased cerebral pathology and death rates during P. berghei ANKA infection than cerebral malaria-resistant BALB/c controls.MethodsTo investigate which regions of the NKC are involved in susceptibility to experimental cerebral malaria (ECM), intra-NKC congenic mice generated by backcrossing recombinant F2 progeny from a (BALB/c x BALB.B6-Cmv1r) F1 intercross to BALB/c mice were infected with P. berghei ANKA.ResultsOur results revealed that C57BL/6 alleles at two locations in the NKC contribute to the development of ECM. The increased severity to severe disease in intra-NKC congenic mice was not associated with higher parasite burdens but correlated with a significantly enhanced systemic IFN-γ response to infection and an increased recruitment of CD8+ T cells to the brain of infected animals.ConclusionsPolymorphisms within the NKC modulate malarial pathogenesis and acquired immune responses to infection.

Rubinstein-Taybi syndrome (RSTS), an autosomal-dominant neurodevelopmental disorder affecting 1 in 125,000 newborns, is characterized by intellectual disability, growth retardation, facial dysmorphisms, and skeletal abnormalities. RSTS results from mutations in epigenetic machinery genes: CREBBP (~60%) or its homologous EP300 (~10%). Up to 30% of patients lack identified causative mutations, complicating early diagnosis due to phenotypic overlap with other syndromes. Here, we report a new RSTS case in an infant with atypical presentation. Wholeexome sequencing at 20 months revealed a de novo heterozygous pathogenic variant in CREBBP, c.6067C>T (p.Gln2023*), establishing the diagnosis. This case introduces a new CREBBP gene variant, illustrating the broad clinical spectrum of Mendelian disorders of the epigenetic apparatus. High WES diagnostic rates emphasize its utility in cases with challenging phenotypes spanning distinct syndromes. [ABSTRACT FROM AUTHOR]

Background Ambulatory ECG (AECG) monitoring is pivotal to the diagnosis of arrhythmias and can be performed with near “real‐time” notification of abnormalities. There are limited data on the relative benefit of real‐time monitoring compared with traditional Holter monitoring. Methods and Results This is a retrospective observational analysis of University of Utah Health patients who underwent ambulatory ECG studies from 2010 to 2022. The study cohort was stratified by patients with an ambulatory ECG that provides real‐time event notification (non‐Holter) versus those who do not (Holter). The outcomes were cardiac implantable electronic device procedure, ablation procedure, emergency department/hospitalization visit, and initiation of anticoagulation out to 6 months. We identified 20 259 patients, 16 650 with non‐Holter studies and 3609 with Holter studies. Holter patients were younger (mean 52 versus 55, P

BackgroundDespite years of attention, avoiding medication-related harm remains a global challenge. Nursing homes provide essential health care for frail older individuals, who often experience multiple chronic diseases and polypharmacy, increasing their risk of medication errors. Evidence of effective interventions to improve medication safety in these settings is inconclusive. Focusing on patient safety culture is a potential key to intervention development as it forms the foundation for overall patient safety and is associated with medication errors. ObjectiveThis study aims to develop an intervention to improve medication safety for nursing home residents through a cocreative process guided by integrated knowledge translation and experience-based codesign. MethodsThis study used a cocreative process guided by integrated knowledge translation and experience-based co-design principles. Evidence on patient safety culture was used as an inspirational source for exploration of medication safety. Data collection involved semistructured focus groups to generate experiential knowledge (stage 1) to inform intervention design in a multidisciplinary workshop (stage 2). Research validation engaging different types of research expertise and municipal managerial representatives in finalizing the intervention design was essential. Acceptance of the final intervention for evaluation was aimed for through contextualization focused on partnership with a municipal advisory board. An abductive, rapid qualitative analytical approach to data analysis was chosen using elements from analyzing in the present, addressing the time-dependent, context-bound aspects of the cocreative process. ResultsExperiential knowledge was represented by three main themes: (1) closed systems and gaps between functions, (2) resource interpretation and untapped potential, and (3) community of medication safety and surveillance. The main themes informed the design of preliminary intervention components in a multidisciplinary workshop. An intervention design process focused on research validation in addition to contextualization resulted in the Safe Medication in Nursing Home Residents (SAME) intervention covering (1) campaign material visualizing key roles and responsibilities regarding medication for nursing home residents and (2) “Medication safety reflexive spaces” focused on social and health care assistants. ConclusionsThe cocreative process successfully resulted in the multifaceted SAME intervention, grounded in lived experiences shared by some of the most important (but often underrepresented in research) stakeholders: frontline health care professionals and representatives of nursing home residents. This study brought attention toward closed systems related to functions in medication management and surveillance, not only informing the SAME intervention design but as opportunities for further exploration in future research. Evaluation of the intervention is an important next step. Overall, this study represents an important contribution to the complex field of medication safety. International Registered Report Identifier (IRRID)RR2-10.2196/43538

Abstract Background Developing evidence for the use of psychosocial interventions for people with dementia is a research priority. This pilot study aimed to provide variability estimates for a set of outcome measures that would inform the development of a more extensive controlled study. The larger study will seek to explore the effect of attending a lifelong learning intervention for people with dementia compared to receiving treatment as usual. This pilot and feasibility stage also analysed how data collectors and researchers evaluated the use of the outcome measures in a sample of people with mild to moderate dementia. Methods Before initiating the pilot study, a participant consultation was conducted with people with dementia, who attend a lifelong learning service known as a dementia school, and their teachers. From this consultation, the research outcomes identified were the mini-mental state examination (MMSE), Quality-of-Life Alzheimer’s Disease (QoL-AD), General Self-Efficacy Scale (GSE), Rosenberg self-esteem scale, and the Friendship scale. The following study was divided into two steps. In step 1, participants were people with dementia attending a dementia school (intervention group) or usual services (control group). The participants were tested at baseline and at a 6-month follow-up. Data were collected between November 2018 and July 2019. In step 2, feasibility and acceptability issues with the recruitment of participants, data collection process, and outcome measures, identified in step 1, were evaluated through a data collector focus group. Results Fifty-five people with dementia were included in the analysis. Step 1 provided estimates of changes from baseline to follow-up, and ancillary standard deviations were supplied for all outcome measures. Step 2 provided reflections on the feasibility and acceptability of the intervention, data collection, and outcome measures. This included views on how people with dementia experience participating in a test situation. Conclusions This study provided estimates of change and variability in the outcome measures. Additionally, issues regarding data collection were identified and should be addressed in future studies. The project demonstrated how to support people with dementia to participate in research that is meaningful to them. Trial registration According to national legislation, registration with a database of clinical studies was optional, as the study evaluated existing activities rather than a clinical intervention.

BackgroundPotentially inappropriate medication remains a significant concern in general practices, particularly in the context of overactive bladder (OAB) treatment for individuals aged 65 years and older. This study focuses on the exploration of alternative options for treating OAB and the deprescribing of anticholinergic drugs commonly used in OAB. The research aims to comprehensively evaluate the efficiency of deprescribing through a mixed methods approach, combining quantitative assessment and qualitative exploration of perceptions, experiences, and potential barriers among patients and health care personnel. ObjectiveThis study aims to evaluate the efficiency and safety of the intervention in which health care staff in primary care encourage patients to participate in deprescribing their drugs for OAB. In addition, we aim to identify factors contributing to or obstructing the deprescribing process that will drive more informed decisions in the field of deprescribing and support effective and safe treatment of patients. MethodsThe drugs for overactive bladder in primary care (DROP) study uses a rigorous research design, using a randomized controlled trial (RCT) with an embedded sequential explanatory mixed methods approach. All general practices within the North Denmark Region will be paired based on the number of general practitioners (GPs) and urban or rural locations. The matched pairs will be randomized into intervention and control groups. The intervention group will receive an algorithm designed to guide the deprescribing of drugs for OAB, promoting appropriate medication use. Quantitative data will be collected from the RCT including data from Danish registries for prescription analysis. Qualitative data will be obtained through interviews and focus groups with GPs, staff members, and patients. Finally, the quantitative and qualitative findings are merged to understand deprescribing for OAB comprehensively. This integrated approach enhances insights and supports future intervention improvement. ResultsThe DROP study is currently in progress, with randomization of general practices underway. While they have not been invited to participate yet, they will be. The inclusion of GP practices is scheduled from December 2023 to April 2024. The follow-up period for each patient is 6 months. Results will be analyzed through an intention-to-treat analysis for the RCT and a thematic analysis for the qualitative component. Quantitative outcomes will focus on changes in prescriptions and symptoms, while the qualitative analysis will explore experiences and perceptions. ConclusionsThe DROP study aims to provide an evidence-based intervention in primary care that ensures the deprescription of drugs for OAB when there is an unfavorable risk-benefit profile. The DROP study’s contribution lies in generating evidence for deprescribing practices and influencing best practices in health care. Trial RegistrationClinicalTrials.gov NCT06110975; https://clinicaltrials.gov/study/NCT06110975 International Registered Report Identifier (IRRID)DERR1-10.2196/56277

BackgroundMedication safety is increasingly challenging patient safety in growing aging populations. Developing positive patient safety cultures is acknowledged as a primary goal to improve patient safety, but evidence on the interventions to do so is inconclusive. Nursing home residents are often cognitively and physically impaired and are therefore highly reliant on frontline health care providers. Thus, interventions to improve medication safety of nursing home residents through patient safety culture among providers are needed. Using cocreative partnerships, integrating knowledge of residents and their relatives, and ensuring managerial support could be beneficial. ObjectiveThe primary aim of the Safe Medication of Nursing Home Residents Through Development and Evaluation of an Intervention (SAME) study is to improve medication safety for nursing home residents through developing an intervention by gaining experiential knowledge of patient safety culture in cocreative partnerships, integrating knowledge of residents and their relatives, and ensuring managerial support. MethodsThe fully integrated mixed method study will be conducted using an integrated knowledge translation approach. Patient safety culture within nursing homes will first be explored through qualitative focus groups (stage 1) including nursing home residents, their relatives, and frontline health care providers. This will inform the development of an intervention in a multidisciplinary panel (stage 2) including cocreators representing the medication management process across the health care system. Evaluation of the intervention will be done in a randomized controlled trial set at nursing homes (stage 3). The primary outcome will be changes in the mean scale score of an adapted version of the Danish “Safety Attitudes Questionnaire” (SAQ-DK) for use in nursing homes. Patient safety–related outcomes will be collected through Danish health registers to assess safety issues and effects, including medication, contacts to health care, diagnoses, and mortality. Finally, a mixed methods analysis on patient safety culture in nursing homes will be done (stage 4), integrating qualitative data (stage 1) and quantitative data (stage 3) to comprehensively understand patient safety culture as a key to medication safety. ResultsThe SAME study is ongoing. Focus groups were carried out from April 2021 to September 2021 and the workshop in September 2021. Baseline SAQ-DK data were collected in January 2022 with expected follow-up in January 2023. Final data analysis is expected in spring 2024. ConclusionsThe SAME study will help not only to generate evidence on interventions to improve medication safety of nursing home residents through patient safety culture but also to give insight into possible impacts of using cocreativity to guide the development. Thus, findings will address multiple gaps in evidence to guide future patient safety improvement efforts within primary care settings of political and scientific scope. Trial RegistrationClinicalTrials.gov NCT04990986; https://clinicaltrials.gov/ct2/show/NCT04990986 International Registered Report Identifier (IRRID)DERR1-10.2196/43538

Preventing utilization of hospital and emergency department after diagnosis of venous thromboembolism is a complex problem. The objective of this study is to assess the impact of a care transition intervention on hospitalizations and emergency department visits after venous thromboembolism. We randomized adults diagnosed with a new episode of venous thromboembolism to usual care or a multicomponent intervention that included a home pharmacist visit in the week after randomization (typically occurring at time of discharge), illustrated medication instructions distributed during home visit, and a follow-up phone call with an anticoagulation expert scheduled for 8 to 30 days from time of randomization. Through physician chart review of the 90 days following randomization, we measured the incidence rate of hospital and emergency department visits for each group and their ratio. We also determined which visits were related to recurrent venous thromboembolism, bleeding, or anticoagulation and which where preventable. We enrolled 77 intervention and 85 control patients. The incidence rate was 4.50 versus 6.01 visits per 1000 patient days in the intervention versus control group (incidence rate ratio = 0.71; 95% confidence interval = 0.40-1.27). Most visits in the control group were not related to venous thromboembolism or bleeding (21%) and of those that were, most were not preventable (25%). The adjusted incidence rate ratio for the intervention was 1.05 (95% confidence interval = 0.57-1.91). Our patients had a significant number of hospital and emergency department visits after diagnosis. Most visits were not related to recurrent venous thromboembolism or bleeding and of those that were, most were not preventable. Our multicomponent intervention did not decrease hospitalizations and emergency department visits.

By using γ-irradiation in the presence of thiocyanate ions, we have generated guanyl radicals in plasmid DNA. These can be detected by using an Escherichia coli base excision repair endonuclease to convert their stable end products to strand breaks. The yield of enzyme-sensitive sites is strongly attenuated by the presence of micromolar concentrations of one of a series of singly substituted phenols, and it is possible to derive bimolecular rate constants for the reduction of DNA guanyl radicals by these phenols. More strongly reducing phenols were found to react more rapidly. This electron-transfer reaction also involves a proton transfer. By comparing the expected energetics of the reaction with the observed rate constants, the electron transfer is found to be mechanistically coupled with the proton transfer. [ABSTRACT FROM AUTHOR]

Background : Several risk scores have been derived to predict the risk of infective endocarditis (IE) amongst patients with Staphylococcus aureus bacteraemia (SAB), which helps to guide clinical management. Methods : We prospectively studied 634 patients admitted with SAB. The cohort was stratified into those with or without IE, and the PREDICT Day 1, Day 5 and VIRSTA scores were tabulated. Area under the receiver operating characteristic (AUC) curves were constructed to compare the performance of each score. Results : Of the 634 patients examined, 36 (5.7%) had IE. These patients were younger (51.6 ± 20.1 vs. 59.2 ± 18.0 years, p = 0.015), tended to have community acquisition of bacteraemia (41.7% vs. 17.9%, p < 0.001), and had persistent bacteraemia beyond 72 h (19.4% vs. 6.0%, p = 0.002). The VIRSTA score had the best performance in predicting IE (AUC 0.76, 95%CI 0.66-0.86) compared with PREDICT Day 1 and Day 5. A VIRSTA score of <3 had the best negative predictive value (97.5%), compared with PREDICT Day 1 (<4) and Day 5 (<2) (94.3% and 96.6%, respectively). Conclusions : Overall, the risk scores performed well in our Asian cohort. If applied, 23.5% of the cohort with a VIRSTA ≥ 3 would require TEE, and a score of <3 had an excellent negative predictive value.

The advent of sequencing technology has endowed us with the capacity to study microbes constituting the human commensal community that were previously non-culturable. Much of the initial works have concentrated on the bacterial flora constituting the gut microbiome, since specimens are readily accessible in health and disease. Less, however, is understood of the "silent population"-the fungal species, also known as the mycobiome. Living in symbiosis with bacteria as commensals in our body, it is perceivable that the mycobiome exerts an inadvertent influence on the microbiome. We review here the recent knowledge gained from study of the interaction between the mycobiome and microbiome in health and disease susceptibility, immunity, and consequences from antimicrobial treatment.

Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC-autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency-was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface., Competing Interests: The authors declare no conflict of interest.

A major global concern is the emergence and spread of systemic life-threatening fungal infections in critically ill patients. The increase in invasive fungal infections, caused most commonly by Candida and Aspergillus species, occurs in patients with impaired defenses due to a number of reasons such as underlying disease, the use of chemotherapeutic and immunosuppressive agents, broad-spectrum antibiotics, prosthetic devices and grafts, burns, neutropenia and HIV infection. The high morbidity and mortality associated with these infections is compounded by the limited therapeutic options and the emergence of drug resistant fungi. Hence, creative approaches to bridge the significant gap in antifungal drug development needs to be explored. Here, we review the potential anti-fungal targets for patient-centered therapies and immune-enhancing strategies for the prevention and treatment of invasive fungal diseases.

Invasive fungal infections (IFIs) are associated with high mortality rates and large economic burdens. Triazole prophylaxis is used for at-risk patients with hematological malignancies or stem cell transplants. We evaluated both the efficacy and the cost-effectiveness of triazole prophylaxis. A network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating fluconazole, itraconazole capsule and solution, posaconazole, and voriconazole was conducted. The outcomes of interest included the incidences of IFIs and deaths. This was coupled with a cost-effectiveness analysis from patient perspective over a lifetime horizon. Probabilities of transitions between health states were derived from the NMA. Resource use and costs were obtained from the Singapore health care institution. Data on 5,505 participants in 21 RCTs were included. Other than itraconazole capsule, all triazole antifungals were effective in reducing IFIs. Posaconazole was better than fluconazole (odds ratio [OR], 0.35 [95% confidence interval [CI], 0.16 to 0.73]) and itraconazole capsule (OR, 0.25 [95% CI, 0.06 to 0.97]), but not voriconazole (OR, 1.31 [95% CI, 0.43 to 4.01]), in preventing IFIs. Posaconazole significantly reduced all-cause deaths, compared to placebo, fluconazole, and itraconazole solution (OR, 0.49 to 0.54 [95% CI, 0.28 to 0.88]). The incremental cost-effectiveness ratio for itraconazole solution was lower than that for posaconazole (Singapore dollars [SGD] 12,546 versus SGD 26,817 per IFI avoided and SGD 5,844 versus SGD 12,423 per LY saved) for transplant patients. For leukemia patients, itraconazole solution was the dominant strategy. Voriconazole was dominated by posaconazole. All triazole antifungals except itraconazole capsule were effective in preventing IFIs. Posaconazole was more efficacious in reducing IFIs and all-cause deaths than were fluconazole and itraconazole. Both itraconazole solution and posaconazole were cost-effective in the Singapore health care setting., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Vitamin D level is linked to susceptibility to infections, but its relevance in candidemia is unknown. We aimed to investigate the in vivo sequelae of vitamin D3 supplementation in systemic Candida infection. Implicating the role of vitamin D in Candida infections, we showed that candidemic patients had significantly lower 25-OHD concentrations. Candida-infected mice treated with low-dose 1,25(OH)2D3 had reduced fungal burden and better survival relative to untreated mice. Conversely, higher 1,25(OH)2D3 doses led to poor outcomes. Mechanistically, low-dose 1,25(OH)2D3 induced proinflammatory immune responses. This was mediated through suppression of SOCS3 and induction of vitamin D receptor binding with the vitamin D-response elements in the promoter of the gene encoding interferon γ. These beneficial effects were negated with higher vitamin D3 doses. While the antiinflammatory effects of vitamin D3 are well described, we found that, conversely, lower doses conferred proinflammatory benefits in Candida infection. Our study highlights caution against extreme deviations of vitamin D levels during infections., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Immune suppression is a recognized risk factor for necrotizing fasciitis. In patients with hematological malignancies, a profoundly immunocompromised group, the predominant causative organisms are Gram negative. Clinical presentation and outcomes in these patients are similar to the immunocompetent. The Laboratory Risk Indicator for Necrotizing Fasciitis score is not reliable for risk stratification of the disease.

Soil has been considered the natural reservoir for the bacterium Burkholderia pseudomallei, which causes melioidosis. We examined 550 melioidosis cases that occurred during a 10-year period in the highly urbanized city of Singapore, where soil exposure is rare, and found that rainfall and humidity levels were associated with disease incidence.

Background: Melioidosis is a problem in the developing tropical regions of Southeast Asia and Northern Australia where the the Gram negative saprophytic bacillus Burkholderia pseudomallei is endemic with the risk of fulminant septicaemia. While diabetes mellitus is a well-established risk factor for melioidiosis, little is known if specific hypoglycemic agents may differentially influence the susceptibility and clinical course of infection with B. pseudomallei (Bp)., Methodology/principal Findings: In this cohort study, patients with pre-existing diabetes and melioidosis were retrospectively studied., Outcome Measures: mortality, length of stay and development of complications (namely hypotension, intubation, renal failure and septicaemia) were studied in relation to prior diabetic treatment regimen. Peripheral blood mononuclear cells (PBMC) from diabetic patients and healthy PBMC primed with metformin, glyburide and insulin were stimulated with purified Bp antigens in vitro. Immune response and specific immune pathway mediators were studied to relate to the clinical findings mechanistically. Of 74 subjects, 44 (57.9%) had sulphonylurea-containing diabetic regimens. Patient receiving sulphonylureas had more severe septic complications (47.7% versus 16.7% p = 0.006), in particular, hypotension requiring intropes (p = 0.005). There was also a trend towards increased mortality in sulphonylurea-users (15.9% versus 3.3% p = 0.08). In-vitro, glyburide suppressed inflammatory cytokine production in a dose-dependent manner. An effect of the drug was the induction of IL-1R-associated kinase-M at the level of mRNA transcription., Conclusion/significance: Sulphonylurea treatment results in suppression of host inflammatory response and may put patients at higher risk for adverse outcomes in melioidosis.

An improved number of anti-fungal drugs are currently available for the treatment of invasive aspergillosis (IA). While serial galactomannan index (GMI) measurement can be used to monitor response to treatment, the extent to which different anti-fungal regimens can affect galactomannan levels is unknown. In 147 IA patients receiving either voriconazole (VCZ) or conventional amphotericin B (CAB) in a multicentre clinical trial, we performed post-hoc analyses of GMI trends in relation to outcomes. The generalized estimation equations approach was used to estimate changes in the effect size for GMI over time within patients. Patients who received VCZ primary therapy and had good treatment response 12 weeks later showed earlier decreases in GMI values at Week 1 and Week 2 (p = 0.001 and 0.046 respectively) as compared to patients who only received CAB. At end-of-randomized therapy (EORT), which was a pre-set secondary assessment point for all patients who switched from randomized primary (CAB or VCZ) to an alternative anti-fungal drug, treatment failure was associated with increasing GMI at Weeks 1 and 2 in CAB-primary treated patients (p = 0.022 and 0.046 respectively). These distinct trends highlight the variations in GMI kinetics with the use of different anti-fungal drugs and their implications in relation to IA treatment response.

Purpose of Review: This review highlights the most important and salient recent developments with regards to invasive pulmonary aspergillosis (IPA), currently the most common opportunistic fungal pneumonia in patients with hematological malignancies., Recent Findings: Besides patients in hematology units, other immunosuppressed and critically ill patients are also at risk of IPA. Identification of patients who possess specific polymorphisms of Toll-like receptor 4 and dectin-1, both of which are involved in the immune sensing of Aspergillus spp., may facilitate risk-stratification. The use of the galactomannan assay in bronchoalveolar fluid to improve diagnosis of IPA is undergoing validation. Trending galactomannan and other biomarker results may prognosticate clinical outcomes. During intensive chemotherapy for leukemia, posaconazole and aerosolized liposomal amphotericin B (L-AMB) have demonstrated efficacy as prophylaxis against invasive fungal infection. However, fluconazole remains an effective prophylactic agent in the setting of hematopoietic stem cell transplantation despite availability of newer antifungal agents. Although voriconazole is still the drug of choice for IPA, both caspofungin and L-AMB are viable alternatives., Summary: Despite increasing knowledge of IPA and availability of newer antifungal agents, clinical management remains a challenge in the setting of a compromised host defense system that is unable to mount an appropriate immune response against the pathogen.

Candida tropicalis is one of the more common Candida causing human disease in tropical countries; the frequency of invasive disease varies by geography causing 3--66% of candidaemia. C. tropicalis is taxonomically close to C. albicans and shares many pathogenic traits. C. tropicalis is particularly virulent in neutropenic hosts commonly with hematogenous seeding to peripheral organs. For candidaemia and invasive candidiasis amphotericin B or an echinocandin are recommended as first-line treatment, with extended-spectrum triazoles acceptable alternatives. Primary fluconazole resistance is uncommon but may be induced on exposure. Physicians in regions where C. tropicalis is common need to be mindful of this lesser-described pathogen.

Background: Methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia remains a condition associated with considerable morbidity and mortality worldwide. It is a common but little-studied problem outside of Europe and North America., Methods: A single-centre retrospective case series profiling all patients with community onset-MSSA bacteraemia presenting between March 2005 and February 2006 to a tertiary acute-care university hospital in Singapore. In addition to epidemiological and clinical data collection, risk factors for complicated bacteremia and attributable mortality were analysed., Results: A total of 100 patients met the case definition. Patients were more likely to be male (65%) and below 65 years of age (69%). Seventeen patients were intravenous drug abusers, while 38 had diabetes mellitus. There were 18 cases of endocarditis, with 11 occurring in intravenous buprenorphine abusers. Attributable mortality was 11%, and 46% of patients developed complicated bacteremia. On multivariate analysis, age > 65 years and presence of chronic pulmonary disease were the only significant risk factors for the former, while valvular heart disease was a significant risk factor for the latter., Conclusion: MSSA bacteraemia is associated with a significant risk of serious complications in Singapore. Other Asian cities should be alert to the risk factors for adverse outcomes for this important cause of morbidity and mortality.