A Role for Antimicrobial Stewardship in Clinical Sepsis Pathways: A Prospective Interventional Study

© 2017 by The Society for Healthcare Epidemiology of America. All rights reserved. OBJECTIVE To evaluate the impact of early infectious diseases (ID) antimicrobial stewardship (AMS) intervention on inpatient sepsis antibiotic management. DESIGN Interventional, nonrandomized, controlled study. SETTING Tertiary-care referral hospital, Sydney, Australia. PATIENTS Consecutive, adult, non-intensive care unit (non-ICU) inpatients triggering an institutional clinical sepsis pathway from May to August 2015. INTERVENTION All patients reviewed by an ID Fellow within 24 hours of sepsis pathway trigger underwent case review and clinic file documentation of recommendations. Those not reviewed by an ID Fellow were considered controls and received standard sepsis pathway care. The primary outcome was antibiotic appropriateness 48 hours after sepsis trigger. RESULTS In total, 164 patients triggered the sepsis pathway: 6 patients were excluded (previous sepsis trigger); 158 patients were eligible; 106 had ID intervention; and 52 were control cases. Of these 158 patients, 91 (58%) had sepsis, and 15 of these 158 (9.5%) had severe sepsis. Initial antibiotic appropriateness, assessable in 152 of 158 patients, was appropriate in 80 (53%) of these 152 patients and inappropriate in 72 (47%) of these patients. In the intervention arm, 93% of ID Fellow recommendations were followed or partially followed, including 53% of cases in which antibiotics were de-escalated. ID Fellow intervention improved antibiotic appropriateness at 48 hours by 24% (adjusted risk ratio, 1.24; 95% confidence interval, 1.04-1.47; P=.035). The appropriateness agreement among 3 blinded ID staff opinions was 95%. Differences in intervention and control group mortality (13% vs 17%) and median length of stay (13 vs 17.5 days) were not statistically significant. CONCLUSION Sepsis overdiagnosis and delayed antibiotic optimization may reduce sepsis pathway effectiveness. Early ID AMS improved antibiotic management of non-ICU inpatients with suspected sepsis, predominantly by de-escalation. Further studies are needed to evaluate clinical outcomes. Infect Control Hosp Epidemiol 2017;38:1032-1038

Dose ratio proton radiography using the proximal side of the Bragg peak

Purpose: In recent years there has been a movement towards single-detector proton radiography, due to its potential ease of implementation within the clinical environment. One such single-detector technique is the dose ratio method, in which the dose maps from two pristine Bragg peaks are recorded beyond the patient. To date, this has only been investigated on the distal side of the lower energy Bragg peak, due to the sharp fall-off. We investigate the limits and applicability of the dose ratio method on the proximal side of the lower energy Bragg peak, which has the potential to allow a much wider range of water-equivalent thicknesses (WET) to be imaged. Comparisons are made with the use of the distal side of the Bragg peak. Methods: Using the analytical approximation for the Bragg peak we generated theoretical dose ratio curves for a range of energy pairs, and then determined how an uncertainty in the dose ratio would translate to a spread in the WET estimate. By defining this spread as the accuracy one could achieve in the WET estimate, we were able to generate look-up graphs of the range on the proximal side of the Bragg peak that one could reliably use. These were dependent on the energy pair, noise level in the dose ratio image and the required accuracy in the WET. Using these look-up graphs we investigated the applicability of the technique for a range of patient treatment sites. We validated the theoretical approach with experimental measurements using a complementary metal oxide semiconductor active pixel sensor (CMOS APS), by imaging a small sapphire sphere in a high energy proton beam. Results: Provided the noise level in the dose ratio image was 1% or less, a larger spread of WETs could be imaged using the proximal side of the Bragg peak (max 5.31 cm) compared to the distal side (max 2.42 cm). In simulation it was found that, for a pediatric brain, it is possible to use the technique to image a region with a square field equivalent size of 7.6 cm2, for a required accuracy in the WET of 3 mm and a 1% noise level in the dose ratio image. The technique showed limited applicability for other patient sites. The CMOS APS demonstrated a good accuracy, with a root-mean-square-error of 1.6 mm WET. The noise in the measured images was found to be σ =1.2% (standard deviation) and theoretical predictions with a 1.96σ noise level showed good agreement with the measured errors. Conclusions: After validating the theoretical approach with measurements, we have shown that the use of the proximal side of the Bragg peak when performing dose ratio imaging is feasible, and allows for a wider dynamic range than when using the distal side. The dynamic range available increases as the demand on the accuracy of the WET decreases. The technique can only be applied to clinical sites with small maximum WETs such as for pediatric brains

Men’s Health Research in New Zealand: A Scoping Review

Background: Globally, there has been a growing awareness of the health challenges faced by men. The current public health agenda in Aotearoa New Zealand (NZ) does not specifically address the needs of men. The aim of this scoping review was to capture the major health issues facing men in NZ and particularly to identify the knowledge gaps in the understanding of men’s health within the NZ context. This was achieved by presenting key data on their health status and systematically mapping research in NZ related to men’s health; international data are also referenced for context as relevant. Method: A search and screening of the literature were conducted using Ovid, Web of Science and Scopus databases from January 1996 to July 2021, with advice from a medical librarian. Search terms included “men’s/male’s health” and “men’s/male’s health NZ.” An environmental scan of international literature was also carried out and information from the Ministry of Health and Statistics NZ was obtained to provide context of the status of research on men’s health in NZ. Main Findings: In keeping with international literature, the major health issues for men in NZ are life-limiting diseases including cancer and cardiovascular disease, the spread of overweight and obesity, issues with masculinity and help-seeking behaviours, unhealthy lifestyles, mental health issues and poor health literacy. The main areas of research related to men’s health from the NZ literature were highlighted. Discussion: Men’s health remains an under-recognised issue in NZ. If we are to address current inequities in health for men, clinicians, researchers and relevant agencies need to pay more attention to men’s health issues and take up the challenge to highlight and promote men’s health status in NZ

Immunization with apical membrane antigen 1 confers sterile infection-blocking immunity against Plasmodium sporozoite challenge in a rodent model

Apical membrane antigen 1 (AMA-1) is a leading blood-stage malaria vaccine candidate. Consistent with a key role in erythrocytic invasion, AMA-1-specific antibodies have been implicated in AMA-1-induced protective immunity. AMA-1 is also expressed in sporozoites and in mature liver schizonts where it may be a target of protective cell-mediated immunity. Here, we demonstrate for the first time that immunization with AMA-1 can induce sterile infection-blocking immunity against Plasmodium sporozoite challenge in 80% of immunized mice. Significantly higher levels of gamma interferon (IFN-γ)/interleukin-2 (IL-2)/tumor necrosis factor (TNF) multifunctional T cells were noted in immunized mice than in control mice. We also report the first identification of minimal CD8 and CD4 T cell epitopes on Plasmodium yoelii AMA-1. These data establish AMA-1 as a target of both preerythrocytic- and erythrocytic-stage protective immune responses and validate vaccine approaches designed to induce both cellular and humoral immunity

Ageing well in older men in Otago and Southland of New Zealand: a focus group study protocol

Background: Men in New Zealand (NZ) do not enjoy the same level of health and wellbeing as women. Men generally experience a higher incidence of, and mortality from, major diseases; most importantly, life expectancies for men in NZ are approximately four years less than for women. Such disparities vary across rural and urban communities, and across ethnic sub-groups. In particular, Māori men live some seven years less than other NZ men. Despite such inequalities, men’s health is not recognised as a priority by healthcare providers, government, or at the wider societal level. This qualitative study seeks to address this, by contributing to our understanding of factors associated with health and wellbeing for men in the ageing process. Study findings will also inform the development of a national survey of older men. Method: Focus groups will be used to explore the expectations and experiences of health and wellbeing in a cohort of older men (≥45 years) in the Otago and Southland regions. Topics to be explored will include gender role conflict, health service help-seeking, lifestyle behaviours, social engagement, and self-identified health risks. In total, five groups are planned (6-10 men per group) and will be conducted in urban, rural, and urban-rural adjunct areas. Focus groups will be recorded, and transcribed verbatim. Transcriptions will be coded for themes using the abductive thematic analysis approach. Results: This paper presents a protocol of a study in progress, and results are not yet known. Discussion: This is the first qualitative study focussing on ageing well in men in NZ. It will contribute to our understanding of this aspect of men’s health, and–ultimately–help to inform interventions and policies to better support men to age positively

Preferential transcription of the mutated allele in NPM1 mutated acute myeloid leukaemia

Nucleophosmin is commonly both over-expressed and mutated in acute myeloid leukemia (AML). NPM1 mutations are always heterozygous. In addition, NPM1 has a number of different splice variants with the major variant encoded by exons 1–9 and 11–12 (NPM1.1). Further variants include NPM1.2 which lacks exons 8 and 10 and NPM1.3 which comprises exons 1–10 (and so lacks the region of sequence mutated in AML). In this study we quantified the expression of these three variants in 108 AML patient samples with and without NPM1 mutations and also assessed the level of expression from the wild-type and mutant alleles in variants NPM1.1 and NPM1.2. The results show that NPM1.1 is the most commonly expressed variant, however transcripts from wild-type and mutated alleles do not occur at equal levels, with a significant bias toward the mutated allele. Considering the involvement of mutant nucleophosmin in the progression and maintenance of AML, a bias towards mutated transcripts could have a significant impact on disease maintenance

The glutathione biosynthetic pathway of Plasmodium is essential for mosquito transmission

1Infection of red blood cells (RBC) subjects the malaria parasite to oxidative stress. Therefore, efficient antioxidant and redox systems are required to prevent damage by reactive oxygen species. Plasmodium spp. have thioredoxin and glutathione (GSH) systems that are thought to play a major role as antioxidants during blood stage infection. In this report, we analyzed a critical component of the GSH biosynthesis pathway using reverse genetics. Plasmodium berghei parasites lacking expression of gamma-glutamylcysteine synthetase (γ-GCS), the rate limiting enzyme in de novo synthesis of GSH, were generated through targeted gene disruption thus demonstrating, quite unexpectedly, that γ-GCS is not essential for blood stage development. Despite a significant reduction in GSH levels, blood stage forms of pbggcs− parasites showed only a defect in growth as compared to wild type. In contrast, a dramatic effect on development of the parasites in the mosquito was observed. Infection of mosquitoes with pbggcs− parasites resulted in reduced numbers of stunted oocysts that did not produce sporozoites. These results have important implications for the design of drugs aiming at interfering with the GSH redox-system in blood stages and demonstrate that de novo synthesis of GSH is pivotal for development of Plasmodium in the mosquito

Experimental and numerical investigation of blade–tower interaction noise

© 2018 Elsevier Ltd. This manuscript version is made available under the CC-BY-NC-ND 4.0 license: http://creativecommons.org/licenses/by-nc-nd/4.0/ This author accepted manuscript is made available following 12 month embargo from date of publication (December 2018) in accordance with the publisher’s archiving policyThis paper describes the generation of blade–tower interaction (BTI) noise from upwind turbines and pylon-mounted fans using a combination of experimental and numerical means. An experimental rotor-rig was used in an anechoic chamber to obtain BTI acoustic data under controlled conditions. A computational model, based on the solution of the unsteady Reynolds Averaged Navier Stokes (URANS) equations and Curle's acoustic analogy, was used to describe the generation of fan and simplistic model of wind turbine BTI noise by the rotor-rig. For both the fan and model wind turbine case, the tower was found to be a more significant source of BTI noise than rotor blades. The acoustic waveforms for both turbine and fan are similar; however, in the case of the turbine, the blade contribution reinforces that from the tower, while in the case of a fan, there is some cancellation between the tower source and the blade source. This behavior can be explained by the unsteady aerodynamics occurring during BTI

Assessment of humoral immune responses to blood-stage malaria antigens following ChAd63-MVA immunization, controlled human malaria infection and natural exposure.

The development of protective vaccines against many difficult infectious pathogens will necessitate the induction of effective antibody responses. Here we assess humoral immune responses against two antigens from the blood-stage merozoite of the Plasmodium falciparum human malaria parasite--MSP1 and AMA1. These antigens were delivered to healthy malaria-naïve adult volunteers in Phase Ia clinical trials using recombinant replication-deficient viral vectors--ChAd63 to prime the immune response and MVA to boost. In subsequent Phase IIa clinical trials, immunized volunteers underwent controlled human malaria infection (CHMI) with P. falciparum to assess vaccine efficacy, whereby all but one volunteer developed low-density blood-stage parasitemia. Here we assess serum antibody responses against both the MSP1 and AMA1 antigens following i) ChAd63-MVA immunization, ii) immunization and CHMI, and iii) primary malaria exposure in the context of CHMI in unimmunized control volunteers. Responses were also assessed in a cohort of naturally-immune Kenyan adults to provide comparison with those induced by a lifetime of natural malaria exposure. Serum antibody responses against MSP1 and AMA1 were characterized in terms of i) total IgG responses before and after CHMI, ii) responses to allelic variants of MSP1 and AMA1, iii) functional growth inhibitory activity (GIA), iv) IgG avidity, and v) isotype responses (IgG1-4, IgA and IgM). These data provide the first in-depth assessment of the quality of adenovirus-MVA vaccine-induced antibody responses in humans, along with assessment of how these responses are modulated by subsequent low-density parasite exposure. Notable differences were observed in qualitative aspects of the human antibody responses against these malaria antigens depending on the means of their induction and/or exposure of the host to the malaria parasite. Given the continued clinical development of viral vectored vaccines for malaria and a range of other diseases targets, these data should help to guide further immuno-monitoring studies of vaccine-induced human antibody responses

A balanced pro-inflammatory and regulatory cytokine signature in young African children is associated with lower risk of clinical malaria

Background: The effect of timing of exposure to first Plasmodium falciparum infections during early childhood on the induction of innate and adaptive cytokine responses and their contribution to the development of clinical malaria immunity is not well established. Methods: As part of a double-blind randomized placebo-controlled trial in Mozambique using monthly chemoprophylaxis with sulfadoxine-pyrimethamine plus artesunate to selectively control timing of malaria exposure during infancy, peripheral blood mononuclear cells collected at ages 2.5, 5.5, 10.5, 15 and 24 months were stimulated ex vivo with parasite schizont and erythrocyte lysates. Cytokine mRNA expressed in cell pellets and proteins secreted in supernatants were quantified by real time quantitative PCR and multiplex flow cytometry, respectively. Children were followed up for clinical malaria from birth until 4 years of age. Results: Higher pro-inflammatory (IL-1, IL-6, TNF) and regulatory (IL-10) cytokine concentrations during the second year of life were associated with reduced incidence of clinical malaria up to 4 years of age, adjusting by chemoprophylaxis and prior malaria exposure. Significantly lower concentrations of antigen-specific TH1 (IL-2, IL-12, IFN-) and TH2 (IL-4, IL-5) cytokines by 2 years of age were measured in children under chemoprophylaxis compared to children receiving placebo (p<0.03). Conclusions: Selective chemoprophylaxis altering early natural exposure to malaria blood stage antigens during infancy had a significant effect on TH lymphocyte cytokine production more than one year later. Importantly, a balanced pro-inflammatory and anti-inflammatory cytokine signature probably by innate cells around age 2 years was associated with protective clinical immunity during childhood