A systematic review and meta-analysis of ambient temperature and precipitation with infections from five food-borne bacterial pathogens.

Studies on climate variables and food pathogens are either pathogen- or region-specific, necessitating a consolidated view on the subject. This study aims to systematically review all studies on the association of ambient temperature and precipitation on the incidence of gastroenteritis and bacteraemia from Salmonella, Shigella, Campylobacter, Vibrio, and Listeria species. PubMed, Ovid MEDLINE, Scopus, and Web of Science databases were searched up to 9 March 2023. We screened 3,204 articles for eligibility and included 83 studies in the review and three in the meta-analysis. Except for one study on Campylobacter, all showed a positive association between temperature and Salmonella, Shigella, Vibrio sp., and Campylobacter gastroenteritis. Similarly, most of the included studies showed that precipitation was positively associated with these conditions. These positive associations were found regardless of the effect measure chosen. The pooled incidence rate ratio (IRR) for the three studies that included bacteraemia from Campylobacter and Salmonella sp. was 1.05 (95 per cent confidence interval (95% CI): 1.03, 1.06) for extreme temperature and 1.09 (95% CI: 0.99, 1.19) for extreme precipitation. If current climate trends continue, our findings suggest these pathogens would increase patient morbidity, the need for hospitalization, and prolonged antibiotic courses.

Field testing Australian bat lyssavirus risk communication resources.

ISSUE ADDRESSED: Australian bat lyssavirus (ABLV) is a fatal zoonosis, which can be transmitted to humans through scratches or bites from infected bats. Currently, there is a lack of research evaluating risk communication resources about ABLV or the dangers from handling bats. The purpose of this study was to field test resources aimed at educating the public about risks to humans and bats from human-bat interaction, then update these resources based upon feedback to ensure they were relevant and appropriately targeted to the public. METHODS: Thirteen semi-structured interviews with a purposive sample of participants chosen for maximum variation of age and sex were conducted. Two investigators analysed the data independently using a deductive approach and then came to consensus by discussion. RESULTS: The main themes were a wide-ranging level of knowledge and opinions about bats, the resources having an effect on people, and messaging in relation to children and pets being particularly important. CONCLUSION: This study highlighted the complexities of risk communication to a broad audience with varied experience and knowledge about bats, and the importance of evaluation prior to implementation to ensure risk communication is relevant and appealing to the intended audience. SO WHAT?: Field testing of health education material prior to implementation is an effective way to ensure key messages are understood, and is important when communicating about fatal but preventable zoonoses such as ABLV.

Comparative chemical genomic profiling across plant-based hydrolysate toxins reveals widespread antagonism in fitness contributions.

The budding yeast Saccharomyces cerevisiae has been used extensively in fermentative industrial processes, including biofuel production from sustainable plant-based hydrolysates. Myriad toxins and stressors found in hydrolysates inhibit microbial metabolism and product formation. Overcoming these stresses requires mitigation strategies that include strain engineering. To identify shared and divergent mechanisms of toxicity and to implicate gene targets for genetic engineering, we used a chemical genomic approach to study fitness effects across a library of S. cerevisiae deletion mutants cultured anaerobically in dozens of individual compounds found in different types of hydrolysates. Relationships in chemical genomic profiles identified classes of toxins that provoked similar cellular responses, spanning inhibitor relationships that were not expected from chemical classification. Our results also revealed widespread antagonistic effects across inhibitors, such that the same gene deletions were beneficial for surviving some toxins but detrimental for others. This work presents a rich dataset relating gene function to chemical compounds, which both expands our understanding of plant-based hydrolysates and provides a useful resource to identify engineering targets.

Clinical experience of intramuscular immunoglobulin for measles prophylaxis in children: Is it practical?

Measles continues to be a public health concern world-wide. Vulnerable individuals including those in which vaccinations is contraindicated, may be reliant on normal human immunoglobulin (NHIG) prophylaxis in an aim to prevent disease. This paper will summarise and discuss a tertiary paediatric hospital's clinical experience and the practicalities of administering intramuscular (IM) NHIG to paediatric patients as per the current measles prophylaxis guidelines in Australia. Following potential exposure within the emergency department, 17 paediatric patients (0-15 years) were recommended IM NHIG for prophylaxis. The dose of NHIG ranged from 0.6 to 15 mL and required multiple (2-8) injections. Two patients required sedation for staff to safely administer the injections. Staff involved with these cases reported administering multiple injections to paediatric patients to be a traumatising experience. They also expressed views that the injection of large volumes via the IM route was an impractical method of administration. Based on this experience, we recommend intravenous immunoglobulin be considered when large volumes of NHIG are recommended intramuscularly.

Evolutionary change during experimental ocean acidification.

Rising atmospheric carbon dioxide (CO2) conditions are driving unprecedented changes in seawater chemistry, resulting in reduced pH and carbonate ion concentrations in the Earth's oceans. This ocean acidification has negative but variable impacts on individual performance in many marine species. However, little is known about the adaptive capacity of species to respond to an acidified ocean, and, as a result, predictions regarding future ecosystem responses remain incomplete. Here we demonstrate that ocean acidification generates striking patterns of genome-wide selection in purple sea urchins (Strongylocentrotus purpuratus) cultured under different CO2 levels. We examined genetic change at 19,493 loci in larvae from seven adult populations cultured under realistic future CO2 levels. Although larval development and morphology showed little response to elevated CO2, we found substantial allelic change in 40 functional classes of proteins involving hundreds of loci. Pronounced genetic changes, including excess amino acid replacements, were detected in all populations and occurred in genes for biomineralization, lipid metabolism, and ion homeostasis--gene classes that build skeletons and interact in pH regulation. Such genetic change represents a neglected and important impact of ocean acidification that may influence populations that show few outward signs of response to acidification. Our results demonstrate the capacity for rapid evolution in the face of ocean acidification and show that standing genetic variation could be a reservoir of resilience to climate change in this coastal upwelling ecosystem. However, effective response to strong natural selection demands large population sizes and may be limited in species impacted by other environmental stressors.

Post-exposure passive immunisation for preventing rubella and congenital rubella syndrome.

BACKGROUND: Control of rubella is desired because infection in early pregnancy can result in miscarriage, foetal death or congenital abnormality. Primary studies examining the effectiveness of immunoglobulins for post-exposure prophylaxis of rubella have small sample sizes and varying results. National public health recommendations suggest a degree of effectiveness. OBJECTIVES: To assess the effectiveness of intramuscular injection or intravenous infusion of polyclonal immunoglobulins of human sera or plasma origin for preventing rubella and congenital rubella syndrome when administered to exposed susceptible people before the onset of disease. SEARCH METHODS: We searched CENTRAL (2014, Issue 7), MEDLINE (1946 to August week 2, 2014), EMBASE (1974 to August 2014), CINAHL (1981 to August 2014), LILACS (1982 to August 2014) and Web of Science (1955 to August 2014). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry on 16 October 2014. We searched the reference lists of relevant retrieved reviews and studies and identified national public health guidelines. SELECTION CRITERIA: For the outcome 'preventing cases of rubella', we included randomised controlled trials (RCTs) and quasi-RCTs. We found several studies addressing this outcome where the design was a controlled clinical trial (CCT) (with exposure to rubella virus controlled by the investigators) but the method of allocation of participants to groups was not reported. We found an alternative report of one of these studies that indicated participants were assigned to groups randomly. We therefore included such studies as meeting criteria for RCTs or quasi-RCTs and undertook sensitivity analyses. For the outcomes, 'congenital rubella infection' and 'congenital rubella syndrome', we included RCTs, quasi-RCTs and prospective controlled (cohort) studies. Participants were necessarily susceptible and exposed to rubella. Polyclonal immunoglobulins derived from human sera or plasma must have been administered intramuscularly or intravenously as the only intervention in at least one group. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included 12 studies (430 participants) in the review: seven RCTs and five CCTs where it was not clear whether participants were randomly allocated to groups. We did not include any unpublished studies. Participants included children and adults of both sexes. Only one study included pregnant women. All studies were conducted in high-income countries.The quality of the 11 studies in the initial meta-analysis was moderate, although we classified no study as having a low risk of bias on all criteria.We included 11 studies in the initial meta-analysis of gamma-globulin (concentrated polyclonal immunoglobulins) versus control (saline or no treatment) for rubella cases. The result favoured the intervention group (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.45 to 0.83) but was heterogenous (Chi² test = 36.59, df = 10 (P value < 0.0001); I² statistic = 73%). Heterogeneity was explained by subgrouping studies according to the estimated volume of gamma-globulin administered per pound of bodyweight and then removing those studies where the intervention was administered more than five days after participant exposure to rubella (post hoc analysis). The test of subgroup differences demonstrated heterogeneity between subgroups according to our protocol definition (P value < 0.1; I² statistic > 60%) and there appeared to be greater effectiveness of the intervention when a greater volume of gamma-globulin was administered ('0.027 to 0.037 ml/lb' RR 1.60 (95% CI 0.57 to 4.52); '0.1 to 0.15 ml/lb' RR 0.53 (95% CI 0.29 to 0.99); '0.2 to 0.5 ml/lb' RR 0.20 (95% CI 0.04 to 1.00)).None of the studies reported the outcome 'congenital rubella infection'. One included study reported on congenital rubella syndrome, with no cases among participants who were fewer than nine weeks pregnant at enrolment and who were randomised to one of two gamma-globulin groups ('high' or 'low' rubella titre). However, the study did not report how congenital rubella syndrome was measured and did not report the length of follow-up according to intervention group. This study did not include a non-treatment group.No included study measured adverse events. AUTHORS' CONCLUSIONS: Compared to no treatment, polyclonal immunoglobulins seem to be of benefit for preventing rubella. The available evidence suggests that this intervention may be of benefit up to five days after exposure, and that effectiveness is dependent on dose. Considering the attack rate for rubella cases in the control group of the highest volume gamma-globulin subgroup (333 per 1000), the absolute risk reduction (calculated from the RR) for this volume of gamma-globulin was 266 (95% CI 0 to 320) and the number needed to treat to benefit is four (95% CI 3 to incalculable).The included studies did not measure rubella-specific antibodies in the immunoglobulin products used in a standard way and thus estimation of the dose of rubella-specific antibodies in international units administered was not possible. As the concentration of rubella-specific antibodies in today's polyclonal immunoglobulin products may vary from those products used in the studies in the review, the volume required per pound of bodyweight to produce similar results may also vary.There is insufficient evidence to make direct conclusions about the effectiveness of polyclonal immunoglobulins for preventing congenital rubella syndrome. This is an area requiring further research.

Post-exposure passive immunisation for preventing measles.

BACKGROUND: Measles outbreaks continue to occur in countries with high vaccination coverage. Passive immunisation is generally considered to prevent measles in someone who is not immune and has been exposed to infection. Estimates of effectiveness have varied and no minimum effective dose has been determined. OBJECTIVES: To assess the effectiveness and safety of intramuscular injection or intravenous infusion of immunoglobulins (passive immunisation) for preventing measles when administered to exposed susceptible people before the onset of symptoms. SEARCH METHODS: We searched CENTRAL (2013, Issue 7), MEDLINE (1946 to July week 5, 2013), CINAHL (1981 to August 2013) and EMBASE (1974 to August 2013). SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-RCTs and prospective, controlled (cohort) studies if: participants were susceptible and exposed to measles, polyclonal immunoglobulins derived from human sera or plasma were administered intramuscularly or intravenously as the only intervention in at least one group and the number of subsequent measles cases was measured. We excluded studies of other sources of immunoglobulins. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and critically appraised the included studies. We attempted to contact study authors for missing information. We described the results of studies not included in meta-analyses. MAIN RESULTS: We included one RCT, two quasi-RCTs and 10 cohort studies (3925 participants). No studies were rated as low risk of bias for all criteria. Critical appraisal was constrained by a lack of information in most studies. The overall quality of the evidence was moderate.Seven studies (1432 participants) assessed cases of measles after immunoglobulin versus no treatment. Heterogeneity was explained by subgrouping according to the blood product used as an approximation of dose of immunoglobulin. When given within seven days of exposure, immunoglobulins were effective at preventing measles: gamma globulin (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.08 to 0.36), convalescent serum (RR 0.21, 95% CI 0.15 to 0.29 to RR 0.49, 95% CI 0.44 to 0.54) and adult serum (RR 0.52, 95% CI 0.45 to 0.59). The differences in the effectiveness of different blood products were supported by studies not included in the meta-analysis and by two studies (702 participants) that found gamma globulin more effective than serum (RR 0.56, 95% CI 0.46 to 0.69).Based on three studies (893 participants) immunoglobulin was effective at preventing death due to measles compared to no treatment (RR 0.24, 95% CI 0.13 to 0.44).Two studies included measles vaccine alone among the intervention groups. Meta-analysis could not be undertaken. Both studies suggested the vaccine was more effective than gamma globulin.No serious adverse events were observed in any of the included studies, although reporting of adverse events was poor overall. Non-serious adverse events included transient fever, rash, muscle stiffness, local redness and induration. AUTHORS' CONCLUSIONS: Passive immunisation within seven days of exposure is effective at preventing measles, with the risk for non-immune people up to 83% less than if no treatment is given. Given an attack rate of 45 per 1000 (per the control group of the most recent included study), gamma globulin compared to no treatment has an absolute risk reduction (ARR) of 37 per 1000 and a number needed to treat to benefit (NNTB) of 27. Given an attack rate of 759 per 1000 (per the attack rate of the other included study assessing gamma globulin), the ARR of gamma globulin compared to no treatment is 629 and the NNTB is two.It seems the dose of immunoglobulin administered impacts on effectiveness. A minimum effective dose of measles-specific antibodies could not be identified.Passive immunisation is effective at preventing deaths from measles, reducing the risk by 76% compared to no treatment. Whether the benefits of passive immunisation vary among subgroups of non-immune exposed people could not be determined.Due to a paucity of evidence comparing vaccine to passive immunisation, no firm conclusions can be drawn regarding relative effectiveness.The included studies were not specifically designed to detect adverse events.Future research should consider the effectiveness of passive immunisation for preventing measles in high-risk populations such as pregnant women, immunocompromised people and infants. Further efforts should be made to determine the minimum effective dose of measles-specific antibodies for post-exposure prophylaxis and the relative effectiveness of vaccine compared to immunoglobulin.

Comparison of Anti-Hepatitis A Antibody Pharmacokinetics in Healthy Australian Subjects Receiving Standard or Weight-Based Dosing of Polyvalent Immunoglobulin.

This randomized controlled trial compared two dosing regimens of the polyvalent immunoglobulin available for hepatitis A post-exposure prophylaxis in Australia. Participants were randomized to receive either 270 IU (standard dose) or 3.375 IU/kg (dose by weight). Quantitative serial serum hepatitis A antibody concentrations were measured at baseline and then on days 1, 3, 7, 28, and 50. Fifteen participants completed the trial. Serum hepatitis A antibody concentrations were not different between the study groups at any time point. Pharmacokinetic parameters estimated from participant data were not different between the study groups. The hepatitis A antibody level of all participants exceeded 10 mIU/mL at day 50. While no difference between dosing regimens was found in this study, further research should examine dosing at the lower limit of current Australian recommendations before making policy decisions.

Mapping of the PDQ-39 to EQ-5D scores in patients with Parkinson's disease.

PURPOSE: The EuroQoL (EQ-5D) is ideal to compare quality of life across conditions. However, the Parkinson's Disease Questionnaire (PDQ-39) is often the only quality-of-life instrument used in Parkinson's disease research. We aimed to identify associations between PDQ-39 domains and EQ-5D domains, and compare different methods of developing a function to map the PDQ-39 to EQ-5D scores. METHODS: Adults with Parkinson's disease self-completed both instruments. Ordinal regression identified associations between PDQ-39 domain scores and each EQ-5D domain. Modeling (n = 80) and validation sets (n = 16) were randomly generated. Overall performance of four methods of mapping the PDQ-39 to EQ-5D scores (using PDQ-39 domains and total score in ordinal and linear regression) was assessed with the validation set, followed by assessing the equivalence of observed and predicted EQ-5D scores on the full dataset controlling for sociodemographic factors. RESULTS: Different sets of PDQ-39 domains were associated with each EQ-5D domain. For example, PDQ-39 "Activities of Daily Living" and "Social Support" were associated with EQ-5D "Personal Care," while PDQ-39 "Emotional Well-being" was associated with EQ-5D "Anxiety/Depression." Over one-third (37.5 %) of predictions from ordinal regressions had an error <0.01 % (compared to 6.3 % for linear regressions). The EQ-5D scores predicted with ordinal regression using PDQ-39 domains were similar in distribution and association with sociodemographic factors to the observed EQ-5D scores. CONCLUSIONS: Of the four methods tested, using PDQ-39 domains in ordinal regression was superior for mapping EQ-5D scores. The function reported here may prove particularly useful for cost-utility analyses comparing Parkinson's disease with other conditions.

Detection of Leishmania (Mundinia) macropodum (Kinetoplastida: Trypanosomatidae) and heterologous Leishmania species antibodies among blood donors in a region of Australia with marsupial Leishmania endemicity.

OBJECTIVES: The Australian Leishmania (Mundinia) macropodum parasite causes cutaneous leishmaniasis among marsupial species. Although cutaneous leishmaniasis is a major public health burden worldwide, it is not clear if humans are naturally exposed to the unique L. macropodum. To assess whether humans have an immunoglobulin (Ig) G response to L. macropodum, we examined anti-Leishmania antibodies among humans residing in a region of marsupial Leishmania endemicity in Australia. METHODS: Using a serological enzyme-linked immunosorbent assay, we characterized Leishmania-specific IgG and IgG subclass responses to soluble Leishmania antigen from L. macropodum, and other Leishmania species (L. donovani, L. major, and L. mexicana) in 282 blood donor samples. RESULTS: We found that 20.57% of individuals demonstrated a positive total IgG response to L. macropodum. For individuals with antibodies to soluble Leishmania antigen from one Leishmania species, there was no increased likelihood of recognition to other Leishmania species. For samples with detectable L. macropodum IgG, IgG1 and IgG2 were the prevalent subclasses detected. CONCLUSION: It is not yet clear whether the IgG antibody detection in this study reflects exposure to Leishmania parasites or a cross-reactive immune response that was induced against an unrelated immunogen. Future studies should investigate whether L. macropodum can result in a viable infection in humans.

Public health response following an iGAS outbreak in a residential aged care facility in Queensland.

Abstract: During an 18-day period, beginning in April 2020, three residents with invasive group A streptococcal infections (iGAS) were reported at a single residential aged care facility (RACF) in Brisbane's northern geographical region. All three cases were hospitalised with severe illness; two of the cases died as a result of the illness. The Metro North Public Health Unit (PHU) led the public health investigation and response, targeting infection control measures and offering chemoprophylaxis to all 142 staff and 119 residents at the facility. The outbreak was declared over in June, after 30 days of no new cases. Isolates from all three cases were shown to have identical strain typing, emm89. The benefits and challenges of implementing mass chemoprophylaxis in this setting are discussed.

Diadenosine tetraphosphate regulates biosynthesis of GTP in Bacillus subtilis.

Diadenosine tetraphosphate (Ap4A) is a putative second messenger molecule that is conserved from bacteria to humans. Nevertheless, its physiological role and the underlying molecular mechanisms are poorly characterized. We investigated the molecular mechanism by which Ap4A regulates inosine-5'-monophosphate dehydrogenase (IMPDH, a key branching point enzyme for the biosynthesis of adenosine or guanosine nucleotides) in Bacillus subtilis. We solved the crystal structure of BsIMPDH bound to Ap4A at a resolution of 2.45 Å to show that Ap4A binds to the interface between two IMPDH subunits, acting as the glue that switches active IMPDH tetramers into less active octamers. Guided by these insights, we engineered mutant strains of B. subtilis that bypass Ap4A-dependent IMPDH regulation without perturbing intracellular Ap4A pools themselves. We used metabolomics, which suggests that these mutants have a dysregulated purine, and in particular GTP, metabolome and phenotypic analysis, which shows increased sensitivity of B. subtilis IMPDH mutant strains to heat compared with wild-type strains. Our study identifies a central role for IMPDH in remodelling metabolism and heat resistance, and provides evidence that Ap4A can function as an alarmone.

Your Call Is Important to Us: COVID-19 and Trends in Public Health Unit Call Service Utilization.

OBJECTIVE: The aim of this study was to analyze coronavirus disease 2019 (COVID-19) -related call data at Metro North Public Health Unit, Brisbane Australia, over the 2020 calendar year to assist surge preparedness. METHODS: Call data were retrieved by call category or reference to "COVID" in summaries from the call management system at a large metropolitan public health service. Under a mixed-methods approach, qualitative data (caller, call purpose, and call outcome) were categorized with categories arising de novo. Resulting variables were numerically analyzed to identify trends by categories and time. RESULTS: Of the 3468 calls retrieved, 160 duplicates and 26 irrelevant calls were excluded. Of 3282 included calls, general practitioners, followed by the public, contributed the greatest call volumes. Health-care-related callers and the public made 84.2% of calls. Calls most frequently related to patient testing (40.7%) and isolation/quarantine (23.2%). Education provision accounted for 29.4% of all outcomes. A total of 11.8% of all call outcomes involved applying relevant case definitions, and 49.1% of calls were identified as potentially preventable through effective emergency risk communication and targeted call-handling. CONCLUSIONS: This study identified key drivers of public health unit phone service use related to the COVID-19 pandemic throughout 2020. The results highlighted where risk perception influenced call volume and provided important insights for future public health preparedness.

Pharmacokinetic modeling to determine the minimum effective dose of disease-specific antibodies for preventing hepatitis A post-exposure.

BACKGROUND: The minimum effective dose of intramuscular polyvalent immune globulin for prevention of hepatitis A post-exposure is unknown. In Australia current dosing is according to weight category. METHODS: The peak concentration and decay of hepatitis A antibodies after intramuscular dosing of immune globulin in adults was modeled utilizing published parameters. Models simulated dosing according to current Australian guidelines, then adjusted the dose in clinically relevant increments to estimate the optimal dose of hepatitis A antibodies for post-exposure prophylaxis of nonimmune individuals. Optimal dosing assumed a target serum concentration of hepatitis A antibodies of the correlate of protection plus a 10% margin of error at an incubation period. The effect of weight on hepatitis A antibody concentration at an incubation period under current guidelines was examined by fixing weight in 5 kg increments. RESULTS: Current dosing guidelines in Australia may underdose people who weigh in excess of 85 kg. The optimal dose of hepatitis A-specific antibodies according to the model was 3.6, 2.5, and 1.9 IU/kg assuming 50%, 75% and 100% bioavailability respectively. CONCLUSIONS: For individuals in Australia recommended passive immunization as post-exposure prophylaxis and weighing in excess of 85 kg, conservative management would include dosing between 2.5 and 3.6 IU hepatitis A antibodies/kg.

(p)ppGpp and c-di-AMP Homeostasis Is Controlled by CbpB in Listeria monocytogenes.

The facultative intracellular pathogen Listeria monocytogenes, like many related Firmicutes, uses the nucleotide second messenger cyclic di-AMP (c-di-AMP) to adapt to changes in nutrient availability, osmotic stress, and the presence of cell wall-acting antibiotics. In rich medium, c-di-AMP is essential; however, mutations in cbpB, the gene encoding c-di-AMP binding protein B, suppress essentiality. In this study, we identified that the reason for cbpB-dependent essentiality is through induction of the stringent response by RelA. RelA is a bifunctional RelA/SpoT homolog (RSH) that modulates levels of (p)ppGpp, a secondary messenger that orchestrates the stringent response through multiple allosteric interactions. We performed a forward genetic suppressor screen on bacteria lacking c-di-AMP to identify genomic mutations that rescued growth while cbpB was constitutively expressed and identified mutations in the synthetase domain of RelA. The synthetase domain of RelA was also identified as an interacting partner of CbpB in a yeast-2-hybrid screen. Biochemical analyses confirmed that free CbpB activates RelA while c-di-AMP inhibits its activation. We solved the crystal structure of CbpB bound and unbound to c-di-AMP and provide insight into the region important for c-di-AMP binding and RelA activation. The results of this study show that CbpB completes a homeostatic regulatory circuit between c-di-AMP and (p)ppGpp in Listeria monocytogenesIMPORTANCE Bacteria must efficiently maintain homeostasis of essential molecules to survive in the environment. We found that the levels of c-di-AMP and (p)ppGpp, two nucleotide second messengers that are highly conserved throughout the microbial world, coexist in a homeostatic loop in the facultative intracellular pathogen Listeria monocytogenes Here, we found that cyclic di-AMP binding protein B (CbpB) acts as a c-di-AMP sensor that promotes the synthesis of (p)ppGpp by binding to RelA when c-di-AMP levels are low. Addition of c-di-AMP prevented RelA activation by binding and sequestering CbpB. Previous studies showed that (p)ppGpp binds and inhibits c-di-AMP phosphodiesterases, resulting in an increase in c-di-AMP. This pathway is controlled via direct enzymatic regulation and indicates an additional mechanism of ribosome-independent stringent activation.

The indications and safety of polyvalent immunoglobulin for post-exposure prophylaxis of hepatitis A, rubella and measles.

Derived from pooled blood donations, polyvalent immunoglobulins are used for post-exposure prophylaxis as one aspect of the public health management of hepatitis A, rubella and measles. This review summarizes the safety profile of these blood products and the current recommendations for their use for the prevention of hepatitis A, rubella and measles among people who have been exposed to these diseases. The current recommendations are drawn from the most recent publicly available national guidelines of the United States, Australia, New Zealand, Canada and the United Kingdom as accessed in February 2019.

The use of normal human immunoglobulin (NHIG) for public health purposes in Queensland 2004-2014 and Australia 2014-2016

Objective To describe the use of normal human immunoglobulin (NHIG) recommended for public health purposes in Queensland and Australia. Methods Queensland public health unit (PHU) data on notified cases of measles, rubella and hepatitis A from 2004 to 2014 were examined; particularly regarding the number of contacts offered NHIG and the volume recommended per contact. The National Blood Authority (NBA) provided unidentified data from NHIG order form inception (June 2014) through December 2016. Queensland orders were compared to PHU data where the data timeframes overlapped. Results NHIG usage varied by condition. For hepatitis A, usage declined after the introduction of vaccination for contacts in 2010. Usage fluctuated across the study period for measles and was not recommended for rubella. Average volumes per contact for hepatitis A and measles were 1.6mL and 11.9mL respectively based on PHU data. PHU data approximated NBA data on NHIG usage for hepatitis A and rubella contacts. Calculated volumes of NHIG per measles contact were also similar, but PHU data underestimated the number of measles contacts for whom NHIG was ordered. Discussion This study is the first to document the use of NHIG for public health purposes in Australia. Results will be valuable for national blood sufficiency planning and cost effectiveness studies in the event of alterations to NHIG dosage recommendations.

The optimal dose of disease-specific antibodies for post-exposure prophylaxis of measles and rubella in Australia: new guidelines recommended.

BACKGROUND: It is unclear whether recommended doses of intramuscular polyvalent immune globulin are optimal for both effectiveness and efficiency of disease prevention when administered post-exposure to measles and rubella. METHODS: The peak concentration and decay of disease-specific antibodies after intramuscular dosing of polyvalent immune globulin in adults were modeled using published pharmacokinetic parameters and product disease-specific antibody concentrations. Models simulated dosing according to current Australian guidelines, then adjusted the dose in clinically relevant increments to estimate the optimal dose of disease-specific immunoglobulins for post-exposure prophylaxis of nonimmune individuals against measles and rubella. Optimal dosing assumed a target serum concentration of disease-specific antibodies of the correlate of protection plus a 10% margin of error at an incubation period. RESULTS: Current Australian guidelines appeared to underdose a measles-naïve subpopulation. The optimal dose of measles-specific antibodies was 17.5 IU/kg assuming 75% bioavailability and 25.5 IU/kg assuming 50% bioavailability. Current Australian guidelines recommend 520 IU/kg rubella antibodies for an 80-kg individual. This model suggests that 13 IU/kg is more than sufficient. CONCLUSIONS: The recommended dose of intramuscular polyvalent immune globulin should be increased following measles exposure and decreased following rubella exposure for recommended subgroups. These models may be adapted for use internationally.