Cost-effectiveness of broadly neutralizing antibodies for infant HIV prophylaxis in settings with high HIV burdens: a simulation modeling study.

Introduction: Approximately 130 000 infants acquire HIV annually despite global maternal antiretroviral therapy scale-up. We evaluated the potential clinical impact and cost-effectiveness of offering long-acting, anti-HIV broadly neutralizing antibody (bNAb) prophylaxis to infants in three distinct settings. Methods: We simulated infants in Côte d'Ivoire, South Africa, and Zimbabwe using the Cost-Effectiveness of Preventing AIDS Complications-Pediatric (CEPAC-P) model. We modeled strategies offering a three-bNAb combination in addition to WHO-recommended standard-of-care oral prophylaxis to infants: a) with known, WHO-defined high-risk HIV exposure at birth (HR-HIVE); b) with known HIV exposure at birth (HIVE); or c) with or without known HIV exposure (ALL). Modeled infants received 1-dose, 2-doses, or Extended (every 3 months through 18 months) bNAb dosing. Base case model inputs included 70% bNAb efficacy (sensitivity analysis range: 10-100%), 3-month efficacy duration/dosing interval (1-6 months), and $20/dose cost ($5-$100/dose). Outcomes included pediatric HIV infections, life expectancy, lifetime HIV-related costs, and incremental cost-effectiveness ratios (ICERs, in US$/year-of-life-saved [YLS], assuming a ≤50% GDP per capita cost-effectiveness threshold). Results: The base case model projects that bNAb strategies targeting HIVE and ALL infants would prevent 7-26% and 10-42% additional pediatric HIV infections, respectively, compared to standard-of-care alone, ranging by dosing approach. HIVE-Extended would be cost-effective (cost-saving compared to standard-of-care) in Côte d'Ivoire and Zimbabwe; ALL-Extended would be cost-effective in South Africa (ICER: $882/YLS). BNAb strategies targeting HR-HIVE infants would result in greater lifetime costs and smaller life expectancy gains than HIVE-Extended. Throughout most bNAb efficacies and costs evaluated in sensitivity analyses, targeting HIVE infants would be cost-effective in Côte d'Ivoire and Zimbabwe, and targeting ALL infants would be cost-effective in South Africa. Discussion: Adding long-acting bNAbs to current standard-of-care prophylaxis would be cost-effective, assuming plausible efficacies and costs. The cost-effective target population would vary by setting, largely driven by maternal antenatal HIV prevalence and postpartum incidence.

Health Economics Research on Non-surgical Biomedical HIV Prevention: Identifying Gaps and Proposing a Way Forward.

BACKGROUND AND OBJECTIVE: Although HIV prevention science has advanced over the last four decades, evidence suggests that prevention technologies do not always reach their full potential. Critical health economics evidence at appropriate decision-making junctures, particularly early in the development process, could help identify and address potential barriers to the eventual uptake of future HIV prevention products. This paper aims to identify key evidence gaps and propose health economics research priorities for the field of HIV non-surgical biomedical prevention. METHODS: We used a mixed-methods approach with three distinct components: (i) three systematic literature reviews (costs and cost effectiveness, HIV transmission modelling and quantitative preference elicitation) to understand health economics evidence and gaps in the peer-reviewed literature; (ii) an online survey with researchers working in this field to capture gaps in yet-to-be published research (recently completed, ongoing and future); and (iii) a stakeholder meeting with key global and national players in HIV prevention, including experts in product development, health economics research and policy uptake, to uncover further gaps, as well as to elicit views on priorities and recommendations based on (i) and (ii). RESULTS: Gaps in the scope of available health economics evidence were identified. Little research has been carried out on certain key populations (e.g. transgender people and people who inject drugs) and other vulnerable groups (e.g. pregnant people and people who breastfeed). Research is also lacking on preferences of community actors who often influence or enable access to health services among priority populations. Oral pre-exposure prophylaxis, which has been rolled out in many settings, has been studied in depth. However, research on newer promising technologies, such as long-acting pre-exposure prophylaxis formulations, broadly neutralising antibodies and multipurpose prevention technologies, is lacking. Interventions focussing on reducing intravenous and vertical transmission are also understudied. A disproportionate amount of evidence on low- and middle-income countries comes from two countries (South Africa and Kenya); evidence from other countries in sub-Saharan Africa as well as other low- and middle-income countries is needed. Further, data are needed on non-facility-based service delivery modalities, integrated service delivery and ancillary services. Key methodological gaps were also identified. An emphasis on equity and representation of heterogeneous populations was lacking. Research rarely acknowledged the complex and dynamic use of prevention technologies over time. Greater efforts are needed to collect primary data, quantify uncertainty, systematically compare the full range of prevention options available, and validate pilot and modelling data once interventions are scaled up. Clarity on appropriate cost-effectiveness outcome measures and thresholds is also lacking. Lastly, research often fails to reflect policy-relevant questions and approaches. CONCLUSIONS: Despite a large body of health economics evidence on non-surgical biomedical HIV prevention technologies, important gaps in the scope of evidence and methodology remain. To ensure that high-quality research influences key decision-making junctures and facilitates the delivery of prevention products in a way that maximises impact, we make five broad recommendations related to: improved study design, an increased focus on service delivery, greater community and stakeholder engagement, the fostering of an active network of partners across sectors and an enhanced application of research.

Colicin E2 expression in Escherichia coli biofilms: Induction and regulation revisited.

Colicins, bacteriocins produced by the gram-negative bacterium Escherichia coli, are tightly regulated by the DNA damage response regulatory system (SOS), and are thus triggered at times of stress. Colicins' regulation and expression profiles were primarily studied in suspended (planktonic) cultures yet, in their natural environments E. coli cells are sessile, assembled in biofilms. We hypothesized that colicin expression would differ between planktonic and biofilm E. coli cultures, even when induced by the same triggers. To test our hypothesis, we compared colicin E2 expression and SOS regulated genes in planktonic and biofilm cultures of E. coli, in response to DNA damaging agents and oxygen depletion. The results indicate that uninduced biofilms express more transcripts of the colicin operon than uninduced planktonic cells. Whole genome expression profiles confirmed that in uninduced biofilms, SOS genes are upregulated compared to planktonic cultures. However, DNA damaging agents and oxygen depletion augmented colicin expression in planktonic cells, while only marginal increase was recorded in biofilms. Our results suggest that the regulation of colicin E2 expression in E. coli biofilms considerably differ from planktonic cells, thus the induction of colicins in their host natural environment, i.e., the gastrointestinal tract, needs to be re-evaluated.

Diversity and Differentiation of Duckweed Species from Israel.

Duckweeds (Lemnaceae) are tiny plants that float on aquatic surfaces and are typically isolated from temperate and equatorial regions. Yet, duckweed diversity in Mediterranean and arid regions has been seldom explored. To address this gap in knowledge, we surveyed duckweed diversity in Israel, an ecological junction between Mediterranean and arid climates. We searched for duckweeds in the north and center of Israel on the surface of streams, ponds and waterholes. We collected and isolated 27 duckweeds and characterized their morphology, molecular barcodes (atpF-atpH and psbK-psbI) and biochemical features (protein content and fatty acids composition). Six species were identified-Lemna minor, L. gibba and Wolffia arrhiza dominated the duckweed populations, and together with past sightings, are suggested to be native to Israel. The fatty acid profiles and protein content further suggest that diverged functions have attributed to different haplotypes among the identified species. Spirodela polyrhiza, W. globosa and L. minuta were also identified but were rarer. S. polyrhiza was previously reported in our region, thus, its current low abundance should be revisited. However, L. minuta and W. globosa are native to America and Far East Asia, respectively, and are invasive in Europe. We hypothesize that they may be invasive species to our region as well, carried by migratory birds that disperse them through their migration routes. This study indicates that the duckweed population in Israel's aquatic environments consists of both native and transient species.

Maltreatment Related Hospitalizations Among Children Ages 17 Years and Younger: New York State, 2011-2013.

BACKGROUND: Child maltreatment is an important societal and public health problem. However, there are limited data on the epidemiology of maltreatment related hospitalizations. OBJECTIVE: The objective of this study was to describe maltreatment related hospitalizations among children ages 17 and younger in New York State (NYS). METHODS: Using 2011-2013 statewide planning and research cooperative system (SPARCS) inpatient hospital discharge data, maltreatment related hospitalizations among children ages 17 years and younger were identified using international classification of diseases, ninth revision, clinical modification codes for diagnoses and external cause of injury. Distributions of demographic and inpatient care characteristics were compared between hospitalizations for maltreatment and those for other causes, and between different types of maltreatment, using chi-square tests (for categorical variables) and t-tests (for continuous variables). RESULTS: During 2011-2013, a total of 853 maltreatment related hospitalizations among 836 children ages 17 years and younger were documented in NYS SPARCS. Infants (children < 1) had the highest rates of hospitalization. Overall, physical abuse was the most prevalent maltreatment type reported. CONCLUSIONS: This is the first study in NYS to describe the epidemiology of child maltreatment hospitalizations; it establishes a statewide baseline for this public health and societal issue.

The effects of microalgae-based fertilization of wheat on yield, soil microbiome and nitrogen oxides emissions.

Overuse of agrochemicals is linked to nutrient loss, greenhouse gases (GHG) emissions, and resource depletion thus requiring the development of sustainable agricultural solutions. Cultivated microalgal biomass could provide such a solution. The environmental consequences of algal biomass application in agriculture and more specifically its effect on soil GHG emissions are understudied. Here we report the results of a field experiment of wheat grown on three different soil types under the same climatic conditions and fertilized by urea or the untreated biomass of fresh-water green microalga (Coelastrella sp.). The results show that neither soil type nor fertilization types impacted the aboveground wheat biomass, whereas, soil microbiomes differed in accordance with soil but not the fertilizer type. However, wheat grain nitrogen (N) content and soil N oxides emissions were significantly lower in plots fertilized by algal biomass compared to urea. Grain N content in the wheat grain that was fertilized by algal biomass was between 1.3%-1.5% vs. 1.6%-2.0% in the urea fertilized wheat. Cumulative soil nitric oxide (NO) emissions were 2-5 fold lower, 313-726 g N ha-1 season-1 vs. 909-3079 g N ha-1 season-1. Cumulative soil nitrous oxide (N2O) emissions were 2-fold lower, 90-348 g N ha-1 season-1 vs. 147-761 g N ha-1 season-1. The lower emissions resulted in a 4-11 fold lower global warming impact of the algal fertilized crops. This calculation excluded the CO2 cost from the algae biomass production. Once included algal fertilization had a similar, or 40% higher, climatic impact compared to the urea fertilization.

The Effects of Colicin Production Rates on Allelopathic Interactions in Escherichia coli Populations.

Allelopathic interactions mediated by bacteriocins production serve microorganisms in the never-ending battle for resources and living space. Competition between the bacteriocin producer and sensitive populations results in the exclusion of one or the other depending on their initial frequencies, the structure of their habitat, their community density and their nutrient availability. These interactions were extensively studied in bacteriocins produced by Escherichia coli, the colicins. In spatially structured environments where interactions are local, colicin production has been shown to be advantageous to the producer population, allowing them to compete even when initially rare. Yet, in a well-mixed, unstructured environment where interactions are global, rare producer populations cannot invade a common sensitive population. Here we are showing, through an experimental model, that colicin-producers can outcompete sensitive and producer populations when the colicin production rates are enhanced. In fact, colicin production rates were proportional to the producer competitive fitness and their overall success in out-competing opponents when invading at very low initial frequencies. This ability of rare populations to invade established communities maintains diversity and allows the dispersal of beneficial traits.

The fate of pathogens in treated wastewater-soil-crops continuum and the effect of physical barriers.

Secondary treated wastewater (TWW) could provide a cheap and sustainable alternative to potable water (PW) irrigation and ensure food security, especially in arid and semi-arid regions. However, TWW may pose a health risk by introducing pathogens to the irrigated soil and crop, and especially to irrigated vegetables that are eaten raw. To avoid contamination, national and international authorities have mandated the use of physical barriers, such as drip irrigation and plastic mulch, to separate the irrigation water and the crops. Although the barriers are mandated, it is not clear whether they prevent contamination of crops. To evaluate the role of barriers on crop safety, cucumbers and melons were cultivated in a field irrigated with TWW or PW with the application of barriers including surface and subsurface drip irrigation and plastic mulch. Over 500 samples of water, soil and the model crops (surface and tissue) were collected during two growing seasons and used to monitor fecal indicator bacteria and pathogens using culture dependent and independent methods. The results showed that there were no statistically significant differences in both the fecal indicator and the pathogen abundance between treatments in either the soil or the crops, regardless of the water quality or barrier applied, even though TWW supported higher diversity and abundance of indicators and pathogens than PW. Moreover, the microbial communities detected in the irrigated soils and crops could not be linked to the irrigation water. The obtained results suggest that irrigation with TWW does not result in fecal pathogen contamination of the irrigated soil or crops.

The role of stress in colicin regulation.

Bacteriocins produced by Enterobacteriaceae are high molecular weight toxic proteins that kill target cells through a variety of mechanisms, including pore formation and nucleic acid degradation. What is remarkable about these toxins is that their expression results in death to the producing cells and therefore bacteriocin induction have to be tightly regulated, often confined to times of stress. Information on the regulation of bacteriocins produced by enteric bacteria is sketchy as their expression has only been elucidated in a handful of bacteria. Here, we review the known regulatory mechanisms of enteric bacteriocins and explore the expression of 12 of them in response to various triggers: DNA-damaging agents, stringent response, catabolite repression, oxidative stress, growth phase, osmolarity, cold shock, nutrient deprivation, anaerobiosis and pH stress. Our results indicate that the expression of bacteriocins is mostly confined to mutagenic triggers, while all other triggers tested are limited inducers.

Auto-regulation of DNA degrading bacteriocins: molecular and ecological aspects.

Colicins, proteinaceous antibiotics produced by Escherichia coli, specifically target competing strains killing them through one of a variety of mechanisms, including pore formation and nucleic acid degradation. The genes encoding colicins display a unique form of expression, which is tightly regulated, involving the DNA damage response regulatory system (the SOS response system), confined to stressful conditions and released by degradation of the producing cell. Given their lethal nature, colicin production has evolved a sophisticated system for repression and expression. While exploring the expression of 13 colicins we identified a novel means of induction unique to strains that kill by DNA degradation: these colicinogenic strains mildly poison themselves inflicting DNA damage that induces their DNA repair system (the SOS system), and their own expression. We established that among the four known DNase colicins (E2, E7, E8 and E9), three act to induce their own production. Using different stresses we show that this form of self-regulation entails high cost when growth conditions are not optimal, and is not carried out by individual cells but is a population-mediated trait. We discuss this novel form of colicins' regulation and expression, and its possible molecular mechanism and evolutionary implications.

The weak shall inherit: bacteriocin-mediated interactions in bacterial populations.

BACKGROUND: Evolutionary arms race plays a major role in shaping biological diversity. In microbial systems, competition often involves chemical warfare and the production of bacteriocins, narrow-spectrum toxins aimed at killing closely related strains by forming pores in their target's membrane or by degrading the target's RNA or DNA. Although many empirical and theoretical studies describe competitive exclusion of bacteriocin-sensitive strains by producers of bacteriocins, the dynamics among producers are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We used a reporter-gene assay to show that the bacterial response to bacteriocins' treatment mirrors the inflicted damage Potent bacteriocins are lethal to competing strains, but at sublethal doses can serve as strong inducing agents, enhancing their antagonists' bacteriocin production. In contrast, weaker bacteriocins are less toxic to their competitors and trigger mild bacteriocin expression. We used empirical and numerical models to explore the role of cross-induction in the arms race between bacteriocin-producing strains. We found that in well-mixed, unstructured environments where interactions are global, producers of weak bacteriocins are selectively advantageous and outcompete producers of potent bacteriocins. However, in spatially structured environments, where interactions are local, each producer occupies its own territory, and competition takes place only in "no man's lands" between territories, resulting in much slower dynamics. CONCLUSION/SIGNIFICANCE: The models we present imply that producers of potent bacteriocins that trigger a strong response in neighboring bacteriocinogenic strains are doomed, while producers of weak bacteriocins that trigger a mild response in bacteriocinogenic strains flourish. This counter-intuitive outcome might explain the preponderance of weak bacteriocin producers in nature. However, the described scenario is prolonged in spatially structured environments thus promoting coexistence, allowing migration and evolution, and maintaining bacterial diversity.

Projections of diagnosed HIV infection in children and adolescents in New York State.

Decreasing mother-to-child transmission is changing the population of children and adolescents with HIV. This project used recent epidemiological data to develop short-term projections of children and adolescents living with diagnosed HIV infection in New York State. A population simulation model was created to project prevalence of diagnosed HIV cases aged 0-19 years by age, sex, race/ethnicity and risk for years 2007-2014. Using 2006 data as the baseline population and 2001-2006 diagnosis and death data, annual diagnoses and deaths were calculated for each age/sex/race/risk category and known cases were 'aged' into the next year. The model produced annual estimates until 2014. The model predicts a decline in the number of persons aged 0-19 years living with diagnosed HIV in New York from 2810 in 2006 to 1431 in 2014, a net decrease of 49%. Living cases with paediatric risk continue to decrease. Cases aged 13-19 with non-paediatric risk increase slowly, leading to a shift in the risk composition of the population. The dominant effect seen in the model is the ageing out of perinatally infected children born before measures to prevent mother-to-child transmission were broadly implemented in the mid- to late 1990s. Changing trends in the young HIV-infected population should be considered in developing public health programmes for HIV prevention and care in New York State for the coming years.

Infestation experience of a rodent host and offspring viability of fleas: variation among host-parasite associations.

We studied survival and development of preimagoes and the ability to withstand starvation of adults in two flea species, host-specific Parapulex chephrenis and host-opportunistic Xenopsylla ramesis, when parent fleas fed on a typical (Acomys cahirinus and Dipodillus dasyurus, respectively) or an atypical (D. dasyurus and A. cahirinus, respectively) rodent host that either had never been parasitized by fleas (pristine) or had previously been exposed to fleas. We asked whether a repeatedly infested host acquired resistance that would cause decreased viability of the next generation fleas. Survival of preimaginal P. chephrenis was similar, independent of host species or its infestation status. Preimaginal X. ramesis had a higher survival rate when their parents fed on preinfested than on pristine typical hosts, whereas no effect of infestation status of an atypical host was found. P. chephrenis developed faster if their parents fed on atypical than on typical hosts and on pristine than on preinfested hosts of either species. X. ramesis developed faster if parents fed on pristine than preinfested typical hosts, but no difference in duration of development was found for atypical hosts. Under starvation, P. chephrenis lived longer if their parents fed on preinfested than on pristine typical hosts, but their lifespan did not depend on infestation status of atypical hosts. The latter was also true for X. ramesis and both host species. We conclude that a host is constrained in its ability to cope with a parasite, whereas a parasite is able to cope with defence responses of a host.

Does acquired resistance of rodent hosts affect metabolic rate of fleas?

We studied whether (a) previous infestation of a rodent host with fleas and (b) the reproductive effort of fleas affect the rate of CO(2) emission in two flea species, host-specific Parapulex chephrenis and host-opportunistic Xenopsylla ramesis when feeding on their typical and atypical rodent hosts. We measured the rate of CO(2) emission in preovipositing and ovipositing female fleas fed on either pristine or previously infested Acomys cahirinus (typical host of P. chephrenis) and Dipodillus dasyurus (typical host of X. ramesis). When P. chephrenis fed on a typical host, its mass-specific rate of CO(2) emission was not affected by previous infestation of a host, whereas when this flea fed on the atypical host, its rate of CO(2) emission was higher when a host was previously infested. This was manifested, however, mainly during the oviposition period. The rate of CO(2) emission by X. ramesis feeding on pristine hosts was significantly lower than in conspecifics feeding on previously infested hosts, independent of host species. Both flea species feeding on their typical hosts emitted CO(2) at similar mass-specific rates during preoviposition and oviposition, except for P. chephrenis feeding on D. dasyurus, which increased its rate during oviposition. There was no effect of the number of eggs produced per female on the rate of CO(2) emission during oviposition.

Recent advances in bacteriocin application as antimicrobials.

The dramatic rise in antibiotic-resistant pathogens has renewed efforts to identify, develop, and redesign antibiotics active against the resistant bacteria. This review will focus on the increasing number of patents aimed at employing the potential of antimicrobial polypeptides i.e., the bacteriocins, in vetrinary medicine and human health. Bacteriocins demonstrate enormous possibilities in treating and containing target bacteria and may be a part of novel approaches for replacing classical antibiotics at a time when many pathogens are no longer susceptible to the existing antibiotics. We will review the new knowledge-based approach to the exploitation of these bacterial produced toxins to treat human and animal infectious diseases as well as inhibit the proliferation of eukaryotic cells i.e., treating tumours. The ability to develop novel bacteriocin-based-drugs aimed at potential target cells, prokaryotic as well as eukaryotic, may open new possibilities for the design of improved antibiotics possessing refined characteristics.

Energy costs of blood digestion in a host-specific haematophagous parasite.

Fleas consume and digest blood from their hosts. We hypothesized that the energy costs of digestion of blood by fleas is dependent on the host species. To test this hypothesis, we studied CO2 emission, a measure of energy expenditure, during digestion of a blood meal taken by Parapulex chephrenis from a preferred (Acomys cahirinus) and a non-preferred (Gerbillus dasyurus) host. We predicted that the energy cost of digestion would be lower for A. cahirinus blood than that for G. dasyurus. Male and female fleas consumed similar amounts of blood per unit body mass, independent of host species. Our prediction was supported in that fleas expended significantly more energy digesting blood of G. dasyurus than blood of A. cahirinus. We also found CO2 emission rates of fed fleas were higher than those of unfed fleas and differed significantly among stages of blood digestion when a flea fed on G. dasyurus but not when it fed on A. cahirinus. When fed on G. dasyurus, fleas spent less energy during earlier than later stages of digestion.