Nature-positive goals for an organization's food consumption.

Organizations are increasingly committing to biodiversity protection targets with focus on 'nature-positive' outcomes, yet examples of how to feasibly achieve these targets are needed. Here we propose an approach to achieve nature-positive targets with respect to the embodied biodiversity impacts of an organization's food consumption. We quantify these impacts using a comprehensive database of life-cycle environmental impacts from food, and map exploratory strategies to meet defined targets structured according to a mitigation and conservation hierarchy. By considering the varying needs and values across the organization's internal community, we identify a range of targeted approaches towards mitigating impacts, which balance top-down and bottom-up actions to different degrees. Delivering ambitious nature-positive targets within current constraints will be challenging, particularly given the need to mitigate cumulative impacts. Our results evidence that however committed an organization is to being nature positive in its food provision, this is unachievable in the absence of systems change.

Optimizing the Application Timing and Dosage of Metarhizium brunneum (Hypocreales: Clavicipitaceae) as a Biological Control Agent of Aedes aegypti (Diptera: Culicidae) Larvae.

Aedes aegypti (Diptera: Culicidae) is the principal vector of dengue and other viruses that cause disease among 100 to 400 million people each year. The recent development of widespread insecticidal resistance has led to the rapid development of biological control solutions aimed at larval control. While the efficacy of Metarhizium brunneum has been shown against Aedes larvae, the impact of larval population dynamics will need to be determined to formulate effective control strategies. In this study, larvae were subjected to four concentrations of M. brunneum (105, 106, 107, 108 conidia ml-1). Larvae were found to be susceptible to M. brunneum with dose-dependent efficacy. When constant larval immigration was added as a parameter, peak mortality was consistently found to occur on the fourth day, before a significant reduction in control efficacy linked to a decline in conidial availability within the water column. This suggests that M. brunneum treatments should be applied at a concentration 1 × 107 conidia ml-1 every four days to effectively control mosquito larvae in the field, regardless of the fungal formulation, water volume, or larval density. Understanding fungal-mosquito dynamics is critical in developing appropriate control programs as it helps optimize the fungal control agent's dose and frequency of application.

Lessons from the use of telemedicine in the austere military environment and the implications for deployed surgical teams.

Over the last 20 years, there have been significant changes in UK surgical training. Civilian surgical training may no longer prepare military surgeons for the range of skills they require on operations. One method to address gaps in knowledge or experience is to use telemedicine to facilitate specialist consultations from UK-based specialists to deployed medical teams. In the UK Defence Medical Services (DMS), this capability is called real-time clinical support (RTCS). RTCS provides a direct audio-visual link from a deployed location anywhere in the world to a supporting medical specialist in the UK. RTCS is currently delivered via a combination of off-the-shelf hardware and commercially available software. This article will outline the current use of RTCS, with emphasis on deployed surgical teams in austere environments, and discuss the advantages and limitations of this capability. However, it must be emphasised that no technology can be a substitute for clinical training and experience. Although several limitations remain, the authors believe that RTCS offers potential benefits for the DMS and could be an important tool aiding deployed clinicians. It can also be argued that by engaging with the concept now, the DMS can shape future developments in this sphere.

The impact of combinatorial stress on the growth dynamics and metabolome of Burkholderia mesoacidophila demonstrates the complexity of tolerance mechanisms.

AIMS: The recently sequenced Burkholderia mesoacidophila (previously Pseudomonas mesoacidophila) is a soil organism and as such will be exposed to multiple concurrent stresses in the natural environment. The combinatorial stress potentially experienced by microbes in soil has not been investigated in detail. METHODS AND RESULTS: The impact of combinatorial stress on growth was investigated using tripartite variables-temperature, nutritional environment and either osmotic or oxidative stress. In nutritionally stringent conditions, increasing diamide concentration had no effect on growth while increasing H2 O2 concentration reduced both growth rate and maximum density. Metabolomic studies with oxidative stress revealed specific (unidentified) metabolites associated with diamide tolerance, and an overwhelming dominance of sugars and sugar alcohols in nutritionally stringent conditions with and without the additional stressor. CONCLUSIONS: Combinatorial stress tolerance is complex. Temperature had the greatest independent impact on growth, while the impact of the nutritional environment played a key role in oxidative stress tolerance. In nutritionally stringent conditions, the metabolome suggested different tolerance mechanisms for different types of oxidative stress. SIGNIFICANCE AND IMPACT OF THE STUDY: This work demonstrates the specificity of the stress response, and the need to consider multiple environmental factors to meaningfully investigate tolerance. Both environmental and clinical settings subject bacteria to combinatorial stress and this should be considered in the design of further studies.

Single operation palladium catalysed C(sp3)-H functionalisation of tertiary aldehydes: investigations into transient imine directing groups.

Simple amine and diamine derivatives can promote the palladium catalysed direct ß-C-H arylation of aliphatic aldehydes via transient imine formation. Trifluoroacetate was shown to be crucial in promoting the reaction. Sub-stoichiometric quantities of simple N-tosylethylenediamine was shown to form a bidentate directing group with an imine linkage. Isolation of an unsymmetrical palladacycle has shown different potential binding modes of the secondary NTs coordinating group by single crystal X-ray diffraction analysis, suggestive of a hemilabile ligand.

Preoperative sentinel lymph node identification, biopsy and localisation using contrast enhanced ultrasound (CEUS) in patients with breast cancer: a systematic review and meta-analysis.

AIM: To evaluate whether contrast-enhanced ultrasound (CEUS)-guided core biopsy of the sentinel lymph node (SLN) could identify metastatic nodes preoperatively and reduce the number of surgical SLN biopsies in patients with breast cancer and normal axillary B-mode ultrasound; and to establish whether CEUS SLN identification and localisation is a viable alternative to standard lymphatic mapping using isotope and blue dye. MATERIALS AND METHODS: A search of several electronic databases was performed and identified studies were assessed using QUADAS-2 for methodological quality. Pooled estimates of sensitivity and specificity for identification of nodal metastases were calculated. RESULTS: Eleven prospective studies and one retrospective study with 1,520 participants were included. The SLN identification and localisation rate for CEUS-guided skin marking was 70-100%, CEUS guided-wire localisation was 89-97%, and CEUS-guided iodine-125 (125I) seed localisation was 60%. Across the four studies that evaluated preoperative CEUS-guided SLN biopsy, pooled sensitivity for identification of nodal metastases was 54% (95% confidence interval [CI]: 47-61) and pooled specificity 100% (95% CI: 99-100). CONCLUSION: CEUS is a promising technique for preoperative staging of the axilla. CEUS-guided core biopsy has the potential to identify nodal metastases in over half (54%) of patients with normal axillary B-mode ultrasound. CEUS-guided identification and localisation of the SLN may offer a viable alternative to standard lymphatic mapping using isotope and blue dye; however, further prospective studies with larger samples are warranted.

Differential Pathogenicity of Metarhizium Blastospores and Conidia Against Larvae of Three Mosquito Species.

Biorational insecticides are being increasingly used in integrated pest management programs. In laboratory bioassays, the pathogenicity of blastospores and conidia of the entomopathogenic fungus Metarhizium brunneum ARSEF 4556 was evaluated against larvae of three mosquito species. Three propagule concentrations (1 × 106, 1 × 107, and 1 × 108 spores ml - 1) were used in the bioassays. Results showed that Aedes aegypti had lower survival rates when exposed to blastospores than when exposed to conidia, whereas the converse was true for Culex quinquefasciatus larvae. Anopheles stephensi larvae survival rates were similar when exposed to blastospores and conidia, except at the higher doses, where blastospores were more virulent. Several assays showed little difference in mortalities when using either 1 × 107 or 1 × 108 spores ml - 1, suggesting a threshold above which no higher control levels or economic benefit would be achieved. When tested at the lowest dose, the LT50 of Cx. quinquefasciatus using blastospores, wet conidia, and dry conidia was 3.2, 1.9, and 4.4 d, respectively. The LT50 of Ae. aegypti using blastospores, wet conidia, and dry conidia was 1.3, 3.3, and 6.2 d, respectively. The LT50 of An. stephensi using blastospores, wet conidia, and dry conidia was 2.0, 1.9, and 2.1 d, respectively. These observations suggest that for optimized control, two different formulations of the fungus may be needed when treating areas where there are mixed populations of Aedes, Anopheles, and Culex.

How humans drive speciation as well as extinction.

A central topic for conservation science is evaluating how human activities influence global species diversity. Humanity exacerbates extinction rates. But by what mechanisms does humanity drive the emergence of new species? We review human-mediated speciation, compare speciation and known extinctions, and discuss the challenges of using net species diversity as a conservation objective. Humans drive rapid evolution through relocation, domestication, hunting and novel ecosystem creation-and emerging technologies could eventually provide additional mechanisms. The number of species relocated, domesticated and hunted during the Holocene is of comparable magnitude to the number of observed extinctions. While instances of human-mediated speciation are known, the overall effect these mechanisms have upon speciation rates has not yet been quantified. We also explore the importance of anthropogenic influence upon divergence in microorganisms. Even if human activities resulted in no net loss of species diversity by balancing speciation and extinction rates, this would probably be deemed unacceptable. We discuss why, based upon 'no net loss' conservation literature-considering phylogenetic diversity and other metrics, risk aversion, taboo trade-offs and spatial heterogeneity. We conclude that evaluating speciation alongside extinction could result in more nuanced understanding of biosphere trends, clarifying what it is we actually value about biodiversity.

Fractal measures of spatial pattern as a heuristic for return rate in vegetative systems.

Measurement of population persistence is a long-standing problem in ecology; in particular, whether it is possible to gain insights into persistence without long time-series. Fractal measurements of spatial patterns, such as the Korcak exponent or boundary dimension, have been proposed as indicators of the persistence of underlying dynamics. Here we explore under what conditions a predictive relationship between fractal measures and persistence exists. We combine theoretical arguments with an aerial snapshot and time series from a long-term study of seagrass. For this form of vegetative growth, we find that the expected relationship between the Korcak exponent and persistence is evident at survey sites where the population return rate can be measured. This highlights a limitation of the use of power-law patch-size distributions and other indicators based on spatial snapshots. Moreover, our numeric simulations show that for a single species and a range of environmental conditions that the Korcak-persistence relationship provides a link between temporal dynamics and spatial pattern; however, this relationship is specific to demographic factors, so we cannot use this methodology to compare between species.

Aggregation dynamics explain vegetation patch-size distributions.

Vegetation patch-size distributions have been an intense area of study for theoreticians and applied ecologists alike in recent years. Of particular interest is the seemingly ubiquitous nature of power-law patch-size distributions emerging in a number of diverse ecosystems. The leading explanation of the emergence of these power-laws is due to local facilitative mechanisms. There is also a common transition from power law to exponential distribution when a system is under global pressure, such as grazing or lack of rainfall. These phenomena require a simple mechanistic explanation. Here, we study vegetation patches from a spatially implicit, patch dynamic viewpoint. We show that under minimal assumptions a power-law patch-size distribution appears as a natural consequence of aggregation. A linear death term also leads to an exponential term in the distribution for any non-zero death rate. This work shows the origin of the breakdown of the power-law under increasing pressure and shows that in general, we expect to observe a power law with an exponential cutoff (rather than pure power laws). The estimated parameters of this distribution also provide insight into the underlying ecological mechanisms of aggregation and death.

Evolutionary decay and the prospects for long-term disease intervention using engineered insect vectors.

After a long history of applying the sterile insect technique to suppress populations of disease vectors and agricultural pests, there is growing interest in using genetic engineering both to improve old methods and to enable new methods. The two goals of interventions are to suppress populations, possibly eradicating a species altogether, or to abolish the vector's competence to transmit a parasite. New methods enabled by genetic engineering include the use of selfish genes toward either goal as well as a variety of killer-rescue systems that could be used for vector competence reduction. This article reviews old and new methods with an emphasis on the potential for evolution of resistance to these strategies. Established methods of population suppression did not obviously face a problem from resistance evolution, but newer technologies might. Resistance to these newer interventions will often be mechanism-specific, and while it is too early to know where resistance evolution will become a problem, it is at least possible to propose properties of interventions that will be more or less effective in blocking resistance evolution.

Studies on the synthesis, stability and conformation of 2-sulfonyl-oxetane fragments.

2-(Arylsulfonyl)oxetanes have been prepared as new structural motifs of interest for medicinal chemistry. These are designed to fit within fragment space and be suitable for screening in fragment based drug discovery, as well as being suitable for further elaboration or incorporation into drug-like compounds. The oxetane ring is constructed through an efficient C-C bond forming cyclisation which allows the incorporation of a wide range of aryl-sulfonyl groups. Furthermore, biaryl-containing compounds can be accessed through Suzuki-Miyaura coupling from halogenated derivatives. With a number of oxetane containing fragment compounds available, their pH stability was assessed, indicating good half-life values for mono-substituted aryl sulfonyl oxetanes across the pH range (1 to 10). Solubility and metabolic stability data is also reported. Finally, the conformation of the fragments is assessed computationally, providing an indication of possible binding orientations.

Racial/ethnic differences in drug disposition and response: review of recently approved drugs.

Race and ethnicity can contribute to interindividual differences in drug exposure and/or response, which may alter risk-benefit in certain populations. Approximately one-fifth of new drugs approved in the past 6 years demonstrated differences in exposure and/or response across racial/ethnic groups, translating to population-specific prescribing recommendations in a few cases. When data from diverse populations were lacking, additional postmarketing studies were recommended. In this review we highlight several cases where race/ethnicity was central to regulatory decision-making.

Evolutionary reversion of live viral vaccines: Can genetic engineering subdue it?

Attenuated, live viral vaccines have been extraordinarily successful in protecting against many diseases. The main drawbacks in their development and use have been reliance on an unpredictable method of attenuation and the potential for evolutionary reversion to high virulence. Methods of genetic engineering now provide many safer alternatives to live vaccines, so if live vaccines are to compete with these alternatives in the future, they must either have superior immunogenicity or they must be able to overcome these former disadvantages. Several live vaccine designs that were historically inaccessible are now feasible because of advances in genome synthesis. Some of those methods are addressed here, with an emphasis on whether they enable predictable levels of attenuation and whether they are stable against evolutionary reversion. These new designs overcome many of the former drawbacks and position live vaccines to be competitive with alternatives. Not only do new methods appear to retard evolutionary reversion enough to prevent vaccine-derived epidemics, but it may even be possible to permanently attenuate live vaccines that are transmissible but cannot evolve to higher virulence under prolonged adaptation.

Importance of baseline specification in evaluating conservation interventions and achieving no net loss of biodiversity.

There is an urgent need to improve the evaluation of conservation interventions. This requires specifying an objective and a frame of reference from which to measure performance. Reference frames can be baselines (i.e., known biodiversity at a fixed point in history) or counterfactuals (i.e., a scenario that would have occurred without the intervention). Biodiversity offsets are interventions with the objective of no net loss of biodiversity (NNL). We used biodiversity offsets to analyze the effects of the choice of reference frame on whether interventions met stated objectives. We developed 2 models to investigate the implications of setting different frames of reference in regions subject to various biodiversity trends and anthropogenic impacts. First, a general analytic model evaluated offsets against a range of baseline and counterfactual specifications. Second, a simulation model then replicated these results with a complex real world case study: native grassland offsets in Melbourne, Australia. Both models showed that achieving NNL depended upon the interaction between reference frame and background biodiversity trends. With a baseline, offsets were less likely to achieve NNL where biodiversity was decreasing than where biodiversity was stable or increasing. With a no-development counterfactual, however, NNL was achievable only where biodiversity was declining. Otherwise, preventing development was better for biodiversity. Uncertainty about compliance was a stronger determinant of success than uncertainty in underlying biodiversity trends. When only development and offset locations were considered, offsets sometimes resulted in NNL, but not across an entire region. Choice of reference frame determined feasibility and effort required to attain objectives when designing and evaluating biodiversity offset schemes. We argue the choice is thus of fundamental importance for conservation policy. Our results shed light on situations in which biodiversity offsets may be an inappropriate policy instrument.

Neoadjuvant chemotherapy with sequential anthracycline-docetaxel with gemcitabine for large operable or locally advanced breast cancer: ANZ 0502 (NeoGem).

BACKGROUND: Neoadjuvant chemotherapy has a sound rationale for use in women with large operable breast cancer, and achievement of pathological complete response (pCR) is prognostic. Epirubicin and cyclophosphamide followed by docetaxel is a standard chemotherapy regimen for early breast cancer. In metastatic breast cancer the combination of gemcitabine and a taxane has shown promising results. This phase II study investigated the efficacy and safety of incorporating gemcitabine into neoadjuvant therapy. METHODS: Female patients with operable breast cancer that was clinically T2 (≥3 cm) or T3-4, N0-1, M0 were enrolled to receive 24 weeks of neoadjuvant chemotherapy using epirubicin and cyclophosphamide followed by docetaxel and gemcitabine, plus trastuzumab if HER2-positive. The primary endpoint was the pathological complete response (pCR) rate in the breast in separate HER2-negative and HER2-positive cohorts. Secondary endpoints included pCR in both the breast and axillary lymph nodes, clinical and radiological response rates, disease free survival and safety. RESULTS: 81 patients were enrolled: 63 HER2-negative and 18 HER2-positive. 67 (84%) completed all cycles of chemotherapy, and 78 (96%) proceeded to surgery. pCR was achieved by 12 (20%) patients with HER2-negative, and 9 (53%) with HER2-positive disease. At the first interim analysis, addition of prophylactic G-CSF was recommended due to excess neutropenia. The HER2-negative cohort was closed to accrual because it did not meet the pre-specified target for pCR, and the HER2-positive cohort was closed due to slow accrual. At a median follow-up of 24 months, 12 of 81 (15%) patients had experienced a relapse of their breast cancer. CONCLUSION: Neoadjuvant gemcitabine, when added to docetaxel, after epirubicin and cyclophosphamide, did not reach the pre-specified expectations for pCR rate in HER2-negative tumours. Excess neutropenia was observed, requiring growth factor support. Addition of gemcitabine to docetaxel in this schedule cannot be recommended. Australia and New Zealand Clinical Trials Registry (www.anzctr.org.au) registration number ACTRN12606000191594.

Bioimpedance of soft tissue under compression.

In this paper compression-dependent bioimpedance measurements of porcine spleen tissue are presented. Using a Cole-Cole model, nonlinear compositional changes in extracellular and intracellular makeup; related to a loss of fluid from the tissue, are identified during compression. Bioimpedance measurements were made using a custom tetrapolar probe and bioimpedance circuitry. As the tissue is increasingly compressed up to 50%, both intracellular and extracellular resistances increase while bulk membrane capacitance decreases. Increasing compression to 80% results in an increase in intracellular resistance and bulk membrane capacitance while extracellular resistance decreases. Tissues compressed incrementally to 80% show a decreased extracellular resistance of 32%, an increased intracellular resistance of 107%, and an increased bulk membrane capacitance of 64% compared to their uncompressed values. Intracellular resistance exhibits double asymptotic curves when plotted against the peak tissue pressure during compression, possibly indicating two distinct phases of mechanical change in the tissue during compression. Based on these findings, differing theories as to what is happening at a cellular level during high tissue compression are discussed, including the possibility of cell rupture and mass exudation of cellular material.

Slow fitness recovery in a codon-modified viral genome.

Extensive synonymous codon modification of viral genomes appears to be an effective way of attenuating strains for use as live vaccines. An assumption of this method is that codon changes have individually small effects, such that codon-attenuated viruses will be slow to evolve back to high fitness (and thus to high virulence). The major capsid gene of the bacterial virus T7 was modified to have varying levels of suboptimal synonymous codons in different constructs, and fitnesses declined linearly with the number of changes. Adaptation of the most extreme design, with 182 codon changes, resulted in a slow fitness recovery by standards of previous experimental evolution with this virus, although fitness effects of substitutions were higher than expected from the average effect of an engineered codon modification. Molecular evolution during recovery was modest, and changes evolved both within the modified gene and outside it. Some changes within the modified gene evolved in parallel across replicates, but with no obvious explanation. Overall, the study supports the premise that codon-modified viruses recover fitness slowly, although the evolution is substantially more rapid than expected from the design principle.

In vivo growth rates are poorly correlated with phage therapy success in a mouse infection model.

Two classes of phages yield profoundly different levels of recovery in mice experimentally infected with an Escherichia coli O18:K1:H7 strain. Phages requiring the K1 capsule for infection (K1-dep) rescue virtually all infected mice, whereas phages not requiring the capsule (K1-ind) rescue modest numbers (∼30%). To rescue infected mice, K1-ind phages require at least a 10(6)-fold-higher inoculum than K1-dep phages. Yet their in vivo growth dynamics are only modestly inferior to those of K1-dep phages, and competition between the two phage types in the same mouse reveals only a slight growth advantage for the K1-dep phage. The in vivo growth rate seems unlikely to be the primary determinant of phage therapy success. An alternative explanation is that the success of K1-dep phages is due substantially to their proteomic composition. They encode an enzyme that degrades the K1 capsule, which has been shown in other work to be sufficient to cure infection in the complete absence of phages.