Rapid diagnostic test value and implementation in antimicrobial stewardship across low-to-middle and high-income countries: a mixed-methods review

Despite technological advancements in infectious disease rapid diagnostic tests (RDTs) and use to direct therapy at the per-patient level, RDT utilisation in antimicrobial stewardship programmes (ASPs) is variable across low-to-middle income and high-income countries. Key insights from a panel of seven infectious disease experts from Colombia, Japan, Nigeria, Thailand, the UK, and the USA, combined with evidence from a literature review, were used to assess the value of RDTs in ASPs. From this, a value framework is proposed which aims to define the benefits of RDT use in ASPs, separate from per-patient benefits. Expert insights highlight that, to realise the value of RDTs within ASPs, effective implementation is key; actionable advice for choosing an RDT is proposed. Experts advocate the inclusion of RDTs in the World Health Organization Model List of essential in vitro diagnostics and in iterative development of national action plans

Evolution of the solar irradiance during the Holocene

Aims. We present a physically consistent reconstruction of the total solar irradiance for the Holocene. Methods. We extend the SATIRE models to estimate the evolution of the total (and partly spectral) solar irradiance over the Holocene. The basic assumption is that the variations of the solar irradiance are due to the evolution of the dark and bright magnetic features on the solar surface. The evolution of the decadally averaged magnetic flux is computed from decadal values of cosmogenic isotope concentrations recorded in natural archives employing a series of physics-based models connecting the processes from the modulation of the cosmic ray flux in the heliosphere to their record in natural archives. We then compute the total solar irradiance (TSI) as a linear combination of the jth and jth + 1 decadal values of the open magnetic flux. Results. Reconstructions of the TSI over the Holocene, each valid for a di_erent paleomagnetic time series, are presented. Our analysis suggests that major sources of uncertainty in the TSI in this model are the heritage of the uncertainty of the TSI since 1610 reconstructed from sunspot data and the uncertainty of the evolution of the Earth's magnetic dipole moment. The analysis of the distribution functions of the reconstructed irradiance for the last 3000 years indicates that the estimates based on the virtual axial dipole moment are significantly lower at earlier times than the reconstructions based on the virtual dipole moment. Conclusions. We present the first physics-based reconstruction of the total solar irradiance over the Holocene, which will be of interest for studies of climate change over the last 11500 years. The reconstruction indicates that the decadally averaged total solar irradiance ranges over approximately 1.5 W/m2 from grand maxima to grand minima

A homogeneous database of sunspot areas covering more than 130 years

The historical record of sunspot areas is a valuable and widely used proxy of solar activity and variability. The Royal Greenwich Observatory (RGO) regularly measured this and other parameters between 1874 and 1976. After that time records from a number of different observatories are available. These, however, show systematic differences and often have significants gaps. Our goal is to obtain a uniform and complete sunspot area time series by combining different data sets. A homogeneus composite of sunspot areas is essential for different applications in solar physics, among others for irradiance reconstructions. Data recorded simultaneously at different observatories are statistically compared in order to determine the intercalibration factors. Using these data we compile a complete and cross-calibrated time series. The Greenwich data set is used as a basis until 1976, the Russian data (a compilation of observations made at stations in the former USSR) between 1977 and 1985 and data compiled by the USAF network since 1986. Other data sets (Rome, Yunnan, Catania) are used to fill up the remaining gaps. Using the final sunspot areas record the Photometric Sunspot Index is calculated. We also show that the use of uncalibrated sunspot areas data sets can seriously affect the estimate of irradiance variations. Our analysis implies that there is no basis for the claim that UV irradiance variations have a much smaller influence on climate than total solar irradiance variations.Comment: 40 pages, 8 figures; JGR - Space Physics, publishe

Evolution of active and polar photospheric magnetic fields during the rise of Cycle 24 compared to previous cycles

The evolution of the photospheric magnetic field during the declining phase and minimum of Cycle 23 and the recent rise of Cycle 24 are compared with the behavior during previous cycles. We used longitudinal full-disk magnetograms from the NSO's three magnetographs at Kitt Peak, the Synoptic Optical Long-term Investigations of the Sun (SOLIS) Vector Spectro-Magnetograph (VSM), the Spectromagnetograph and the 512-Channel Magnetograph instruments, and longitudinal full-disk magnetograms from the Mt. Wilson 150-foot tower. We analyzed 37 years of observations from these two observatories that have been observing daily, weather permitting, since 1974, offering an opportunity to study the evolving relationship between the active region and polar fields in some detail over several solar cycles. It is found that the annual averages of a proxy for the active region poloidal magnetic field strength, the magnetic field strength of the high-latitude poleward streams, and the time derivative of the polar field strength are all well correlated in each hemisphere. These results are based on statistically significant cyclical patterns in the active region fields and are consistent with the Babcock-Leighton phenomenological model for the solar activity cycle. There was more hemispheric asymmetry in the activity level, as measured by total and maximum active region flux, during late Cycle 23 (after around 2004), when the southern hemisphere was more active, and Cycle 24 up to the present, when the northern hemisphere has been more active, than at any other time since 1974. The active region net proxy poloidal fields effectively disappeared in both hemispheres around 2004, and the polar fields did not become significantly stronger after this time. We see evidence that the process of Cycle 24 field reversal has begun at both poles.Comment: Accepted for publication in Solar Physic

Understanding mixed sequence DNA recognition by novel designed compounds: the kinetic and thermodynamic behavior of azabenzimidazole diamidines

Sequence-specific recognition of DNA by small organic molecules offers a potentially effective approach for the external regulation of gene expression and is an important goal in cell biochemistry. Rational design of compounds from established modules can potentially yield compounds that bind strongly and selectively with specific DNA sequences. An initial approach is to start with common A·T bp recognition molecules and build in G·C recognition units. Here we report on the DNA interaction of a synthetic compound that specifically binds to a G·C bp in the minor groove of DNA by using an azabenzimidazole moiety. The detailed interactions were evaluated with biosensor-surface plasmon resonance (SPR), isothermal calorimetric (ITC), and mass spectrometry (ESI-MS) methods. The compound, DB2277, binds with single G·C bp containing sequences with subnanomolar potency and displays slow dissociation kinetics and high selectivity. A detailed thermodynamic and kinetic study at different experimental salt concentrations and temperatures shows that the binding free energy is salt concentration dependent but essentially temperature independent under our experimental conditions, and binding enthalpy is temperature dependent but salt concentration independent. The results show that in the proper compound structural context novel heterocyclic cations can be designed to strongly recognize complex DNA sequences

Molecular and Physiological Properties Associated with Zebra Complex Disease in Potatoes and Its Relation with Candidatus Liberibacter Contents in Psyllid Vectors

Zebra complex (ZC) disease on potatoes is associated with Candidatus Liberibacter solanacearum (CLs), an α-proteobacterium that resides in the plant phloem and is transmitted by the potato psyllid Bactericera cockerelli (Šulc). The name ZC originates from the brown striping in fried chips of infected tubers, but the whole plants also exhibit a variety of morphological features and symptoms for which the physiological or molecular basis are not understood. We determined that compared to healthy plants, stems of ZC-plants accumulate starch and more than three-fold total protein, including gene expression regulatory factors (e.g. cyclophilin) and tuber storage proteins (e.g., patatins), indicating that ZC-affected stems are reprogrammed to exhibit tuber-like physiological properties. Furthermore, the total phenolic content in ZC potato stems was elevated two-fold, and amounts of polyphenol oxidase enzyme were also high, both serving to explain the ZC-hallmark rapid brown discoloration of air-exposed damaged tissue. Newly developed quantitative and/or conventional PCR demonstrated that the percentage of psyllids in laboratory colonies containing detectable levels of CLs and its titer could fluctuate over time with effects on colony prolificacy, but presumed reproduction-associated primary endosymbiont levels remained stable. Potato plants exposed in the laboratory to psyllid populations with relatively low-CLs content survived while exposure of plants to high-CLs psyllids rapidly culminated in a lethal collapse. In conclusion, we identified plant physiological biomarkers associated with the presence of ZC and/or CLs in the vegetative potato plant tissue and determined that the titer of CLs in the psyllid population directly affects the rate of disease development in plants

Design and Synthesis of Heterocyclic Cations for Specific DNA Recognition: From AT-Rich to Mixed-Base-Pair DNA Sequences

The compounds synthesized in this research were designed with the goal of establishing a new paradigm for mixed-base-pair DNA sequence-specific recognition. The design scheme starts with a cell-permeable heterocyclic cation that binds to AT base pair sites in the DNA minor groove. Modifications were introduced in the original compound to include an Hbond accepting group to specifically recognize the G-NH that projects into the minor groove. Therefore, a series of heterocyclic cations substituted with an azabenzimidazole ring has been designed and synthesized for mixed-base-pair DNA recognition. The most successful compound, 12a, had an azabenzimidazole to recognize G and additional modifications for general minor groove interactions. It binds to the DNA site −AAAGTTT− more strongly than the −AAATTT− site without GC and indicates the design success. Structural modifications of 12a generally weakened binding. The interactions of the new compound with a variety of DNA sequences with and without GC base pairs were evaluated by thermal melting analysis, circular dichroism, fluorescence emission spectroscopy, surface plasmon resonance, and molecular modeling

The Susceptibility of Trypanosomatid Pathogens to PI3/mTOR Kinase Inhibitors Affords a New Opportunity for Drug Repurposing

In our study we describe the potency of established phosphoinositide-3-kinase (PI3K) and mammalian Target of Rapamycin (mTOR) kinase inhibitors against three trypanosomatid parasites: Trypanosoma brucei, T. cruzi, and Leishmania sp., which are the causative agents for African sleeping sickness, Chagas disease, and leishmaniases, respectively. We noted that these parasites and humans express similar kinase enzymes. Since these similar human targets have been pursued by the drug industry for many years in the discovery of cellular growth and proliferation inhibitors, compounds developed as human anti-cancer agents should also have effect on inhibiting growth and proliferation of the parasites. With that in mind, we selected eight established PI3K and mTOR inhibitors for profiling against these pathogens. Among these inhibitors is an advanced clinical candidate against cancer, NVP-BEZ235, which we demonstrate to be a highly potent trypanocide in parasite cultures, and in a mouse model of T. brucei infection. Additionally, we describe observations of these inhibitors' effects on parasite growth and other cellular characteristics

Value of hospital antimicrobial stewardship programs [ASPs]:a systematic review

Abstract Background Hospital antimicrobial stewardship programs (ASPs) aim to promote judicious use of antimicrobials to combat antimicrobial resistance. For ASPs to be developed, adopted, and implemented, an economic value assessment is essential. Few studies demonstrate the cost-effectiveness of ASPs. This systematic review aimed to evaluate the economic and clinical impact of ASPs. Methods An update to the Dik et al. systematic review (2000–2014) was conducted on EMBASE and Medline using PRISMA guidelines. The updated search was limited to primary research studies in English (30 September 2014–31 December 2017) that evaluated patient and/or economic outcomes after implementation of hospital ASPs including length of stay (LOS), antimicrobial use, and total (including operational and implementation) costs. Results One hundred forty-six studies meeting inclusion criteria were included. The majority of these studies were conducted within the last 5 years in North America (49%), Europe (25%), and Asia (14%), with few studies conducted in Africa (3%), South America (3%), and Australia (3%). Most studies were conducted in hospitals with 500–1000 beds and evaluated LOS and change in antibiotic expenditure, the majority of which showed a decrease in LOS (85%) and antibiotic expenditure (92%). The mean cost-savings varied by hospital size and region after implementation of ASPs. Average cost savings in US studies were $732 per patient (range:$2.50 to $2640), with similar trends exhibited in European studies. The key driver of cost savings was from reduction in LOS. Savings were higher among hospitals with comprehensive ASPs which included therapy review and antibiotic restrictions. Conclusions Our data indicates that hospital ASPs have significant value with beneficial clinical and economic impacts. More robust published data is required in terms of implementation, LOS, and overall costs so that decision-makers can make a stronger case for investing in ASPs, considering competing priorities. Such data on ASPs in lower- and middle-income countries is limited and requires urgent attention