Formulation and antibacterial properties of clay mineral-tetracycline and -doxycycline composites

Clay minerals have been used as adsorbents for decades but research into their use within healthcare as drug-carriers and modified drug release materials is an increasingly common area of interest. In current clinical practice the management of acute bacterial skin and skin-structure infections (ABSSSIs) requires patients to take systemic antibacterial treatment due to a lack of appropriate topical options. In this research tetracycline (TC) and doxycycline (DC) were adsorbed onto a range of clay minerals (kaolinite, montmorillonite, acid-activated montmorillonite, Laponite® RD and Laponite® XL21) to evaluate their potential as materials for the delivery of these antibiotics to infected wounds. A dispersion pH that favoured the zwitterionic form of the antibiotic molecules was shown to favour adsorption onto the clay minerals. FTIR and pXRD showed that positively charged groups on the antibiotic molecules interacted with the negatively charged clay mineral surface, whilst negatively charged groups on the antibiotic molecules could interact with the positively charged edge-sites of the clay minerals. Swelling clays such as the two Laponites® were able to adsorb much more TC and DC due to their structure and chemistry. The clay minerals alone did not have any antibacterial effects against Staphylococcus epidermidis, Cutibacterium acnes, and Pseudomonas aeruginosa. Antibiotic containing composites successfully released TC and DC, exhibiting activity against the three bacterial strains proportional to the antibiotic-loading on the composites. This research demonstrates the ability of these clay minerals to deliver TC and DC against common skin pathogens and their potential for future development towards clinical applications

Guideline interval: A new time interval in the diagnostic pathway for symptomatic cancer

This is the final version. Available on open access from Elsevier via the DOI in this recordBACKGROUND: A standard measure of the cancer diagnostic pathway, diagnostic interval, is the time from "first presentation of cancer" to diagnosis. Cancer presentation may be unclear in patients with multimorbidity or non-specific symptoms, signs or test results ("features"). We propose an alternative, guideline interval, with a more certain start date; namely, when the patient first meets suspected-cancer criteria for investigation or referral. METHODS: This retrospective cohort study used Clinical Practice Research Datalink (CPRD) and English cancer registry data. Participants, aged ≥55 years, had diagnostic codes for oesophagogastric cancers in 1/1/12-31/12/17. Features of oesophagogastric cancer in the year before diagnosis were identified from CPRD codes for dysphagia, haematemesis, upper-abdominal mass or pain, low haemoglobin, reflux, dyspepsia, nausea, vomiting, weight loss or thrombocytosis. Diagnostic interval was the time from first feature to diagnosis; guidance interval, the time from first meeting criteria in NICE suspected-cancer guidance to diagnosis. Multimorbidity burden was quantified using Adjusted Clinical Groups®. Accelerated failure-time models explored associations between multimorbidity burden and length of both diagnostic and guideline interval. RESULTS: There were 3,793 eligible participants (69.0 % male), mean age 74.1 years (SD 10.5). 3,097 (81.7 %) presented with ≥1 feature in the year before diagnosis, and 1,990 (52.5 %) met NICE suspected-cancer criteria. The median for both intervals was 11 days in healthy users, and rose with increasing morbidity burden. At very high multimorbidity burden, diagnostic interval was 5.47 (95%CI 3.25-9.20) times longer and guideline interval was 3.91 (2.63-5.80) times longer than for healthy users. CONCLUSIONS: Guideline interval is proposed as a new measure of the cancer diagnostic pathway. It has a more certain start date than diagnostic interval, and is lengthened less than diagnostic interval in people with a very high multimorbidity burden. Guideline interval has potential for assessing the implementation of suspected-cancer policies.Cancer Research UKNational Institute for Health Research (NIHR

By hook or by crook? Morphometry, competition and cooperation in rodent sperm

Background Sperm design varies enormously across species and sperm competition is thought to be a major factor influencing this variation. However, the functional significance of many sperm traits is still poorly understood. The sperm of most murid rodents are characterised by an apical hook of the sperm head that varies markedly in extent across species. In the European woodmouse Apodemus sylvaticus (Muridae), the highly reflected apical hook of sperm is used to form sperm groups, or “trains,” which exhibited increased swimming velocity and thrusting force compared to individual sperm. Methodology/Principal Findings Here we use a comparative study of murine rodent sperm and demonstrate that the apical hook and sperm cooperation are likely to be general adaptations to sperm competition in rodents. We found that species with relatively larger testes, and therefore more intense sperm competition, have a longer, more reflected apical sperm hook. In addition, we show that sperm groups also occur in rodents other than the European woodmouse. Conclusions Our results suggest that in rodents sperm cooperation is more widespread than assumed so far and highlight the importance of diploid versus haploid selection in the evolution of sperm design and function

Trypanosoma rangeli is phylogenetically closer to Old World trypanosomes than to Trypanosoma cruzi.

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.Trypanosoma rangeli and Trypanosoma cruzi are generalist trypanosomes sharing a wide range of mammalian hosts; they are transmitted by triatomine bugs, and are the only trypanosomes infecting humans in the Neotropics. Their origins, phylogenetic relationships, and emergence as human parasites have long been subjects of interest. In the present study, taxon-rich analyses (20 trypanosome species from bats and terrestrial mammals) using ssrRNA, glycosomal glyceraldehyde-3-phosphate dehydrogenase (gGAPDH), heat shock protein-70 (HSP70) and Spliced Leader RNA sequences, and multilocus phylogenetic analyses using 11 single copy genes from 15 selected trypanosomes, provide increased resolution of relationships between species and clades, strongly supporting two main sister lineages: lineage Schizotrypanum, comprising T. cruzi and bat-restricted trypanosomes, and Tra[Tve-Tco] formed by T. rangeli, Trypanosoma vespertilionis and Trypanosoma conorhini clades. Tve comprises European T. vespertilionis and African T. vespertilionis-like of bats and bat cimicids characterised in the present study and Trypanosoma sp. Hoch reported in monkeys and herein detected in bats. Tco included the triatomine-transmitted tropicopolitan T. conorhini from rats and the African NanDoum1 trypanosome of civet (carnivore). Consistent with their very close relationships, Tra[Tve-Tco] species shared highly similar Spliced Leader RNA structures that were highly divergent from those of Schizotrypanum. In a plausible evolutionary scenario, a bat trypanosome transmitted by cimicids gave origin to the deeply rooted Tra[Tve-Tco] and Schizotrypanum lineages, and bat trypanosomes of diverse genetic backgrounds jumped to new hosts. A long and independent evolutionary history of T. rangeli more related to Old World trypanosomes from bats, rats, monkeys and civets than to Schizotrypanum spp., and the adaptation of these distantly related trypanosomes to different niches of shared mammals and vectors, is consistent with the marked differences in transmission routes, life-cycles and host-parasite interactions, resulting in T. cruzi (but not T. rangeli) being pathogenic to humans.This study was supported by grants awarded to MMGT and EPC from CNPq (National Council for Scientific and Technological Development) PROAFRICA, PROSUL and UNIVERSAL programs, CAPES (Coordination for the Improvement of Higher Education Personnel) PNIPB, PNPD and PROTAX programs, and FAPESP (São Paulo Research Foundation; process 2016/07487-0). Genome sequencing was supported by the Assembling the Tree of Life (ATOL) Project of the National Science Foundation, USA (NSF DEB-0830056), and TCC-USP (Trypanosomatid Culture Collection of the University of São Paulo) projects. OEA received PhD fellowships from CNPq (PROTAX) and COLCIENCIAS (Administrative Department of Science, Technology and Innovation, Colombia); PAO is a postdoctoral fellow of CAPES (PNPD); LL and AGCM are supported by a postdoctoral fellowship from CAPES (PROTAX)

The Cost of Sex: Quantifying Energetic Investment in Gamete Production by Males and Females

The relative energetic investment in reproduction between the sexes forms the basis of sexual selection and life history theories in evolutionary biology. It is often assumed that males invest considerably less in gametes than females, but quantifying the energetic cost of gamete production in both sexes has remained a difficult challenge. For a broad diversity of species (invertebrates, reptiles, amphibians, fishes, birds, and mammals), we compared the cost of gamete production between the sexes in terms of the investment in gonad tissue and the rate of gamete biomass production. Investment in gonad biomass was nearly proportional to body mass in both sexes, but gamete biomass production rate was approximately two to four orders of magnitude higher in females. In both males and females, gamete biomass production rate increased with organism mass as a power law, much like individual metabolic rate. This suggests that whole-organism energetics may act as a primary constraint on gamete production among species. Residual variation in sperm production rate was positively correlated with relative testes size. Together, these results suggest that understanding the heterogeneity in rates of gamete production among species requires joint consideration of the effects of gonad mass and metabolism

Variation in 'fast-track' referrals for suspected cancer by patient characteristic and cancer diagnosis: evidence from 670 000 patients with cancers of 35 different sites.

BACKGROUND: In England, 'fast-track' (also known as 'two-week wait') general practitioner referrals for suspected cancer in symptomatic patients are used to shorten diagnostic intervals and are supported by clinical guidelines. However, the use of the fast-track pathway may vary for different patient groups. METHODS: We examined data from 669 220 patients with 35 cancers diagnosed in 2006-2010 following either fast-track or 'routine' primary-to-secondary care referrals using 'Routes to Diagnosis' data. We estimated the proportion of fast-track referrals by sociodemographic characteristic and cancer site and used logistic regression to estimate respective crude and adjusted odds ratios. We additionally explored whether sociodemographic associations varied by cancer. RESULTS: There were large variations in the odds of fast-track referral by cancer (P<0.001). Patients with testicular and breast cancer were most likely to have been diagnosed after a fast-track referral (adjusted odds ratios 2.73 and 2.35, respectively, using rectal cancer as reference); whereas patients with brain cancer and leukaemias least likely (adjusted odds ratios 0.05 and 0.09, respectively, for brain cancer and acute myeloid leukaemia). There were sex, age and deprivation differences in the odds of fast-track referral (P<0.013) that varied in their size and direction for patients with different cancers (P<0.001). For example, fast-track referrals were least likely in younger women with endometrial cancer and in older men with testicular cancer. CONCLUSIONS: Fast-track referrals are less likely for cancers characterised by nonspecific presenting symptoms and patients belonging to low cancer incidence demographic groups. Interventions beyond clinical guidelines for 'alarm' symptoms are needed to improve diagnostic timeliness

The Forward-Discount Puzzle in Central and Eastern Europe

This paper adds to evidence that the forward-discount puzzle is at least partly explained as a compensation for taking crash-risk. A number of Central and Eastern European exchange rates are compared. A Hidden Markov Model is used to identify two regimes for most of the exchange rates. These two regimes can be characterised as being either periods of stability or periods of instability. The level of international risk aversion and changes in US interest rates affect the probability of switching from one regime to the other. This model is then used to assess the way that these two factors affect the probability of a currency crisis. While the Czech Republic, Hungary and Bulgaria are very sensitive to international financial conditions, Poland and Romania are relatively immune. JEL classifications: C24, F31, F32; Key words: Exchange rates, uncovered interest parity, foreign exchange risk discount, hidden-Markov model, carry-trad

Using molecular data for epidemiological inference: assessing the prevalence of Trypanosoma brucei rhodesiense in Tsetse in Serengeti, Tanzania

Background: Measuring the prevalence of transmissible Trypanosoma brucei rhodesiense in tsetse populations is essential for understanding transmission dynamics, assessing human disease risk and monitoring spatio-temporal trends and the impact of control interventions. Although an important epidemiological variable, identifying flies which carry transmissible infections is difficult, with challenges including low prevalence, presence of other trypanosome species in the same fly, and concurrent detection of immature non-transmissible infections. Diagnostic tests to measure the prevalence of T. b. rhodesiense in tsetse are applied and interpreted inconsistently, and discrepancies between studies suggest this value is not consistently estimated even to within an order of magnitude. Methodology/Principal Findings: Three approaches were used to estimate the prevalence of transmissible Trypanosoma brucei s.l. and T. b. rhodesiense in Glossina swynnertoni and G. pallidipes in Serengeti National Park, Tanzania: (i) dissection/microscopy; (ii) PCR on infected tsetse midguts; and (iii) inference from a mathematical model. Using dissection/microscopy the prevalence of transmissible T. brucei s.l. was 0% (95% CI 0–0.085) for G. swynnertoni and 0% (0–0.18) G. pallidipes; using PCR the prevalence of transmissible T. b. rhodesiense was 0.010% (0–0.054) and 0.0089% (0–0.059) respectively, and by model inference 0.0064% and 0.00085% respectively. Conclusions/Significance: The zero prevalence result by dissection/microscopy (likely really greater than zero given the results of other approaches) is not unusual by this technique, often ascribed to poor sensitivity. The application of additional techniques confirmed the very low prevalence of T. brucei suggesting the zero prevalence result was attributable to insufficient sample size (despite examination of 6000 tsetse). Given the prohibitively high sample sizes required to obtain meaningful results by dissection/microscopy, PCR-based approaches offer the current best option for assessing trypanosome prevalence in tsetse but inconsistencies in relating PCR results to transmissibility highlight the need for a consensus approach to generate meaningful and comparable data

Risk prediction tools for cancer in primary care.

Numerous risk tools are now available, which predict either current or future risk of a cancer diagnosis. In theory, these tools have the potential to improve patient outcomes through enhancing the consistency and quality of clinical decision-making, facilitating equitable and cost-effective distribution of finite resources such as screening tests or preventive interventions, and encouraging behaviour change. These potential uses have been recognised by the National Cancer Institute as an 'area of extraordinary opportunity' and an increasing number of risk prediction models continue to be developed. The data on predictive utility (discrimination and calibration) of these models suggest that some have potential for clinical application; however, the focus on implementation and impact is much more recent and there remains considerable uncertainty about their clinical utility and how to implement them in order to maximise benefits and minimise harms such as over-medicalisation, anxiety and false reassurance. If the potential benefits of risk prediction models are to be realised in clinical practice, further validation of the underlying risk models and research to assess the acceptability, clinical impact and economic implications of incorporating them in practice are needed.This is the final version of the article. It was first available from NPG via http://dx.doi.org/10.1038/bjc.2015.40