Multiple Targets, One Goal: Compounding life-extending effects through Polypharmacology.

Analysis of lifespan-extending compounds suggested the most effective geroprotectors target multiple biogenic amine receptors. To test this hypothesis, we used graph neural networks to predict such polypharmacological compounds and evaluated them in C. elegans. Over 70% of the selected compounds extended lifespan, with effect sizes in the top 5% compared to the DrugAge database. This reveals that rationally designing polypharmacological compounds enables the design of geroprotectors with exceptional efficacy.

One Health: opportunities for Defence Engagement (Health).

The One Health concept continues to gain traction as a necessary approach to tackle emerging threats to human, animal and environmental health but has not yet been adopted within Defence Engagement (Health). The health of humans, animals and ecosystems are closely interlinked. The One Health concept recognises this interdependence and seeks to balance and optimise the health of all three through an integrated and unifying approach. With a focus on zoonoses, vectorborne disease, antimicrobial resistance and food safety it encourages collaboration, communication, coordination and capacity building. The UK has made commitments to the One Health approach in the Global Health and Security Agenda, and the Integrated Review. This article explores how the One Health approach could and should be adopted within Defence Engagement (Health) activity to offer the potential for high-impact, low-risk activity while facilitating long-term relationship building.

Evaluation of the Efficacy of Doxycycline, Ciprofloxacin, Levofloxacin, and Co-trimoxazole Using In Vitro and In Vivo Models of Q Fever.

Q fever, caused by the intracellular pathogen Coxiella burnetii, is traditionally treated using tetracycline antibiotics, such as doxycycline. Doxycycline is often poorly tolerated, and antibiotic-resistant strains have been isolated. In this study, we have evaluated a panel of antibiotics (doxycycline, ciprofloxacin, levofloxacin, and co-trimoxazole) against C. burnetii using in vitro methods (determination of MIC using liquid and solid media; efficacy assessment in a THP cell infection model) and in vivo methods (wax moth larvae and mouse models of infection). In addition, the schedule for antibiotic treatment has been evaluated, with therapy initiated at 24 h pre- or postchallenge. Both doxycycline and levofloxacin limited overt clinical signs during treatment in the AJ mouse model of aerosol infection, but further studies are required to investigate the possibility of disease relapse or incomplete bacterial clearance after the antibiotics are stopped. Levofloxacin was well tolerated and therefore warrants further investigation as an alternative to the current recommended treatment with doxycycline.

Use of axenic media to determine antibiotic efficacy against coxiella burnetii.

The traditional methods of measuring minimum inhibitory concentration (MIC) of antibiotics against Coxiella burnetii are time-consuming and technically difficult. The discovery of axenic media for C. burnetii culture provided an opportunity to determine the feasibility of using both broth dilution and an antimicrobial gradient method (Etest) as a convenient method of measuring MICs. The MICs for a range of antibiotics that have proven or potential use in the treatment of Q fever, namely doxycycline, ciprofloxacin, levofloxacin, moxifloxacin and co-trimoxazole, were measured. It was possible to measure MICs using both microdilution and Etest methods. MICs obtained were comparable to those from other methods. This study demonstrates the potential use of a relatively simple test to measure MIC in an organism that is difficult to culture.

Enhanced case management can be delivered for patients with EVD in Africa: Experience from a UK military Ebola treatment centre in Sierra Leone.

BACKGROUND: Limited data exist describing supportive care management, laboratory abnormalities and outcomes in patients with Ebola virus disease (EVD) in West Africa. We report data which constitute the first description of the provision of enhanced EVD case management protocols in a West African setting. METHODS: Demographic, clinical and laboratory data were collected by retrospective review of clinical and laboratory records of patients with confirmed EVD admitted between 5 November 2014 and 30 June 2015. RESULTS: A total of 44 EVD patients were admitted (median age 37 years (range 17-63), 32/44 healthcare workers), and excluding those evacuated, the case fatality rate was 49% (95% CI 33%-65%). No pregnant women were admitted. At admission 9/44 had stage 1 disease (fever and constitutional symptoms only), 12/44 had stage 2 disease (presence of diarrhoea and/or vomiting) and 23/44 had stage 3 disease (presence of diarrhoea and/or vomiting with organ failure), with case fatality rates of 11% (95% CI 1%-58%), 27% (95% CI 6%-61%), and 70% (95% CI 47%-87%) respectively (p = 0.009). Haemorrhage occurred in 17/41 (41%) patients. The majority (21/40) of patients had hypokalaemia with hyperkalaemia occurring in 12/40 patients. Acute kidney injury (AKI) occurred in 20/40 patients, with 14/20 (70%, 95% CI 46%-88%) dying, compared to 5/20 (25%, 95% CI 9%-49%) dying who did not have AKI (p = 0.01). Ebola virus (EBOV) PCR cycle threshold value at baseline was mean 20.3 (SD 4.3) in fatal cases and 24.8 (SD 5.5) in survivors (p = 0.007). Mean national early warning score (NEWS) at admission was 5.5 (SD 4.4) in fatal cases and 3.0 (SD 1.9) in survivors (p = 0.02). Central venous catheters were placed in 37/41 patients and intravenous fluid administered to 40/41 patients (median duration of 5 days). Faecal management systems were inserted in 21/41 patients, urinary catheters placed in 27/41 and blood component therapy administered to 20/41 patients. CONCLUSIONS: EVD is commonly associated life-threatening electrolyte imbalance and organ dysfunction. We believe that the enhanced levels of protocolized care, scale and range of medical interventions we report, offer a blueprint for the future management of EVD in resource-limited settings.

Leptospirosis in a British soldier after travel to Borneo.

Undifferentiated febrile illness in a returning soldier is a common problem encountered by serving medical officers. A 32-year-old soldier presented to Birmingham Heartlands Hospital with fever and acute kidney injury after return from Borneo. Leptospirosis was suspected and empirical antibiotics were started before subsequent confirmation by serology and PCR. Leptospirosis is common in South-East Asia, and troops exercising in jungle areas, and in the UK, are at risk. Advice, including inpatient management when appropriate, is available from the UK Role 4 Military Infectious Diseases and Tropical Medicine Service.

Foreign Medical Teams in support of the Ebola outbreak: a UK military model of pre-deployment training and assurance.

We discuss the training methodology developed and utilised to prepare UK military medical teams to establish an Ebola Treatment Centre in Sierra Leone. We highlight the process of identifying and mitigating nosocomial risk in the Pre-Deployment Training process, encompassing the challenges of developing, training and assuring a capability at pace, which deployed to deliver high quality clinical care to patients with Ebola Virus Disease.

Use of an ultraviolet tracer in simulation training for the clinical management of Ebola virus disease.

In October 2014 the UK military deployed to Sierra Leone to provide care for healthcare workers affected by Ebola virus disease. A training package designed by the Army Medical Services Training Centre prepared the deploying personnel in the required infection prevention and control measures. The training used ultraviolet tracer to provide validation of the skills required when treating patients with Ebola and to confirm subsequent decontamination. This training construct provided useful feedback to clinicians on their infection control measures and would be useful in the context of any infection spread by droplets and fomites.

People with diagnosed HIV infection not attending for specialist clinical care: UK national review.

BACKGROUND: Regular clinical care is important for the well-being of people with HIV. We sought to audit and describe the characteristics of adults with diagnosed HIV infection not reported to be attending for clinical care in the UK. METHODS: Public Health England (PHE) provided clinics with lists of patients diagnosed or seen for specialist HIV care in 2010 but not linked to a clinic report or known to have died in 2011. Clinics reviewed case-notes of these individuals and completed questionnaires. A nested case-control analysis was conducted to compare those who had remained in the UK in 2011 while not attending care with individuals who received specialist HIV care in both 2010 and 2011. RESULTS: Among 74,418 adults living with diagnosed HIV infection in the UK in 2010, 3510 (4.7%) were not reported as seen for clinical care or died in 2011. Case note reviews and outcomes were available for 2255 (64%) of these: 456 (20.2%) remained in the UK and did not attend care; 590 (26.2%) left UK; 508 (22.6%) received care in the UK: 73 (3.2%) died and 628 (27.8%) had no documented outcome. Individuals remaining in the UK and not attending care were more likely to be treatment naïve than those in care, but duration since HIV diagnosis was not significant. HIV/AIDS related hospitalisations were observed among non-attenders. CONCLUSION: Retention in UK specialist HIV care is excellent. Our audit indicates that the 'true' loss to follow up rate in 2011 was <2.5% with no evidence of health tourism. Novel interventions to ensure high levels of clinic engagement should be explored to minimise disease progression among non-attenders.

Infective endocarditis in the military patient.

Infective endocarditis (IE) is a potentially fatal cardiac infection associated with an inhospital mortality rate of up to 22%. Fifty per cent of IE cases develop in patients with no known history of valve disease. It is therefore important to remain vigilant to the possibility of the diagnosis in patients with a febrile illness and unknown source. From a military perspective, our patients are unique due to the breadth of pathogens they are exposed to, and blood-culture-negative IE is a risk. In particular, there should be awareness of Coxiella burnetii as a possible causative pathogen. In this review we incorporate the latest consensus from systematic reviews and publications identified by a literature search through Medline. We describe the diagnosis and management of IE with particular reference to the military population.

Management of postpartum depression.

The mainstays of treatment for peripartum depression are psychotherapy and antidepressant medications. More research is needed to understand which treatments are safe, preferable, and effective. Postpartum depression, now termed peripartum depression by the DSM-V, is one of the most common complications in the postpartum period and has potentially significant negative consequences for mothers and their families. This article highlights common clinical challenges in the treatment of peripartum depression and reviews the evidence for currently available treatment options. Psychotherapy is the first-line treatment option for women with mild to moderate peripartum depression. Antidepressant medication in combination with therapy is recommended for women with moderate to severe depression. Although pooled case reports and small controlled studies have demonstrated undetectable infant serum levels and no short-term adverse events in infants of mothers breastfeeding while taking sertraline (Zoloft) and paroxetine (Paxil), further research is needed including larger samples and long-term follow-up of infants exposed to antidepressants via breastfeeding controlling for maternal depression. Pharmacologic treatment recommendations for women who are lactating must include discussion with the patient regarding the benefits of breastfeeding, risks of antidepressant use during lactation, and risks of untreated illness. There is a growing evidence base for nonpharmacologic interventions including repetitive transcranial magnetic stimulation, which may offer an attractive option for women who wish to continue to breastfeed and are concerned about their infants being exposed to medication. Among severe cases of peripartum depression with psychosis, referral to a psychiatrist or psychiatric advanced practice registered nurse is warranted. Suicidal or homicidal ideation with a desire, intent, or plan to harm oneself or anyone else, including the infant, is a psychiatric emergency, and an evaluation by a mental health professional should be conducted immediately. Peripartum depression treatment research is limited by small sample sizes and few controlled studies. Much work is still needed to better understand which treatments women prefer and are the most effective in ameliorating the symptoms and disease burden associated with peripartum depression.

Sexual health and HIV in the Army.

Sexual acquisition of infections has always been an important part of military history and although disease patterns have changed over time, the problem has not gone away. This article will look at how to recognise infection, the general principles of management, where to access guidance and how to get specialised help within the complexities of the military environment.

Fungal Planet description sheets: 154-213.

Novel species of microfungi described in the present study include the following from South Africa: Camarosporium aloes, Phaeococcomyces aloes and Phoma aloes from Aloe, C. psoraleae, Diaporthe psoraleae and D. psoraleae-pinnatae from Psoralea, Colletotrichum euphorbiae from Euphorbia, Coniothyrium prosopidis and Peyronellaea prosopidis from Prosopis, Diaporthe cassines from Cassine, D. diospyricola from Diospyros, Diaporthe maytenicola from Maytenus, Harknessia proteae from Protea, Neofusicoccum ursorum and N. cryptoaustrale from Eucalyptus, Ochrocladosporium adansoniae from Adansonia, Pilidium pseudoconcavum from Greyia radlkoferi, Stagonospora pseudopaludosa from Phragmites and Toxicocladosporium ficiniae from Ficinia. Several species were also described from Thailand, namely: Chaetopsina pini and C. pinicola from Pinus spp., Myrmecridium thailandicum from reed litter, Passalora pseudotithoniae from Tithonia, Pallidocercospora ventilago from Ventilago, Pyricularia bothriochloae from Bothriochloa and Sphaerulina rhododendricola from Rhododendron. Novelties from Spain include Cladophialophora multiseptata, Knufia tsunedae and Pleuroascus rectipilus from soil and Cyphellophora catalaunica from river sediments. Species from the USA include Bipolaris drechsleri from Microstegium, Calonectria blephiliae from Blephilia, Kellermania macrospora (epitype) and K. pseudoyuccigena from Yucca. Three new species are described from Mexico, namely Neophaeosphaeria agaves and K. agaves from Agave and Phytophthora ipomoeae from Ipomoea. Other African species include Calonectria mossambicensis from Eucalyptus (Mozambique), Harzia cameroonensis from an unknown creeper (Cameroon), Mastigosporella anisophylleae from Anisophyllea (Zambia) and Teratosphaeria terminaliae from Terminalia (Zimbabwe). Species from Europe include Auxarthron longisporum from forest soil (Portugal), Discosia pseudoartocreas from Tilia (Austria), Paraconiothyrium polonense and P. lycopodinum from Lycopodium (Poland) and Stachybotrys oleronensis from Iris (France). Two species of Chrysosporium are described from Antarctica, namely C. magnasporum and C. oceanitesii. Finally, Licea xanthospora is described from Australia, Hypochnicium huinayensis from Chile and Custingophora blanchettei from Uruguay. Novel genera of Ascomycetes include Neomycosphaerella from Pseudopentameris macrantha (South Africa), and Paramycosphaerella from Brachystegia sp. (Zimbabwe). Novel hyphomycete genera include Pseudocatenomycopsis from Rothmannia (Zambia), Neopseudocercospora from Terminalia (Zambia) and Neodeightoniella from Phragmites (South Africa), while Dimorphiopsis from Brachystegia (Zambia) represents a novel coelomycetous genus. Furthermore, Alanphillipsia is introduced as a new genus in the Botryosphaeriaceae with four species, A. aloes, A. aloeigena and A. aloetica from Aloe spp. and A. euphorbiae from Euphorbia sp. (South Africa). A new combination is also proposed for Brachysporium torulosum (Deightoniella black tip of banana) as Corynespora torulosa. Morphological and culture characteristics along with ITS DNA barcodes are provided for all taxa.

Microbial communities and interactions in the lone star tick, Amblyomma americanum.

To quantify microbial composition and interactions, we identified prokaryotic communities in the lone star tick (Amblyomma americanum) based on 16S rRNA gene sequences and direct probing. The lone star tick is the vector of emerging diseases and host to additional symbionts of unknown activity, and is representative of other blood-sucking arthropods. We evaluated the potential for vertical (transovarial) transmission by molecular analysis of microbial symbionts from egg and larval clutches. Direct probing of adults (N = 8 populations from the southeastern and midwestern USA, 900 ticks total) revealed three vertically transmitted symbionts: a Coxiella symbiont occurred at 100% frequency, Rickettsia species occurred in 45-61% of all ticks in every population and an Arsenophonus symbiont occurred in 0-90% of ticks per population. Arsenophonus and Rickettsia exhibited significant heterogeneity in frequency among populations. The human pathogens Ehrlichia chafeensis and Borrelia lonestari were rare in most populations. Additional microbes were detected sporadically. Most ticks (78%) were co-infected by two or three microbes but statistical analysis indicated no significant deviation from random co-occurrence. Our findings indicate that microbial communities within lone star ticks are diverse, and suggest that direct probing for a wider range of prokaryotes and application of quantitative polymerase chain reaction (PCR) may provide further insights into microbial interactions within disease vectors. Our results also emphasize the close phylogenetic relationship between tick symbionts and human pathogens, and consistent differences in their prevalence.

Rapid characterization of the ultraviolet induced fiber Bragg grating complex coupling coefficient as a function of irradiance and exposure time.

We report the application of optical frequency domain reflectometry and a discrete-layer-peeling inverse scattering algorithm to the spatial characterization of the UV induced complex coupling coefficient during fiber Bragg grating growth. The fiber grating is rapidly characterized using this technique to give irradiance dependent growth as a function of exposure time, thereby providing the complete characterization of the coupling coefficient in the form of a "growth surface," which is related to the fiber's photosensitivity. We compare measurements of fiber Bragg grating growth in SMF-28 when exposed to continuous wave 244 nm irradiation from 0 to 90 W cm(-2) for exposure times up to 3230 s with a selection of other fibers including high germanium concentration fiber and erbium doped fiber.

Phosphatidylethanolamine has an essential role in Saccharomyces cerevisiae that is independent of its ability to form hexagonal phase structures.

Two yeast enzymes, Psd1p and Psd2p, catalyze the decarboxylation of phosphatidylserine to produce phosphatidylethanolamine (PtdEtn). Mitochondrial Psd1p provides approximately 90% of total cellular phosphatidylserine decarboxylase activity. When the PSD1 gene is deleted, the resultant strain (psd1Delta) grows normally at 30 degrees C in glucose and in the absence of exogenous choline or ethanolamine. However, at elevated temperature (37 degrees C) or on the nonfermentable carbon source lactate, the growth of psd1Delta strains is minimal without ethanolamine supplementation. The reduced growth and viability correlate with a PtdEtn content below 4% of total phospholipid. These results suggest that there is a critical level of PtdEtn required to support growth. This theory is supported by growth data revealing that a psd1Delta psd2Delta dpl1Delta strain can only grow in the presence of ethanolamine. In contrast, a psd1Delta psd2Delta strain, which makes low levels of PtdEtn from sphingolipid breakdown, can be rescued by ethanolamine, choline, or the ethanolamine analogue propanolamine. psd1Delta psd2Delta cells grown in 2 mm propanolamine accumulate a novel lipid, which was determined by mass spectrometry to be phosphatidylpropanolamine (PtdPrn). PtdPrn can comprise up to 40% of the total phospholipid content in supplemented cells at the expense of phosphatidylcholine and PtdEtn. The absolute level of PtdEtn required for growth when PtdPrn is present appears to be 1% of the total phospholipid content. The essential function of the PtdEtn in the presence of propanolamine does not appear to be the formation of hexagonal phase lipid, insofar as PtdPrn readily forms hexagonal phase structures detectable by (31)P NMR.

Evidence for the involvement of the NADPH oxidase enzyme complex in the optimal accumulation of Platelet-activating factor in the human cell line PLB-985.

Platelet-activating factor (PAF) is an early product of the inflammatory environment, influencing development and resolution of inflammation. Its production is greater in neutrophils and macrophages, which predominantly synthesize 1-alkyl sn-2 acetyl glycerophosphocholine (GPC) than in nongranulocytes (B cells and endothelial cells), which lack a respiratory burst and synthesize 1-acyl sn-2 acetyl GPC as their major PAF species. This study investigated whether the respiratory burst was responsible for the quantitative and qualitative differences in sn-2 acetyl GPC species generation by neutrophils and macrophages versus those cells lacking the NADPH oxidase complex. The myeloid cell line PLB-985 (capable of differentiation into neutrophils) was used to test this hypothesis, since these cells had previously been generated with a non-functional respiratory burst (X-CGD PLB-985). Differentiated PLB-985 cells underwent a large respiratory burst in response to PMA (phorbol ester), and smaller respiratory bursts in response to A23187 (calcium ionophore), and the bacterial polypeptide fMLP (receptor mediated activation). Concurrently, treated cells were assessed for production of 1-hexadecyl and 1-palmitoyl sn-2 acetyl GPC species by gas chromatography/mass spectrometry. Neither cell type generated these lipid species in response to PMA, but both cell types generated equal levels of sn-2 acetyl GPC in response to A23187, with five times more 1-hexadecyl than 1-palmitoyl species. Upon fMLP activation, X-CGD PLB-985 cells produced significantly less 1-hexadecyl and 1-palmitoyl sn-2 acetyl GPC in comparison to the wild-type PLB-985 cells. These findings suggest phagocytic oxidant production by NADPH oxidase is not essential for sn-2 acetyl GPC generation, but appears important for optimal production of PAF in response to some stimuli.

Acute keratinocyte damage stimulates platelet-activating factor production.

Recent evidence suggests that the phosphocholine-derived lipid mediator platelet-activating factor (PAF) is involved in keratinocyte function and cutaneous inflammation. PAF is found in various inflammatory skin diseases, and intradermal injection of PAF directly results in cutaneous inflammation. Keratinocytes also synthesize PAF and related 1-acyl species in response to ionophores, cytokines and growth factors, and in response to activation of the epidermal PAF receptor. Since keratinocytes are routinely exposed to potential damage by thermal or oxidative stressors with resultant induction of cutaneous inflammation, the objective of these studies was to assess whether exogenous thermal or oxidative damage can induce the production of PAF and related 1-acyl species. Cells of the immortalized human keratinocyte cell line HaCaT were subjected to acute heat or cold, or treatment with the pro-oxidant lipid tertiary butyl hydroperoxide, and PAF and 1-palmitoyl-2-acetyl-GPC were measured by gas chromatography/mass spectrometry. We report that these diverse toxic stimuli resulted in the accumulation of these biologically active lipids. These studies suggest that the PAF system is involved in the inflammatory response seen following acute epidermal damage.

Soil pathogens and spatial patterns of seedling mortality in a temperate tree.

The Janzen-Connell hypothesis proposes that host-specific, distance- and/or density-dependent predators and herbivores maintain high tree diversity in tropical forests. Negative feedback between plant and soil communities could be a more effective mechanism promoting species coexistence because soil pathogens can increase rapidly in the presence of their host, causing conditions unfavourable for local conspecific recruitment. Here we show that a soil pathogen leads to patterns of seedling mortality in a temperate tree (Prunus serotina) as predicted by the Janzen-Connell hypothesis. In the field, the mean distance to parent of seedling cohorts shifted away from maternal trees over a period of 3 years. Seedlings were grown in soil collected 0-5 m or 25-30 m from Prunus trees. Sterilization of soil collected beneath trees improved seedling survival relative to unsterilized soil, whereas sterilization of distant soil did not affect survival. Pythium spp., isolated from roots of dying seedlings and used to inoculate healthy seedlings, decreased survival by 65% relative to controls. Our results provide the most complete evidence that native pathogens influence tree distributions, as predicted by the Janzen-Connell hypothesis, and suggest that similar ecological mechanisms operate in tropical and temperate forests.

Fungal endophyte symbiosis and plant diversity in successional fields

Increasing evidence suggests that microbial interactions are important determinants of plant biodiversity. The hypothesis that fungal endophyte symbiosis reduces diversity in successional fields was tested by manipulating infection of tall fescue, the most abundant perennial grass in the eastern United States. Over a 4-year period, species richness declined and tall fescue dominance increased in infected plots relative to uninfected plots without differences in total productivity. A host-specific endophyte, with negligible biomass, altered plant community structure in this long-term field experiment and may be reducing plant diversity throughout its expanding range.