Lipid analogs reveal features critical for hemolysis and diminish granadaene mediated Group B Streptococcus infection

Although certain microbial lipids are toxins, the structural features important for cytotoxicity remain unknown. Increased functional understanding is essential for developing therapeutics against toxic microbial lipids. Group B Streptococci (GBS) are bacteria associated with preterm births, stillbirths, and severe infections in neonates and adults. GBS produce a pigmented, cytotoxic lipid, known as granadaene. Despite its importance to all manifestations of GBS disease, studies towards understanding granadaene’s toxic activity are hindered by its instability and insolubility in purified form. Here, we report the synthesis and screening of lipid derivatives inspired by granadaene, which reveal features central to toxin function, namely the polyene chain length. Furthermore, we show that vaccination with a non-toxic synthetic analog confers the production of antibodies that inhibit granadaene-mediated hemolysis ex vivo and diminish GBS infection in vivo. This work provides unique structural and functional insight into granadaene and a strategy to mitigate GBS infection, which will be relevant to other toxic lipids encoded by human pathogens.This work was supported by funding from the National Institutes of Health Grants R01AI112619, R01AI133976, R01AI100989, and R21AI125907 and seed funds from Seattle Childrens Research Institute to L.

A Randomized Controlled Pilot Trial of Azithromycin or Artesunate Added to Sulfadoxine-Pyrimethamine as Treatment for Malaria in Pregnant Women

New anti-malarial regimens are urgently needed in sub-Saharan Africa because of the increase in drug resistance. We investigated the safety and efficacy of azithromycin or artesunate combined with sulfadoxine-pyrimethamine used for treatment of malaria in pregnant women in Blantyre, Malawi.This was a randomized open-label clinical trial, conducted at two rural health centers in Blantyre district, Malawi. A total of 141 pregnant women with uncomplicated Plasmodium falciparum malaria were recruited and randomly allocated to 3 treatment groups: sulfadoxine-pyrimethamine (SP; 3 tablets, 500 mg sulfadoxine and 25 mg pyrimethamine per tablet); SP plus azithromycin (1 g/dayx2 days); or SP plus artesunate (200 mg/dayx3 days). Women received two doses administered at least 4 weeks apart. Heteroduplex tracking assays were performed to distinguish recrudescence from new infections. Main outcome measures were incidence of adverse outcomes, parasite and fever clearance times and recrudescence rates. All treatment regimens were well tolerated. Two women vomited soon after ingesting azithromycin. The parasite clearance time was significantly faster in the SP-artesunate group. Recrudescent episodes of malaria were less frequent with SP-azithromycin [Hazard Ratio 0.19 (95% confidence interval 0.06 to 0.63)] and SP-artesunate [Hazard Ratio 0.25 (95% confidence interval 0.10 to 0.65)] compared with SP monotherapy. With one exception (an abortion in the SP-azithromycin group), all adverse pregnancy outcomes could be attributed to known infectious or obstetrical causes. Because of the small sample size, the effect on birth outcomes, maternal malaria or maternal anemia could not be evaluated.Both SP-artesunate and SP-azithromycin appeared to be safe, well tolerated and efficacious for the treatment of malaria during pregnancy. A larger study is needed to determine their safety and efficacy in preventing poor birth outcomes.ClinialTrials.gov NCT00287300

Risk factors for recurrent injurious falls that require hospitalization for older adults with dementia: a population based study

Background: Older adults with dementia are at an increased risk of falls, however, little is known about risk factors for recurrent injurious falls (a subsequent fall after the first fall has occurred) among this group. This study aimed to identify risk factors for recurrent injurious falls requiring hospitalization among adults aged 60+ years with dementia. Methods: This retrospective, whole-population cohort study was conducted using the Western Australian Hospital Morbidity Data System and Western Australian Death Registrations from 2001 to 2013. Survival analysis using a stratified conditional Cox model (type 1) was undertaken to identify risk factors for recurrent injurious falls requiring hospitalization. Results: There were 32,519 participants with an index hospital admission with dementia during the study period. Over 27 % (n = 8970) of the cohort experienced a total of 11,073 injurious falls requiring hospitalization during follow up with 7297 individuals experiencing a single fall, 1330 experiencing two falls and 343 experiencing three or more falls. The median follow-up time for each individual was 2.49 years. Females were at a significantly increased risk of 7 % for recurrent injurious falls resulting in hospitalization (adjusted hazard ratio 1.07, 95 % CI 1.01–1.12), compared to males. Increasing age, living in rural areas, and having an injurious fall in the year prior to the index hospital admission with dementia also increased the risk of recurrent injurious falls resulting in hospitalization. Conclusions: Screening those with dementia for injurious falls history could help to identify those most at risk of recurrent injurious falls. Improvement of heath care an

Living in the Past: Phylogeography and Population Histories of Indo-Pacific Wrasses (Genus Halichoeres) in Shallow Lagoons versus Outer Reef Slopes

Sea level fluctuations during glacial cycles affect the distribution of shallow marine biota, exposing the continental shelf on a global scale, and displacing coral reef habitat to steep slopes on oceanic islands. In these circumstances we expect that species inhabiting lagoons should show shallow genetic architecture relative to species inhabiting more stable outer reefs. Here we test this expectation on an ocean-basin scale with four wrasses (genus Halichoeres): H. claudia (N = 194, with ocean-wide distribution) and H. ornatissimus (N = 346, a Hawaiian endemic) inhabit seaward reef slopes, whereas H. trimaculatus (N = 239) and H. margaritaceus (N = 118) inhabit lagoons and shallow habitats throughout the Pacific. Two mitochondrial markers (cytochrome oxidase I and control region) were sequenced to resolve population structure and history of each species. Haplotype and nucleotide diversity were similar among all four species. The outer reef species showed significantly less population structure, consistent with longer pelagic larval durations. Mismatch distributions and significant negative Fu’s F values indicate Pleistocene population expansion for all species, and (contrary to expectations) shallower histories in the outer slope species. We conclude that lagoonal wrasses may persist through glacial habitat disruptions, but are restricted to refugia during lower sea level stands. In contrast, outer reef slope species have homogeneous and well-connected populations through their entire ranges regardless of sea level fluctuations. These findings contradict the hypothesis that shallow species are less genetically diverse as a consequence of glacial cycles

Heterogeneous natural selection on oxidative phosphorylation genes among fishes with extreme high and low aerobic performance

Background: Oxidative phosphorylation (OXPHOS) is the primary source of ATP in eukaryotes and serves as a mechanistic link between variation in genotypes and energetic phenotypes. While several physiological and anatomical factors may lead to increased aerobic capacity, variation in OXPHOS proteins may influence OXPHOS efficiency and facilitate adaptation in organisms with varied energy demands. Although there is evidence that natural selection acts on OXPHOS genes, the focus has been on detection of directional (positive) selection on specific phylogenetic branches where traits that increase energetic demands appear to have evolved. We examined patterns of selection in a broader evolutionary context, i.e., on multiple lineages of fishes with extreme high and low aerobic performance. Results: We found that patterns of natural selection on mitochondrial OXPHOS genes are complex among fishes with different swimming performance. Positive selection is not consistently associated with high performance taxa and appears to be strongest on lineages containing low performance taxa. In contrast, within high performance lineages, purifying (negative) selection appears to predominate. Conclusions: We provide evidence that selection on OXPHOS varies in both form and intensity within and among lineages through evolutionary time. These results provide evidence for fluctuating selection on OXPHOS associated with divergence in aerobic performance. However, in contrast to previous studies, positive selection was strongest on low performance taxa suggesting that adaptation of OXPHOS involves many factors beyond enhancing ATP production in high performance taxa. The broader pattern indicates a complex interplay between organismal adaptations, ATP demand, and OXPHOS function.This work was supported by NSF award DEB-0732988 (to REB).Ye

Evaluation of a Rapid Immunochromatographic ODK-0901 Test for Detection of Pneumococcal Antigen in Middle Ear Fluids and Nasopharyngeal Secretions

Since the incidence of penicillin-resistant Streptococcus pneumoniae has been increasing at an astonishing rate throughout the world, the need for accurate and rapid identification of pneumococci has become increasingly important to determine the appropriate antimicrobial treatment. We have evaluated an immunochromatographic test (ODK-0901) that detects pneumococcal antigens using 264 middle ear fluids (MEFs) and 268 nasopharyngeal secretions (NPSs). A sample was defined to contain S. pneumoniae when optochin and bile sensitive alpha hemolytic streptococcal colonies were isolated by culture. The sensitivity and specificity of the ODK-0901 test were 81.4% and 80.5%, respectively, for MEFs from patients with acute otitis media (AOM). In addition, the sensitivity and specificity were 75.2% and 88.8%, respectively, for NPSs from patients with acute rhinosinusitis. The ODK-0901 test may provide a rapid and highly sensitive evaluation of the presence of S. pneumoniae and thus may be a promising method of identifying pneumococci in MEFs and NPSs

A sub-Neptune transiting the young field star HD 18599 at 40 pc

Transiting exoplanets orbiting young nearby stars are ideal laboratories for testing theories of planet formation and evolution. However, to date only a handful of stars with age <1 Gyr have been found to host transiting exoplanets. Here we present the discovery and validation of a sub-Neptune around HD 18599 , a young (300 Myr), nearby (d = 40 pc) K star. We validate the transiting planet candidate as a bona fide planet using data from the TESS , Spitzer , and Gaia  missions, ground-based photometry from IRSF , LCO , PEST , and NGTS , speckle imaging from Gemini, and spectroscopy from CHIRON , NRES , FEROS , and Minerva-Australis . The planet has an orbital period of 4.13 d , and a radius of 2.7 R⊕ . The RV data yields a 3-σ mass upper limit of 30.5 M⊕  which is explained by either a massive companion or the large observed jitter typical for a young star. The brightness of the host star (V∼9 mag) makes it conducive to detailed characterization via Doppler mass measurement which will provide a rare view into the interior structure of young planets

Could a simple antenatal package combining micronutritional supplementation with presumptive treatment of infection prevent maternal deaths in sub-Saharan Africa?

BACKGROUND: Reducing maternal mortality is a key goal of international development. Our objective was to determine the potential impact on maternal mortality across sub-Saharan Africa of a combination of dietary supplementation and presumptive treatment of infection during pregnancy. Our aim was to demonstrate the importance of antenatal interventions in the fight against maternal mortality, and to stimulate debate about the design of an effective antenatal care package which could be delivered at the lowest level of the antenatal health system or at community level. METHODS: We collated evidence for the effectiveness of antenatal interventions from systematic reviews and controlled trials, and we selected interventions which have demonstrated potential to prevent maternal deaths. We used a model-based analysis to estimate the total reduction in maternal mortality in sub-Saharan Africa which could be achieved by combining these interventions into a single package, based on a WHO systematic review of causes of maternal deaths. RESULTS: Severe hypertensive disorders, puerperal sepsis and anemia are causes of maternal deaths which could be prevented to some extent by prophylactic measures during pregnancy. A package of pills comprising calcium and iron supplements and appropriate anti-microbial and anti-malarial drugs could reduce maternal mortality in sub-Saharan Africa by 8% (range <1% to 20%). This estimate is based on Cochrane Review estimates for the effectiveness of daily calcium supplements in reducing the risk of death/serious morbidity due to hypertensive disorders (RR = 0.80, 95% CI 0.65-0.97), anti-microbial prophylaxis in reducing the odds of puerperal sepsis/postpartum endometritis (OR = 0.49, 95% CI 0.23-1.06), anti-malarial prophylaxis in reducing the risk of severe antenatal anemia (RR = 0.62, 95% CI 0.50-0.78), and iron supplementation in reducing the risk of iron deficiency anemia at term (RR = 0.33, 95% CI 0.16-0.69). CONCLUSION: Maternal mortality could be reduced by a combination of micronutrient supplementation and presumptive treatment of infection during pregnancy. Such an approach could be adopted in resource-poor settings where visits to antenatal clinics are infrequent and would complement existing Safe Motherhood activities