Search

Streptococcus pneumoniae (the pneumococcus) is a major human pathogen causing invasive disease, including community-acquired bacteraemia, and remains a leading cause of global mortality. Understanding the role of phagocytes in killing bacteria is still limited, especially in vivo. In this study, we established a zebrafish model to study the interaction between intravenously administered pneumococci and professional phagocytes such as macrophages and neutrophils, to unravel bacterial killing mechanisms employed by these immune cells. Our model confirmed the key role of polysaccharide capsule in promoting pneumococcal virulence through inhibition of phagocytosis. Conversely, we show pneumococci lacking a capsule are rapidly internalised by macrophages. Low doses of encapsulated S. pneumoniae cause near 100% mortality within 48 hours postinfection (hpi), while 50 times higher doses of unencapsulated pneumococci are easily cleared. Time course analysis of in vivo bacterial numbers reveals that while encapsulated pneumococcus proliferates to levels exceeding 105 CFU at the time of host death, unencapsulated bacteria are unable to grow and are cleared within 20 hpi. Using genetically induced macrophage depletion, we confirmed an essential role for macrophages in bacterial clearance. Additionally, we show that upon phagocytosis by macrophages, phagosomes undergo rapid acidification. Genetic and chemical inhibition of vacuolar ATPase (v-ATPase) prevents intracellular bacterial killing and induces host death indicating a key role of phagosomal acidification in immunity to invading pneumococci. We also show that our model can be used to study the efficacy of antimicrobials against pneumococci in vivo. Collectively, our data confirm that larval zebrafish can be used to dissect killing mechanisms during pneumococcal infection in vivo and highlight key roles for phagosomal acidification in macrophages for pathogen clearance. [ABSTRACT FROM AUTHOR]

For all parasites, transmission is composed of two processes: host contact with parasites ('exposure') and risk of infection given such contact ('susceptibility'). Classic models, such as mass action (density-dependent) transmission, lump these processes together., However, separating these processes could enhance predictions for disease dynamics, especially for free-living parasites. Here, we outline three transmission models that partition exposure and susceptibility., Using data from a study of Schistosoma mansoni (trematode) infections in Biomphalaria glabrata snails, we competed these three models against four alternative models, including the mass action model (which lumps exposure and susceptibility)., The models that separately accounted for exposure and susceptibility best predicted prevalence across the density gradients of hosts and parasites, outperforming all other models based on Akaike information criterion. When embedded into a dynamic epidemiological model, the exposure-explicit models all predicted lower equilibrium densities of infected snails and human-infectious cercariae., Thus, population-level epidemiological models that utilize the classic mass action transmission model might overestimate human risk of schistosomiasis. More generally, the presented approach for disentangling exposure and susceptibility can distinguish between behavioural and immunological resistance, identify mechanisms of 'disease dilution' and provide a more complete dissection of drivers of parasite transmission. [ABSTRACT FROM AUTHOR]

Background: We sought to determine factors affecting time to surgery (TTS) to identify potential modifiable factors to improve timeliness of care. Methods: Patients with clinical stage 0-3 breast cancer undergoing partial mastectomy in 2 clinical trials, conducted in ten centers across the US, were analyzed. No preoperative workup was mandated by the study; those receiving neoadjuvant therapy were excluded. Results: The median TTS among the 583 patients in this cohort was 34 days (range: 1-289). Patient age, race, tumor palpability, and genomic subtype did not influence timeliness of care defined as TTS ≤30 days. Hispanic patients less likely to have a TTS ≤30 days (P =.001). There was significant variation in TTS by surgeon (P <.001); those practicing in an academic center more likely to have TTS ≤30 days than those in a community setting (55.1% vs 19.3%, P <.001). Patients who had a preoperative ultrasound had a similar TTS to those who did not (TTS ≤30 days 41.9% vs 51.9%, respectively, P =.109), but those who had a preoperative MRI had a significantly increased TTS (TTS ≤30 days 25.0% vs 50.9%, P <.001). On multivariate analysis, patient ethnicity was no longer significantly associated with TTS ≤30 (P =.150). Rather, use of MRI (OR:.438; 95% CI:.287-.668, P <.001) and community practice type (OR:.324; 95% CI:.194-.541, P <.001) remained independent predictors of lower likelihood of TTS ≤30 days. Conclusions: Preoperative MRI significantly increases time to surgery; surgeons should consider this in deciding on its use. [ABSTRACT FROM AUTHOR]

Kinetic resolution provided a highly enantioselective method to access a range of 3-aryl-3,4-dihydro-2 H -1,4-benzoxazines using n -butyllithium and the chiral ligand sparteine. The enantioenrichment remained high on removing the tert -butoxycarbonyl (Boc) protecting group. The intermediate organolithium undergoes ring opening to an enamine. The kinetic resolution was extended to give enantiomerically enriched substituted 1,2,3,4-tetrahydroquinoxalines and was applied to the synthesis of an analogue of the antibiotic levofloxacin that was screened for its activity against the human pathogen Streptococcus pneumoniae. [ABSTRACT FROM AUTHOR]

Most animal species are infected with multiple parasite species; however, the role of interspecific parasite interactions in influencing parasite dynamics and shaping parasite communities has been unclear. Although laboratory studies have found evidence of cross-immunity, immunosuppression and competition, analyses of hosts in the field have generally concluded that parasite communities are little more than random assemblages. Here we present evidence of consistent interspecific interactions in a natural mammalian system, revealed through the analysis of parasite intensity data collected from a free-ranging rabbit (Oryctolagus cuniculus) population, sampled monthly for a period of 23?yr. The wild rabbit plays host to a diverse gut helminth community that reflects the communities seen in other economically important domestic herbivores. These findings suggest that parasite interactions could have profound implications for the dynamics of parasite communities. The efficacy of parasite control programmes could be jeopardized if such interactions are not taken into account. In contrast, a clear understanding of such interactions may provide the basis for the development of more environmentally acceptable methods of parasite control. [ABSTRACT FROM AUTHOR]

Firearm-related deaths and injuries are a serious public health problem in California and the United States. The rate of firearm-related deaths is many times higher in the US than other democratic, industrialized nations, yet many of the deaths and injuries are preventable. The California American College of Emergency Physicians Firearm Injury Prevention Policy was approved and adopted in 2013 as an evidence-based, apolitical statement to promote harm reduction. It recognizes and frames firearm injuries as a public health epidemic requiring allocation of robust resources, including increased governmental funding of high-quality research and the development of a national database system. The policy further calls for relevant legislation to be informed by best evidence and expert consensus, and advocates for legislation regarding the following: mandatory universal background checks; mandatory reporting of firearm loss/theft; restrictions against law-enforcement or military-style assault weapons and high capacity magazines; child-protective safety and storage systems; and prohibitions for high-risk individuals. It also strongly defends the right of physicians to screen and counsel patients about firearm-related risk factors and safety. Based upon best-available evidenced, the policy was recently updated to include extreme risk protection orders, which are also known as gun violence restraining orders. [ABSTRACT FROM AUTHOR]

Human and animal research both operate within established standards. In the United States, criticism of the human research environment and recorded abuses of human research subjects served as the impetus for the establishment of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, and the resulting Belmont Report. The Belmont Report established key ethical principles to which human research should adhere: respect for autonomy, obligations to beneficence and justice, and special protections for vulnerable individuals and populations. While current guidelines appropriately aim to protect the individual interests of human participants in research, no similar, comprehensive, and principled effort has addressed the use of (nonhuman) animals in research. Although published policies regarding animal research provide relevant regulatory guidance, the lack of a fundamental effort to explore the ethical issues and principles that should guide decisions about the potential use of animals in research has led to unclear and disparate policies. Here, we explore how the ethical principles outlined in the Belmont Report could be applied consistently to animals. We describe how concepts such as respect for autonomy and obligations to beneficence and justice could be applied to animals, as well as how animals are entitled to special protections as a result of their vulnerability. [ABSTRACT FROM AUTHOR]

Chronic infections may have negative impacts on wildlife populations, yet their effects are difficult to detect in the absence of long-term population monitoring. Brucella abortus, the bacteria responsible for bovine brucellosis, causes chronic infections and abortions in wild and domestic ungulates, but its impact on population dynamics is not well understood., We report infection patterns and fitness correlates of bovine brucellosis in African buffalo based on (1) 7 years of cross-sectional disease surveys and (2) a 4-year longitudinal study in Kruger National Park ( KNP), South Africa. We then used a matrix population model to translate these observed patterns into predicted population-level effects., Annual brucellosis seroprevalence ranged from 8·7% (95% CI = 1·8-15·6) to 47·6% (95% CI = 35·1-60·1) increased with age until adulthood (>6) and varied by location within KNP. Animals were on average in worse condition after testing positive for brucellosis ( F = −5·074, P < 0·0001), and infection was associated with a 2·0 (95% CI = 1·1-3·7) fold increase in mortality (χ2 = 2·039, P = 0·036). Buffalo in low body condition were associated with lower reproductive success ( F = 2·683, P = 0·034), but there was no association between brucellosis and pregnancy or being observed with a calf., For the range of body condition scores observed in the population, the model-predicted growth rate was λ = 1·11 (95% CI = 1·02-1·21) in herds without brucellosis and λ = 1·00 (95% CI = 0·85-1·16) when brucellosis seroprevalence was 30%., Our results suggest that brucellosis infection can potentially result in reduced population growth rates, but because these effects varied with demographic and environmental conditions, they may remain unseen without intensive, longitudinal monitoring. [ABSTRACT FROM AUTHOR]

Host extinction can alter disease transmission dynamics, influence parasite extinction and ultimately change the nature of host-parasite systems. While theory predicts that single-host parasites are among the parasite species most susceptible to extinction following declines in their hosts, documented parasite extinctions are rare., Using a comparative approach, we investigate how the richness of single-host and multi-host parasites is influenced by extinction risk among ungulate and carnivore hosts. Host-parasite associations for free-living carnivores (order Carnivora) and terrestrial ungulates (orders Perissodactyla + Cetartiodactyla minus cetaceans) were merged with host trait data and IUCN Red List status to explore the distribution of single-host and multi-host parasites among threatened and non-threatened hosts., We find that threatened ungulates harbour a higher proportion of single-host parasites compared to non-threatened ungulates, which is explained by decreases in the richness of multi-host parasites. However, among carnivores threat status is not a significant predictor of the proportion of single-host parasites, or the richness of single-host or multi-host parasites., The loss of multi-host parasites from threatened ungulates may be explained by decreased cross-species contact as hosts decline and habitats become fragmented. Among carnivores, threat status may not be important in predicting patterns of parasite specificity because host decline results in equal losses of both single-host parasites and multi-host parasites through reduction in average population density and frequency of cross-species contact., Our results contrast with current models of parasite coextinction and highlight the need for updated theories that are applicable across host groups and account for both inter- and intraspecific contact. [ABSTRACT FROM AUTHOR]