Gangliosides Block Aggregatibacter Actinomycetemcomitans Leukotoxin (LtxA)-Mediated Hemolysis

Aggregatibacter actinomycetemcomitans is an oral pathogen and etiologic agent of localized aggressive periodontitis. The bacterium is also a cardiovascular pathogen causing infective endocarditis. A. actinomycetemcomitans produces leukotoxin (LtxA), an important virulence factor that targets white blood cells (WBCs) and plays a role in immune evasion during disease. The functional receptor for LtxA on WBCs is leukocyte function antigen-1 (LFA-1), a β-2 integrin that is modified with N-linked carbohydrates. Interaction between toxin and receptor leads to cell death. We recently discovered that LtxA can also lyse red blood cells (RBCs) and hemolysis may be important for pathogenesis of A. actinomycetemcomitans. In this study, we further investigated how LtxA might recognize and lyse RBCs. We found that, in contrast to a related toxin, E. coli α-hemolysin, LtxA does not recognize glycophorin on RBCs. However, gangliosides were able to completely block LtxA-mediated hemolysis. Furthermore, LtxA did not show a preference for any individual ganglioside. LtxA also bound to ganglioside-rich C6 rat glioma cells, but did not kill them. Interaction between LtxA and C6 cells could be blocked by gangliosides with no apparent specificity. Gangliosides were only partially effective at preventing LtxA-mediated cytotoxicity of WBCs, and the effect was only observed when a high ratio of ganglioside:LtxA was used over a short incubation period. Based on the results presented here, we suggest that because of the similarity between N-linked sugars on LFA-1 and the structures of gangliosides, LtxA may have acquired the ability to lyse RBCs

A latent class analysis of risk factors for acquiring HIV among men who have sex with men: implications for implementing pre-exposure prophylaxis programs

Current Centers for Disease Control and Prevention (CDC) guidelines for prescribing pre-exposure prophylaxis (PrEP) to prevent HIV transmission are broad. In order to better characterize groups who may benefit most from PrEP, we reviewed demographics, behaviors, and clinical outcomes for individuals presenting to a publicly-funded sexually transmitted diseases (STD) clinic in Providence, Rhode Island, from 2012 to 2014. Latent class analysis (LCA) was used to identify subgroups of men who have sex with men (MSM) at highest risk for contracting HIV. A total of 1723 individuals presented for testing (75% male; 31% MSM). MSM were more likely to test HIV positive than heterosexual men or women. Among 538 MSM, we identified four latent classes. Class 1 had the highest rates of incarceration (33%), forced sex (24%), but had no HIV infections. Class 2 had <5 anal sex partners in the previous 12 months, the lowest rates of drug/alcohol use during sex and lower HIV prevalence (3%). Class 3 had the highest prevalence of HIV (7%) and other STDs (16%), > 10 anal sex partners in the previous 12 months (69%), anonymous partners (100%), drug/alcohol use during sex (76%), and prior STDs (40%). Class 4 had similar characteristics and HIV prevalence as Class 2. In this population, MSM who may benefit most from PrEP include those who have >10 sexual partners per year, anonymous partners, drug/alcohol use during sex and prior STDs. LCA is a useful tool for identifying clusters of characteristics that may place individuals at higher risk for HIV infection and who may benefit most from PrEP in clinical practice

Geomorphological signature of topographically controlled ice flow-switching at a glacier margin: Breiðamerkurjökull (Iceland) as a modern analogue for palaeo-ice sheets

Ice low-switching, which can involve changes in ice flow velocity and direction, is crucial to a full understanding of ice masses and their response to climate change. A topographically controlled ice flow switch near a glacier margin was recently documented at Breiðamerkurjökull, southeast Iceland, where the central flow unit migrated eastward in response to variations in subglacial topography and the influence of Jökulsárlón glacial lagoon. This site provides an opportunity to study the geomorphic response to ice-margin reconfiguration. Investigating contemporary processes can offer valuable insights into analogous landforms created during the deglaciation of palaeo-ice sheets. The landform assemblage and topographic setting of our Icelandic study site is compared to a palaeo-example from Alberta, Canada, which was once covered by the Laurentide ice sheet. Uncrewed aerial vehicle-(UAV) derived data was used to assess the geomorphic response to this switching and related processes across a 1.5 km2 area of the central flow unit which deglaciated between 2010 and 2023. From 2010 to 2017, the landscape featured streamlined subglacial material, a stable subglacial esker system and proglacial lakes (Landsystem A), shifting to a spillway-dominated system between 2018 and 2023 (Landsystem B). Since 2018 this section of Breiðamerkurjökull has been retreating across a reverse slope bed, resulting in the formation of quasi-annual ice-marginal spillways. Meltwater impoundment at the ice margin, formed ice-contact lakes which eventually initiated ice-margin parallel spillways draining proglacial meltwater along the local land-surface gradient, towards Jökulsárlón. As the ice retreats, an ice-contact lake forms again at the new margin and initiates the erosion of the next ice-marginal spillway. The geomorphological signature demonstrates how subglacial topography and ice-flow switching can significantly influence ice and meltwater dynamics. Since the glacier flow-switch, part of the central unit is now lake-terminating with areas of the margin evolving into a stagnant system, as it is now cut off from the accumulation centre. Therefore, Landsystem B could be analogous to regions of ice stream shut down and where ice masses retreated across reverse slope beds. For example, the Pakowki Lake region of Southeastern Alberta displays a similar landform assemblage and is presented as a palaeo-example in this work. Such insights are important for assessing the efficacy of numerical models in reconstructing the finer scale dynamics of past ice sheets during retreat

The evolution and preservation potential of englacial eskers: An example from Breiðamerkurjökull, SE Iceland

Directly observing glacial drainage systems (englacial and subglacial) is challenging. The distribution, morphology and internal structure of eskers can provide valuable information about the glacial drainage system and meltwater processes. This work presents the annual evolution (meltout) and internal structure of an esker emerging from the Breiðamerkurjökull ice margin, southeast Iceland. Changes in esker morphology have been repeatedly mapped over a 1‐year period using high temporal and spatial resolution data acquired by an uncrewed aerial vehicle (UAV). The internal architecture of the esker was investigated using ground‐penetrating radar (GPR) surveys. These data are used to identify the dominant processes driving the formation of this englacial esker and to evaluate the preservation potential. The englacial esker was up to 2.6 m thick and ice‐cored. A large moulin upglacier of the esker, which evolved into an englacial conduit, supplied meltwater to the englacial channel. Upglacier dipping debris‐filled basal hydrofractures, formed by pressurised subglacial meltwater rising up the retrograde bed slope, likely supplied sediment to the englacial conduit. Over the 1‐year period of observation the crest morphology evolved from flat‐ to sharp‐crested and the esker footprint increased by a factor of 5.7 in response to post‐depositional processes. The findings presented here indicate that englacial eskers may have low preservation potential due to post‐depositional reworking such as slumping through ice‐core meltout and erosion by later meltwater flow. As englacial eskers may not be preserved in the landscape, they could represent important glacial drainage system components that are not currently captured in palaeo‐ice sheet reconstructions. This work highlights the value of creating a time series of high‐temporal resolution data to quantify morphological evolution and improve glacial process‐form models

Longitudinal changes in DNA methylation associated with clozapine use in treatment-resistant schizophrenia from two international cohorts

The second-generation antipsychotic clozapine is used as a medication for treatment-resistant schizophrenia. It has previously been associated with epigenetic changes in pre-clinical rodent models and cross-sectional studies of treatment-resistant schizophrenia. Cross-sectional studies are susceptible to confounding, however, and cannot disentangle the effects of diagnosis and medication. We therefore profiled DNA methylation in sequential blood samples (n = 126) from two independent cohorts of patients (n = 38) with treatment-resistant schizophrenia spectrum disorders who commenced clozapine after study enrolment and were followed up for up to six months. We identified significant non-linear changes in cell-type proportion estimates derived from DNA methylation data - specifically B-cells - associated with time on clozapine. Mixed effects regression models were used to identify changes in DNA methylation at specific sites associated with time on clozapine, identifying 37 differentially methylated positions (DMPs) (p < 5 × 10-5) in a linear model and 90 DMPs in a non-linear quadratic model. We compared these results to data from our previous epigenome-wide association study (EWAS) meta-analysis of psychosis, finding evidence that many previously identified DMPs associated with schizophrenia and treatment-resistant schizophrenia might reflect exposure to clozapine. In conclusion, our results indicate that clozapine exposure is associated with changes in DNA methylation and cellular composition. Our study shows that medication effects might confound many case-control studies of neuropsychiatric disorders performed in blood

Changes in brain glutamate on switching to clozapine in treatment-resistant schizophrenia

It has been suggested that the antipsychotic clozapine may modulate brain glutamate, and that this effect could contribute to its efficacy in treatment-resistant schizophrenia (TRS). The aim of this study was to examine the effects of clozapine on brain glutamate in TRS longitudinally. This study examined individuals with TRS before and 12 weeks after switching from a non-clozapine antipsychotic to treatment with clozapine as part of their normal clinical care. Proton magnetic resonance spectroscopy (1H-MRS) measured concentrations, corrected for voxel tissue content, of glutamate (Glucorr), and glutamate plus glutamine (Glxcorr) in the anterior cingulate cortex (ACC) and right caudate nucleus. Symptoms were monitored using the Positive and Negative Syndrome Scale (PANSS). Of 37 recruited patients (27 men, 39.30 years old, 84% clozapine naïve), 25 completed 1H-MRS at both timepoints. 12 weeks of clozapine was associated with a longitudinal reduction in Glucorr in the caudate (n = 23, F = 7.61 P =. 01) but not in the ACC (n = 24, F = 0.02, P =. 59). Percentage reduction in caudate Glucorr was positively correlated with percentage improvement in symptoms (total PANSS score, n = 23, r =. 42, P =. 04). These findings indicate that reductions in glutamate in the caudate nucleus may contribute to symptomatic improvement during the first months of clozapine treatment

Exploring the role of competing demands and routines during the implementation of a self-management tool for type 2 diabetes: A theory-based qualitative interview study

Background The implementation of new medical interventions into routine care involves healthcare professionals adopting new clinical behaviours and changing existing ones. Whilst theory-based approaches can help understand healthcare professionals’ behaviours, such approaches often focus on a single behaviour and conceptualise its performance in terms of an underlying reflective process. Such approaches fail to consider the impact of non-reflective influences (e.g. habit and automaticity) and how the myriad of competing demands for their time may influence uptake. The current study aimed to apply a dual process theoretical approach to account for reflective and automatic determinants of healthcare professional behaviour while integrating a multiple behaviour approach to understanding the implementation and use of a new self-management tool by healthcare professionals in the context of diabetes care. Methods Following Diabetes UK’s national release of the ‘Information Prescription’ (DUK IP; a self-management tool targeting the management of cholesterol, blood pressure and HbA1c) in January 2015, we conducted semi-structured interviews with 13 healthcare professionals (general practitioners and nurses) who had started to use the DUK IP during consultations to provide self-management advice to people with type 2 diabetes. A theory-based topic guide included pre-specified constructs from a previously developed logic model. We elicited healthcare professionals’ views on reflective processes (outcome expectations, self-efficacy, intention, action and coping planning), automatic processes (habit), and multiple behaviour processes (goal priority, goal conflict and goal facilitation). All interviews were audio recorded and transcribed verbatim and all transcripts were independently double coded and analysed using content analysis. Results The majority of healthcare professionals interviewed reported strong intentions to use the DUK IP and having formed a habit of using them after a minimum of one month continuous use. Pop-up cues in the electronic patient records were perceived to facilitate the use of the tool. Factors that conflicted with the use of the DUK IP included existing pathways of providing self-management advice. Conclusion Data suggests that constructs from dual process and multiple behaviour approaches are useful to provide supplemental understanding of the implementation of new self-management tools such as the DUK IP and may help to advance behavioural approaches to implementation science

Keeping the Faith: African American Faith Leaders’ Perspectives and Recommendations for Reducing Racial Disparities in HIV/AIDS Infection

In Philadelphia, 66% of new HIV infections are among African Americans and 2% of African Americans are living with HIV. The city of Philadelphia has among the largest numbers of faith institutions of any city in the country. Although faith-based institutions play an important role in the African American community, their response to the AIDS epidemic has historically been lacking. We convened 38 of Philadelphia’s most influential African American faith leaders for in-depth interviews and focus groups examining the role of faith-based institutions in HIV prevention. Participants were asked to comment on barriers to engaging faith-based leaders in HIV prevention and were asked to provide normative recommendations for how African American faith institutions can enhance HIV/AIDS prevention and reduce racial disparities in HIV infection. Many faith leaders cited lack of knowledge about Philadelphia’s racial disparities in HIV infection as a common reason for not previously engaging in HIV programs; others noted their congregations’ existing HIV prevention and outreach programs and shared lessons learned. Barriers to engaging the faith community in HIV prevention included: concerns about tacitly endorsing extramarital sex by promoting condom use, lack of educational information appropriate for a faith-based audience, and fear of losing congregants and revenue as a result of discussing human sexuality and HIV/AIDS from the pulpit. However, many leaders expressed a moral imperative to respond to the AIDS epidemic, and believed clergy should play a greater role in HIV prevention. Many participants noted that controversy surrounding homosexuality has historically divided the faith community and prohibited an appropriate response to the epidemic; many expressed interest in balancing traditional theology with practical public health approaches to HIV prevention. Leaders suggested the faith community should: promote HIV testing, including during or after worship services and in clinical settings; integrate HIV/AIDS topics into health messaging and sermons; couch HIV/AIDS in social justice, human rights and public health language rather than in sexual risk behavior terms; embrace diverse approaches to HIV prevention in their houses of worship; conduct community outreach and host educational sessions for youth; and collaborate on a citywide, interfaith HIV testing and prevention campaign to combat stigma and raise awareness about the African American epidemic. Many African American faith-based leaders are poised to address racial disparities in HIV infection. HIV prevention campaigns should integrate leaders’ recommendations for tailoring HIV prevention for a faith-based audience

Dronar—Geoforensic Search Sonar from a Drone

Lightweight sonar devices may be tethered to an unmanned aerial vehicle or drone and quickly deployed over water for real-time imaging in 2D and the on site creation of geolocated, interactive bathymetric maps without the need for a boat. We show how such data is useful in the preliminary stages of water searches, by providing geophysicists, hydrologists and divers with spatial depth information, the distribution of dive and equipment hazards such as entanglement objects (weed, discarded items) and sediment types. One bathymetry case study location is described in detail, with a further two summarized to demonstrate reconnaissance surveys. Limitations of drone-based sonar surveys are outlined, including dense water weed cover; limits on flight times and adverse weather conditions