Broadly neutralizing antibodies (bnAbs) can protect against HIV infection but have not been induced by human vaccination. A key barrier to bnAb induction is vaccine priming of rare bnAb-precursor B ...cells. In a randomized, double-blind, placebo-controlled phase 1 clinical trial, the HIV vaccine-priming candidate eOD-GT8 60mer adjuvanted with AS01
had a favorable safety profile and induced VRC01-class bnAb precursors in 97% of vaccine recipients with median frequencies reaching 0.1% among immunoglobulin G B cells in blood. bnAb precursors shared properties with bnAbs and gained somatic hypermutation and affinity with the boost. The results establish clinical proof of concept for germline-targeting vaccine priming, support development of boosting regimens to induce bnAbs, and encourage application of the germline-targeting strategy to other targets in HIV and other pathogens.
We conducted a systematic international review of tobacco smoking
habits among medical students. Particular attention was paid to
countries where smoking rates have been historically well-documented ...in
local journals, but were less often included in larger international
review articles. The methodology involved a search of relevant medical
subject headings, after which the reference lists of journal papers
were also examined to find additional publications. A total of 66
manuscripts met the inclusion criteria. The most common countries
previously studied included India, the United States, Australia, Japan,
Pakistan, Turkey and the United Kingdom. Overall, our review suggests
that the prevalence of smoking among medical students varies widely
amongst different countries and also between male and female students
within the same areas. Consistently low smoking rates were found in
Australia and the United States, while generally high rates were
reported in Spain and Turkey. Given their important future role as
exemplars, more effective measures to help reduce tobacco smoking among
medical students are clearly needed worldwide.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Pneumococcal polysaccharide vaccines have been used to elicit a protective anti-pneumococcal polysaccharide antibody response against Streptococcus pneumoniae in healthy individuals. Identifying ...human B cells which respond to T-cell independent type-2 antigens, such as pneumococcal polysaccharides, has been challenging. We employed pneumococcal polysaccharides directly conjugated to fluorophores in conjunction with flow cytometry to identify the phenotype of B cells that respond to pneumococcal polysaccharide vaccination. We have previously identified that the majority of pneumococcal polysaccharide-selected cells responding to vaccination are CD27 super(+)IgM super(+) (IgM super(+) memory) cells. In this study, we further characterized pneumococcal polysaccharide-selected cells in the peripheral blood to better identify how the various B cell phenotypes responded 7 and 30 days post-immunization. We show that 7 days post-immunization the majority of pneumococcal polysaccharide-selected IgM super(+) memory cells (PPS14 super(+) 56.5%, PPS23F super(+) 63.8%) were CD19 super(+)CD20 super(+)CD27 super(+)IgM super(+)CD43 super(+)CD5 super(+/-)CD70 super(-), which was significantly increased compared to pre-immunization levels. This phenotype is in alignment with recent publications describing human B-1 cells. PPS-responsive B cells receded to pre-immunization levels by day-30. These findings suggest that this B-1 like cell population plays an important role in early responses to S. pneumoniae infection and possibly other T-cell independent type-2 antigens in humans.
Vaccine priming immunogens that activate germline precursors for broadly neutralizing antibodies (bnAbs) have promise for development of precision vaccines against major human pathogens. In a ...clinical trial of the eOD-GT8 60mer germline-targeting immunogen, higher frequencies of vaccine-induced VRC01-class bnAb-precursor B cells were observed in the high dose compared to the low dose group. Through immunoglobulin heavy chain variable (IGHV) genotyping, statistical modeling, quantification of IGHV1-2 allele usage and B cell frequencies in the naive repertoire for each trial participant, and antibody affinity analyses, we found that the difference between dose groups in VRC01-class response frequency was best explained by IGHV1-2 genotype rather than dose and was most likely due to differences in IGHV1-2 B cell frequencies for different genotypes. The results demonstrate the need to define population-level immunoglobulin allelic variations when designing germline-targeting immunogens and evaluating them in clinical trials.
Cytokines have been used extensively as adjuvants in vaccines. However, practical considerations limit their use; diffusion from antigen, short half-lives and additional production costs. To address ...these problems we have developed a technology that efficiently produces inactivated, whole-virus influenza vaccine bearing membrane-bound cytokines. To provide "proof of principle," we chose chicken interleukin-2 (IL-2) and chicken granulocyte-macrophage colony-stimulating factor. Fusion constructs were generated in which their coding regions were linked to the influenza virus transmembrane encoding domains of the neuraminidase and hemagglutinin genes, respectively. These fusion constructs were used to establish stable Madin-Darby Canine Kidney cell lines, constitutively expressing membrane-bound cytokine. Cell surface expression was verified by immunofluorescence and cytokine-specific bioassays. Influenza virus harvested from infected cytokine-bearing cells was purified, inactivated, and confirmed to include membrane-bound cytokine by immunofluorescence, Western blotting and bioassay. Cytokine bioactivity was preserved using several standard virus inactivation protocols. Both cytokine-bearing influenza vaccines are now being tested for immunogenicity in vivo. Initial experiments indicate that chickens injected with IL-2-bearing influenza have elevated antiviral antibody levels, compared to chickens given conventional vaccine. In conclusion, this technology offers a novel method to utilize cytokines and other immunostimulatory molecules as adjuvants for viral vaccines.
Despite numerous technical advances in recent years, many occupational health problems still persist in modern dentistry. These include percutaneous exposure incidents (PEI); exposure to infectious ...diseases (including bioaerosols), radiation, dental materials, and noise; musculoskeletal disorders; dermatitis and respiratory disorders; eye injuries; and psychological problems. PEI remain a particular concern, as there is an almost constant risk of exposure to serious infectious agents. Strategies to minimise PEI and their consequences should continue to be employed, including sound infection control practices, continuing education and hepatitis B immunisation. As part of any infection control protocols, dentists should continue to utilise personal protective measures and appropriate sterilisation or other high-level disinfection techniques. Aside from biological hazards, dentists continue to suffer a high prevalence of musculoskeletal disorders (MSD), especially of the back, neck and shoulders. To fully understand the nature of these problems, further studies are needed to identify causative factors and other correlates of MSD. Continuing education and investigation of appropriate interventions to help reduce the prevalence of MSD and contact dermatitis are also needed. For these reasons, it is therefore important that dentists remain constantly informed regarding up-to-date measures on how to deal with newer technologies and dental materials.
Background: Musculoskeletal disorders (MSD) represent an important occupational health issue in dentistry. Given the significance of this topic, we considered it necessary to investigate the ...prevalence and impact of MSD among Australian dentists.
Methods: In 2004, a self‐reporting questionnaire was mailed to a random sample of 400 dentists registered with the Queensland Branch of the Australian Dental Association.
Results: A total of 285 questionnaires (73.1 per cent) were completed and returned. Of the respondents, 73.3 per cent were male and 26.7 per cent female, with a mean age of 45.2 years (SD = 11.9 years). Most were general dentists (89.1 per cent), with the remainder being specialists (10.9 per cent). Most dentists (87.2 per cent) reported having experienced at least one MSD symptom in the past 12 months. The most prevalent MSD during the previous 12 months were reported at the neck (57.5 per cent), lower back (53.7 per cent) and shoulder (53.3 per cent). MSD which interfered with daily activities during the previous 12 months were reported at the neck (24.6 per cent), the lower back (22.1 per cent) and the shoulders (21.8 per cent). Over one‐third (37.5 per cent) of dentists had sought medical advice or treatment for an MSD during the previous 12‐month period. Almost 1 in 10 dentists (9.1 per cent) reported taking leave in the previous 12 months because of an MSD. Among those who took sick leave for an MSD, the mean time taken was 11.5 days (SD=16.0 days).
Conclusions: Overall, this study suggests that MSD represents a major occupational health issue for Queensland dentists, the occurrence of which is similar to reports from other countries. MSD was shown to interfere with daily activities in some cases, while a considerable proportion of dentists had also sought medical attention for their symptoms. Further research is now needed to more carefully elucidate the impact of MSD in this particular occupational group, especially in relation to cessation or reduction of clinical practice, and also to help identify specific risk factors and effective measures for reducing MSD among dentists in Queensland and elsewhere.
Complex textured surfaces occur in nature and industry, from fingerprints to lithography-based micropatterns. Wrinkling by confinement to an incompatible substrate is an attractive way of generating ...reconfigurable patterned topographies, but controlling the often asymmetric and apparently stochastic wrinkles that result remains an elusive goal. Here, we describe a new approach to understanding the wrinkles of confined elastic shells, using a Lagrange multiplier in place of stress. Our theory reveals a simple set of geometric rules predicting the emergence and layout of orderly wrinkles, and explaining a surprisingly generic co-existence of ordered and disordered wrinkle domains. The results agree with numerous test cases across simulation and experiment and represent an elementary geometric toolkit for designing complex wrinkle patterns.Wrinkling happens because of mechanical instabilities arising from length mismatches. A theory now describes wrinkling in confined elastic shells and is expected to be relevant for the controlled design of complex wrinkle patterns.
Coral bleaching events threaten the sustainability of the Great Barrier Reef (GBR). Here we show that bleaching events of the past three decades have been mitigated by induced thermal tolerance of ...reef-building corals, and this protective mechanism is likely to be lost under near-future climate change scenarios. We show that 75% of past thermal stress events have been characterized by a temperature trajectory that subjects corals to a protective, sub-bleaching stress, before reaching temperatures that cause bleaching. Such conditions confer thermal tolerance, decreasing coral cell mortality and symbiont loss during bleaching by over 50%. We find that near-future increases in local temperature of as little as 0.5°C result in this protective mechanism being lost, which may increase the rate of degradation of the GBR.
Severe marine heatwaves have recently become a common feature of global ocean conditions due to a rapidly changing climate 1, 2. These increasingly severe thermal conditions are causing an ...unprecedented increase in the frequency and severity of mortality events in marine ecosystems, including on coral reefs 3. The degradation of coral reefs will result in the collapse of ecosystem services that sustain over half a billion people globally 4, 5. Here, we show that marine heatwave events on coral reefs are biologically distinct to how coral bleaching has been understood to date, in that heatwave conditions result in an immediate heat-induced mortality of the coral colony, rapid coral skeletal dissolution, and the loss of the three-dimensional reef structure. During heatwave-induced mortality, the coral skeletons exposed by tissue loss are, within days, encased by a complex biofilm of phototrophic microbes, whose metabolic activity accelerates calcium carbonate dissolution to rates exceeding accretion by healthy corals and far greater than has been documented on reefs under normal seawater conditions. This dissolution reduces the skeletal density and hardness and increases porosity. These results demonstrate that severe-heatwave-induced mortality events should be considered as a distinct biological phenomenon from bleaching events on coral reefs. We also suggest that such heatwave mortality events, and rapid reef decay, will become more frequent as the intensity of marine heatwaves increases and provides further compelling evidence for the need to mitigate climate change and instigate actions to reduce marine heatwaves.
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•Marine heatwaves lead to rapid coral mortality and microbial biofilm formation•Microbial metabolic activity results in rapid dissolution of the coral skeleton•Dissolution reduces skeletal hardness and density and increased porosity
Due to climate change, coral reefs are now being subjected to extreme marine heatwave (MHW) conditions. Leggat et al. show that large-scale mortality due to MHWs and microbial colonization leads to a previously undescribed rapid dissolution of the coral skeleton.
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