Human skin penetration of a copper tripeptide in vitro as a function of skin layer

Objective and designSkin retention and penetration by copper applied as glycyl-L-histidyl-L-lysine cuprate diacetate was evaluated in vitro in order to assess its potential for its transdermal delivery as an anti-inflammatory agent.Materials and methodsFlow-through diffusion cells with 1 cm(2) exposure area were used under infinite dose conditions. 0.68% aq. copper tripeptide as permeant was applied on isolated stratum corneum, heat-separated epidermis and dermatomed skin and receptor fluid collected over 48 h in 4 h intervals using inductively coupled plasma mass spectrometry to analyze for copper in tissues and receptor fluid.ResultsThe permeability coefficient of the compound through dermatomed skin was 2.43 ± 0.51 × 10(-4) cm/h; 136.2 ± 17.5 μg/cm(2) copper permeated 1 cm(2) of that tissue over 48 h, while 97 ± 6.6 μg/cm(2) were retained as depot.ConclusionsCopper as tripeptide was delivered in potentially therapeutically effective amounts for inflammatory disease

Human skin penetration of a copper tripeptide in vitro as a function of skin layer

We study a set of 28 GRB light-curves detected between 15 December 2002 and 9 June 2003 by the anti-coincidence shield of the spectrometer (SPI) of INTEGRAL. During this period it has detected 50 bursts, that have been confirmed by other instruments, with a time resolution of 50 ms. First, we derive the basic characteristics of the bursts: various duration measures, the count peak flux and the count fluence. Second, a sub-sample of 11 bursts with 12 individual, well-separated pulses is studied. We fit the pulse shape with a model by Kocevski et al. (2003) and find that the pulses are quite self-similar in shape. There is also a weak tendency for the pulses with steep power-law decays to be more asymmetric. Third, the variability of the complex light-curves is studied by analyzing their power-density-spectra (PDS) and their RMS variability.
The averaged PDS, of the whole sample, is a power-law with index of $1.60\pm0.05$ and a break between 1–2 Hz. Fourth, we also discuss the background and noise levels. We found that the background noise has a Gaussian distribution and its power is independent of frequency, i.e., it is white noise. However, it does not follow a Poisson statistic since on average the variance is ~1.6 larger than the mean. We discuss our results in context of the current theoretical picture in which GRBs are created in an anisotropic, highly relativistic outflow from collapsing massive stars. Finally, we note that the exact behaviour of the instrument is not yet known and therefore the above results should be treated as preliminary.

The impact of vector migration on the effectiveness of strategies to control gambiense human African trypanosomiasis

BACKGROUND: Several modeling studies have been undertaken to assess the feasibility of the WHO goal of eliminating gambiense human African trypanosomiasis (g-HAT) by 2030. However, these studies have generally overlooked the effect of vector migration on disease transmission and control. Here, we evaluated the impact of vector migration on the feasibility of interrupting transmission in different g-HAT foci. METHODS: We developed a g-HAT transmission model of a single tsetse population cluster that accounts for migration of tsetse fly into this population. We used a model calibration approach to constrain g-HAT incidence to ranges expected for high, moderate and low transmission settings, respectively. We used the model to evaluate the effectiveness of current intervention measures, including medical intervention through enhanced screening and treatment, and vector control, for interrupting g-HAT transmission in disease foci under each transmission setting. RESULTS: We showed that, in low transmission settings, under enhanced medical intervention alone, at least 70% treatment coverage is needed to interrupt g-HAT transmission within 10 years. In moderate transmission settings, a combination of medical intervention and a vector control measure with a daily tsetse mortality greater than 0.03 is required to achieve interruption of disease transmission within 10 years. In high transmission settings, interruption of disease transmission within 10 years requires a combination of at least 70% medical intervention coverage and at least 0.05 tsetse daily mortality rate from vector control. However, the probability of achieving elimination in high transmission settings decreases with an increased tsetse migration rate. CONCLUSION: Our results suggest that the WHO 2030 goal of G-HAT elimination is, at least in theory, achievable. But the presence of tsetse migration may reduce the probability of interrupting g-HAT transmission in moderate and high transmission foci. Therefore, optimal vector control programs should incorporate monitoring and controlling of vector density in buffer areas around foci of g-HAT control efforts

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Pro-inflammatory activation of primary microglia and macrophages increases 18kDa Translocator Protein (TSPO) expression in rodents but not humans

The 18kDa Translocator Protein (TSPO) is the most commonly used tissue-specific marker of inflammation in positron emission tomography (PET) studies. It is expressed in myeloid cells such as microglia and macrophages, and in rodent myeloid cells expression increases with cellular activation. We assessed the effect of myeloid cell activation on TSPO gene expression in both primary human and rodent microglia and macrophages in vitro, and also measured TSPO radioligand binding with 3H-PBR28 in primary human macrophages. As observed previously, we found that TSPO expression increases (∼9-fold) in rodent-derived macrophages and microglia upon pro-inflammatory stimulation. However, TSPO expression does not increase with classical pro-inflammatory activation in primary human microglia (fold change 0.85 [95% CI 0.58–1.12], p = 0.47). In contrast, pro-inflammatory activation of human monocyte-derived macrophages is associated with a reduction of both TSPO gene expression (fold change 0.60 [95% CI 0.45–0.74], p = 0.02) and TSPO binding site abundance (fold change 0.61 [95% CI 0.49–0.73], p < 0.0001). These findings have important implications for understanding the biology of TSPO in activated macrophages and microglia in humans. They are also clinically relevant for the interpretation of PET studies using TSPO targeting radioligands, as they suggest changes in TSPO expression may reflect microglial and macrophage density rather than activation phenotype