Summary Background In the Step Study, the MRKAd5 HIV-1 gag/pol/nef vaccine did not reduce plasma viraemia after infection, and HIV-1 incidence was higher in vaccine-treated than in placebo-treated ...men with pre-existing adenovirus serotype 5 (Ad5) immunity. We assessed vaccine-induced immunity and its potential contributions to infection risk. Methods To assess immunogenicity, we characterised HIV-specific T cells ex vivo with validated interferon-γ ELISPOT and intracellular cytokine staining assays, using a case–cohort design. To establish effects of vaccine and pre-existing Ad5 immunity on infection risk, we undertook flow cytometric studies to measure Ad5-specific T cells and circulating activated (Ki-67+/BcL-2lo ) CD4+ T cells expressing CCR5. Findings We detected interferon-γ-secreting HIV-specific T cells (range 163/106 to 686/106 peripheral blood mononuclear cells) ex vivo by ELISPOT in 77% (258/354) of people receiving vaccine; 218 of 354 (62%) recognised two to three HIV proteins. We identified HIV-specific CD4+ T cells by intracellular cytokine staining in 58 of 142 (41%) people. In those with reactive CD4+ T cells, the median percentage of CD4+ T cells expressing interleukin 2 was 88%, and the median co-expression of interferon γ or tumor necrosis factor α (TNFα), or both, was 72%. We noted HIV-specific CD8+ T cells (range 0·4–1·0%) in 117 of 160 (73%) participants, expressing predominantly either interferon γ alone or with TNFα. Vaccine-induced HIV-specific immunity, including response rate, magnitude, and cytokine profile, did not differ between vaccinated male cases (before infection) and non-cases. Ad5-specific T cells were lower in cases than in non-cases in several subgroup analyses. The percentage of circulating Ki-67+BcL-2lo /CCR5+CD4+ T cells did not differ between cases and non-cases. Interpretation Consistent with previous trials, the MRKAd5 HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T cells. Our findings suggest that future candidate vaccines have to elicit responses that either exceed in magnitude or differ in breadth or function from those recorded in this trial. Funding National Institute of Allergy and Infectious Diseases, US National Institutes of Health; and Merck Research Laboratories.
Summary Background Stem-cell-based, tissue engineered transplants might offer new therapeutic options for patients, including children, with failing organs. The reported replacement of an adult ...airway using stem cells on a biological scaffold with good results at 6 months supports this view. We describe the case of a child who received a stem-cell-based tracheal replacement and report findings after 2 years of follow-up. Methods A 12-year-old boy was born with long-segment congenital tracheal stenosis and pulmonary sling. His airway had been maintained by metal stents, but, after failure, a cadaveric donor tracheal scaffold was decellularised. After a short course of granulocyte colony stimulating factor, bone marrow mesenchymal stem cells were retrieved preoperatively and seeded onto the scaffold, with patches of autologous epithelium. Topical human recombinant erythropoietin was applied to encourage angiogenesis, and transforming growth factor β to support chondrogenesis. Intravenous human recombinant erythropoietin was continued postoperatively. Outcomes were survival, morbidity, endoscopic appearance, cytology and proteomics of brushings, and peripheral blood counts. Findings The graft revascularised within 1 week after surgery. A strong neutrophil response was noted locally for the first 8 weeks after surgery, which generated luminal DNA neutrophil extracellular traps. Cytological evidence of restoration of the epithelium was not evident until 1 year. The graft did not have biomechanical strength focally until 18 months, but the patient has not needed any medical intervention since then. 18 months after surgery, he had a normal chest CT scan and ventilation-perfusion scan and had grown 11 cm in height since the operation. At 2 years follow-up, he had a functional airway and had returned to school. Interpretation Follow-up of the first paediatric, stem-cell-based, tissue-engineered transplant shows potential for this technology but also highlights the need for further research. Funding Great Ormond Street Hospital NHS Trust, The Royal Free Hampstead NHS Trust, University College Hospital NHS Foundation Trust, and Region of Tuscany.
We report maps of the concentrations of H, Si, Cl, K, Fe, and Th as determined by the Gamma Ray Spectrometer (GRS) on board the 2001 Mars Odyssey Mission for ±∼45° latitudes. The procedures by which ...the spectra are processed to yield quantitative concentrations are described in detail. The concentrations of elements determined over the locations of the various Mars landers generally agree well with the lander values except for Fe, although the mean of the GRS Fe data agrees well with that of Martian meteorites. The water‐equivalent concentration of hydrogen by mass varies from about 1.5% to 7.5% (by mass) with the most enriched areas being near Apollinaris Patera and Arabia Terra. Cl shows a distribution similar to H over the surface except that the Cl content over Medusae Fossae is much greater than elsewhere. The map of Fe shows enrichment in the northern lowlands versus the southern highlands. Silicon shows only very modest variation over the surface with mass fractions ranging from 19% to 22% over most of the planet, though a significant depletion in Si is noted in a region west of Tharsis Montes and Olympus Mons where the Si content is as low as 18%. K and Th show a very similar pattern with depletions associated with young volcanic deposits and enrichments associated with the TES Surface Type‐2 material. It is noted that there appears to be no evidence of significant globally distributed thick dust deposits of uniform composition.
Using the Gamma-Ray Spectrometer on the Mars Odyssey, we have identified two regions near the poles that are enriched in hydrogen. The data indicate the presence of a subsurface layer enriched in ...hydrogen overlain by a hydrogen-poor layer. The thickness of the upper layer decreases with decreasing distance to the pole, ranging from a column density of about 150 grams per square centimeter at -42° latitude to about 40 grams per square centimeter at -77°. The hydrogen-rich regions correlate with regions of predicted ice stability. We suggest that the host of the hydrogen in the subsurface layer is ice, which constitutes 35 ± 15% of the layer by weight.
The 2001 Mars Odyssey Gamma Ray Spectrometer (GRS) has made the first measurement of the equatorial and midlatitude distribution of Cl at the near‐surface of Mars. A mean concentration value of 0.49 ...wt% Cl has been determined from a grand sum of GRS spectra collected over the planet excluding high‐latitude regions. Cl is significantly enriched within the upper few tens of centimeters of the surface relative to the Martian meteorites and estimates for the bulk composition of the planet. However, Cl is not homogeneously distributed and varies by a factor of ∼4 even after smoothing of data with a 10°‐arc‐radius filter. Several contiguous, geographically large (>20°) regions of high and low Cl concentrations are present. In particular, a region centered over the Medusae Fossae Formation west of Tharsis shows significantly elevated Cl. A large region north of Syrtis Major extending into Utopia Planitia in the northern hemisphere shows the lowest Cl concentrations. On the basis of hierarchical multivariate correlations, Cl is positively associated with H while negatively associated with Si and thermal inertia. We discuss four possible geologic mechanisms (aeolian, volcanic, aqueous, and hydrothermal) that may have affected the Cl distribution seen by GRS. While some of the distribution may be due to Cl‐rich dust deposits transported by aeolian processes, this mechanism does not appear to account for all of the observed variability. We propose that reactions with volcanic exhalations may have been important for enriching Cl in Medusae Fossae Formation material.
Background: The PROGRESS Registry (Promoting Global Research Excellence in Severe Sepsis) was designed to provide comparative data reflecting everyday clinical practice, thereby allowing ...participating institutions to explore and benchmark medical interventions in severe sepsis. Materials and Methods: PROGRESS was an international, noninterventional, prospective, observational registry collecting data that describe the management and outcomes of severe sepsis patients in intensive care units (ICUs). Patients were enrolled who had been diagnosed with severe sepsis (suspected or proven infection and >= 1 acute sepsis-induced organ dysfunction) at the participating institutions, where de-identified data were entered directly into a secured website. PROGRESS was governed by an independent international medical advisory board. Results: PROGRESS took place in 276 ICUs in 37 countries, and 12,881 patients were identified as having severe sepsis. There was considerable variation among countries in enrollment levels, provision of standard treatment and supportive therapies, and ICU and hospital outcomes. Eight countries accounted for 65.2% of the enrolled patients. Males (59.3%) and Caucasian (48.6%) patients predominated the patient cohort. Diagnosis of severe sepsis was prior to ICU admission in 45.7% of patients, at ICU admission in 29.1% of patients, and after ICU admission in the remainder. Globally, ICU and hospital mortality rates were 39.2% and 49.6%, respectively. The mean length of ICU and hospital stay was 14.6 days and 28.2 days, respectively. Conclusions: The PROGRESS international sepsis registry demonstrates that a large web-based sepsis registry is feasible. Wide variations in outcomes and use of sepsis therapies were observed between countries. These results also suggest that additional opportunities exist across countries to improve severe sepsis outcomes.
The creation of a pharmacokinetic (PK) curve, which follows the plasma concentration of an administered drug as a function of time, is a critical aspect of the drug development process and includes ...such information as the drug's bioavailability, clearance, and elimination half-life. Prior to a drug of interest gaining clearance for use in human clinical trials, research is performed during the preclinical stages to establish drug safety and dosing metrics from data obtained from the PK studies. Both in vivo animal models and in vitro platforms have limitations in predicting human reaction to a drug due to differences in species and associated simplifications, respectively. As a result, in silico experiments using computer simulation have been implemented to accurately predict PK parameters in human studies. This review assesses these three approaches (in vitro, in vivo, and in silico) when establishing PK parameters and evaluates the potential for in silico studies to be the future gold standard of PK preclinical studies.
Free functional muscle transfer is an attractive option within reconstructive surgery when seeking to restore critical muscle function. The gracilis muscle has long been utilized for this purpose due ...to its expendability and consistent anatomy. Historically, survival of the skin overlying the distal one-third of the myocutaneous gracilis flap has been unpredictable. To address this, the myofasciocutaneous technique was developed, with prior studies demonstrating improved distal skin paddle viability with this approach; however, the mechanism is poorly defined. This study aimed to understand what factors contribute to survival benefit in myofasciocutaneous gracilis flaps. Using cadaveric dissections followed by latex dye injections, we discuss the creation of a deep fascial sheath that contains a rich vascular network and permits adhesion-free excursion at the recipient site. This study advances our understanding of the myofasciocutaneous gracilis flap and provides wider clinical applicability in free functional muscle transfer.
The gamma ray spectrometer on the Mars Odyssey spacecraft measured an enhancement of atmospheric argon over southern high latitudes during autumn followed by dissipation during winter and spring. ...Argon does not freeze at temperatures normal for southern winter (∼145 kelvin) and is left in the atmosphere, enriched relative to carbon dioxide (CO
2
), as the southern seasonal cap of CO
2
frost accumulates. Calculations of seasonal transport of argon into and out of southern high latitudes point to meridional (north-south) mixing throughout southern winter and spring.
Conjugate vaccines have reduced pneumococcal disease in vaccinated children and unvaccinated adults, but non-vaccine serotypes are of concern, particularly if antibiotic resistant. We reviewed ...Streptococcus pneumoniae collected via: (i) the British Society for Antimicrobial Chemotherapy (BSAC) surveillances from 2001-2014; (ii) Public Health England's (PHE) invasive isolate surveillance from 2005-2014 and (iii) referral to PHE for resistance investigation from 2005-2014. Serotype 15A increased in all series, with many representatives showing triple resistance to macrolides, tetracyclines and penicillin. 15A was consistently among the 10 most prevalent serotypes from 2011 in PHE and BSAC invasive isolate/bacteraemia surveillance but never previously; 26-33% of these invasive 15A isolates had triple resistance. BSAC respiratory isolates were only serotyped in 2013/14 and 2014/15 (October to September); 15A was most prevalent serotype in both periods, comprising 9-11% of isolates, 38-48% of them with triple resistance. Serotype 15A represented 0-4% of S. pneumoniae referred to PHE for reference investigation annually until 2008 but rose to 29% (2013) and 32% (2014). Almost all multidrug-resistant 15A isolates were sequence type (ST) 63 variants, whereas susceptible 15A isolates were clonally diverse. The rise of serotype 15A suggests that pneumococcal conjugate vaccines will need ongoing adaptation.
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