Safety and immunogenicity of H1/IC31®, an adjuvanted TB subunit vaccine, in HIV-infected adults with CD4+ lymphocyte counts greater than 350 cells/mm3: a phase II, multi-centre, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Novel tuberculosis vaccines should be safe, immunogenic, and effective in various population groups, including HIV-infected individuals. In this phase II multi-centre, double-blind, placebo-controlled trial, the safety and immunogenicity of the novel H1/IC31 vaccine, a fusion protein of Ag85B-ESAT-6 (H1) formulated with the adjuvant IC31, was evaluated in HIV-infected adults. METHODS: HIV-infected adults with CD4+ T cell counts >350/mm3 and without evidence of active tuberculosis were enrolled and followed until day 182. H1/IC31 vaccine or placebo was randomly allocated in a 5:1 ratio. The vaccine was administered intramuscularly at day 0 and 56. Safety assessment was based on medical history, clinical examinations, and blood and urine testing. Immunogenicity was determined by a short-term whole blood intracellular cytokine staining assay. RESULTS: 47 of the 48 randomised participants completed both vaccinations. In total, 459 mild or moderate and 2 severe adverse events were reported. There were three serious adverse events in two vaccinees classified as not related to the investigational product. Local injection site reactions were more common in H1/IC31 versus placebo recipients (65.0% vs. 12.5%, p = 0.015). Solicited systemic and unsolicited adverse events were similar by study arm. The baseline CD4+ T cell count and HIV viral load were similar by study arm and remained constant over time. The H1/IC31 vaccine induced a persistent Th1-immune response with predominately TNF-α and IL-2 co-expressing CD4+ T cells, as well as polyfunctional IFN-γ, TNF-α and IL-2 expressing CD4+ T cells. CONCLUSION: H1/IC31 was well tolerated and safe in HIV-infected adults with a CD4+ Lymphocyte count greater than 350 cells/mm3. The vaccine did not have an effect on CD4+ T cell count or HIV-1 viral load. H1/IC31 induced a specific and durable Th1 immune response. TRIAL REGISTRATION: Pan African Clinical Trials Registry (PACTR) PACTR201105000289276

Variational Mass Perturbation Theory for Light-Front Bound-State Equations

We investigate the mesonic light-front bound-state equations of the 't Hooft and Schwinger model in the two-particle, i.e. valence sector, for small fermion mass. We perform a high precision determination of the mass and light-cone wave function of the lowest lying meson by combining fermion mass perturbation theory with a variational approach. All calculations are done entirely in the fermionic representation without using any bosonization scheme. In a step-by-step procedure we enlarge the space of variational parameters. For the first two steps, the results are obtained analytically. Beyond that we use computer algebraic and numerical methods. We achieve good convergence so that the calculation of the meson mass squared can be extended to third order in the fermion mass. Within the numerical treatment we include higher Fock states up to six particles. Our results are consistent with all previous numerical investigations, in particular lattice calculations. For the massive Schwinger model, we find a small discrepancy (less than 2 percent) in comparison with known bosonization results. Possible resolutions of this discrepancy are discussed.Comment: some points clarified, representation straightened, to appear in Phys. Rev. D, 31 pages, Latex, REVTeX, epsfig, 3 postscript figures include

Towards Solving QCD - The Transverse Zero Modes in Light-Cone Quantization

We formulate QCD in (d+1) dimensions using Dirac's front form with periodic boundary conditions, that is, within Discretized Light-Cone Quantization. The formalism is worked out in detail for SU(2) pure glue theory in (2+1) dimensions which is approximated by restriction to the lowest {\it transverse} momentum gluons. The dimensionally-reduced theory turns out to be SU(2) gauge theory coupled to adjoint scalar matter in (1+1) dimensions. The scalar field is the remnant of the transverse gluon. This field has modes of both non-zero and zero {\it longitudinal} momentum. We categorize the types of zero modes that occur into three classes, dynamical, topological, and constrained, each well known in separate contexts. The equation for the constrained mode is explicitly worked out. The Gauss law is rather simply resolved to extract physical, namely color singlet states. The topological gauge mode is treated according to two alternative scenarios related to the In the one, a spectrum is found consistent with pure SU(2) gluons in (1+1) dimensions. In the other, the gauge mode excitations are estimated and their role in the spectrum with genuine Fock excitations is explored. A color singlet state is given which satisfies Gauss' law. Its invariant mass is estimated and discussed in the physical limit.Comment: LaTex document, 26 pages, one figure (obtainable by contacting authors). To appear in Physical. Review

Flavor Physics in an SO(10) Grand Unified Model

In supersymmetric grand-unified models, the lepton mixing matrix can possibly affect flavor-changing transitions in the quark sector. We present a detailed analysis of a model proposed by Chang, Masiero and Murayama, in which the near-maximal atmospheric neutrino mixing angle governs large new b -> s transitions. Relating the supersymmetric low-energy parameters to seven new parameters of this SO(10) GUT model, we perform a correlated study of several flavor-changing neutral current (FCNC) processes. We find the current bound on B(tau -> mu gamma) more constraining than B(B -> X_s gamma). The LEP limit on the lightest Higgs boson mass implies an important lower bound on tan beta, which in turn limits the size of the new FCNC transitions. Remarkably, the combined analysis does not rule out large effects in B_s-B_s-bar mixing and we can easily accomodate the large CP phase in the B_s-B_s-bar system which has recently been inferred from a global analysis of CDF and DO data. The model predicts a particle spectrum which is different from the popular Constrained Minimal Supersymmetric Standard Model (CMSSM). B(tau -> mu gamma) enforces heavy masses, typically above 1 TeV, for the sfermions of the degenerate first two generations. However, the ratio of the third-generation and first-generation sfermion masses is smaller than in the CMSSM and a (dominantly right-handed) stop with mass below 500 GeV is possible.Comment: 44 pages, 5 figures. Footnote and references added, minor changes, Fig. 2 corrected; journal versio

Dose-Dependent Associations of Dietary Glycemic Index, Glycemic Load, and Fiber With 3-Year Weight Loss Maintenance and Glycemic Status in a High-Risk Population : A Secondary Analysis of the Diabetes Prevention Study PREVIEW

OBJECTIVE To examine longitudinal and dose-dependent associations of dietary glycemic index (GI), glycemic load (GL), and fiber with body weight and glycemic status during 3-year weight loss maintenance (WLM) in adults at high risk of type 2 diabetes. RESEARCH DESIGN AND METHODS In this secondary analysis we used pooled data from the PREVention of diabetes through lifestyle Intervention and population studies in Europe and around the World (PREVIEW) randomized controlled trial, which was designed to test the effects of four diet and physical activity interventions. A total of 1,279 participants with overweight or obesity (age 25-70 years and BMI >= 25 kg . m(-2)) and prediabetes at baseline were included. We used multiadjusted linear mixed models with repeated measurements to assess longitudinal and dose-dependent associations by merging the participants into one group and dividing them into GI, GL, and fiber tertiles, respectively. RESULTS In the available-case analysis, each 10-unit increment in GI was associated with a greater regain of weight (0.46 kg . year(-1); 95% CI 0.23, 0.68; P < 0.001) and increase in HbA(1c). Each 20-unit increment in GL was associated with a greater regain of weight (0.49 kg . year(-1); 0.24, 0.75; P < 0.001) and increase in HbA(1c). The associations of GI and GL with HbA(1c) were independent of weight change. Compared with those in the lowest tertiles, participants in the highest GI and GL tertiles had significantly greater weight regain and increases in HbA(1c). Fiber was inversely associated with increases in waist circumference, but the associations with weight regain and glycemic status did not remain robust in different analyses. CONCLUSIONS Dietary GI and GL were positively associated with weight regain and deteriorating glycemic status. Stronger evidence on the role of fiber is needed.Peer reviewe

The PREVIEW intervention study : Results from a 3-year randomized 2 x 2 factorial multinational trial investigating the role of protein, glycaemic index and physical activity for prevention of type 2 diabetes

Aim To compare the impact of two long-term weight-maintenance diets, a high protein (HP) and low glycaemic index (GI) diet versus a moderate protein (MP) and moderate GI diet, combined with either high intensity (HI) or moderate intensity physical activity (PA), on the incidence of type 2 diabetes (T2D) after rapid weight loss. Materials and Methods A 3-year multicentre randomized trial in eight countries using a 2 x 2 diet-by-PA factorial design was conducted. Eight-week weight reduction was followed by a 3-year randomized weight-maintenance phase. In total, 2326 adults (age 25-70 years, body mass index >= 25 kg/m(2)) with prediabetes were enrolled. The primary endpoint was 3-year incidence of T2D analysed by diet treatment. Secondary outcomes included glucose, insulin, HbA1c and body weight. Results The total number of T2D cases was 62 and the cumulative incidence rate was 3.1%, with no significant differences between the two diets, PA or their combination. T2D incidence was similar across intervention centres, irrespective of attrition. Significantly fewer participants achieved normoglycaemia in the HP compared with the MP group (P <.0001). At 3 years, normoglycaemia was lowest in HP-HI (11.9%) compared with the other three groups (20.0%-21.0%, P <.05). There were no group differences in body weight change (-11% after 8-week weight reduction; -5% after 3-year weight maintenance) or in other secondary outcomes. Conclusions Three-year incidence of T2D was much lower than predicted and did not differ between diets, PA or their combination. Maintaining the target intakes of protein and GI over 3 years was difficult, but the overall protocol combining weight loss, healthy eating and PA was successful in markedly reducing the risk of T2D. This is an important clinically relevant outcome.Peer reviewe

The kinematics of swimming and relocation jumps in copepod nauplii

Copepod nauplii move in a world dominated by viscosity. Their swimming-by-jumping propulsion mode, with alternating power and recovery strokes of three pairs of cephalic appendages, is fundamentally different from the way other microplankters move. Protozoans move using cilia or flagella, and copepodites are equipped with highly specialized swimming legs. In some species the nauplius may also propel itself more slowly through the water by beating and rotating the appendages in a different, more complex pattern. We use high-speed video to describe jumping and swimming in nauplii of three species of pelagic copepods: Temora longicornis, Oithona davisae and Acartia tonsa. The kinematics of jumping is similar between the three species. Jumps result in a very erratic translation with no phase of passive coasting and the nauplii move backwards during recovery strokes. This is due to poorly synchronized recovery strokes and a low beat frequency relative to the coasting time scale. For the same reason, the propulsion efficiency of the nauplii is low. Given the universality of the nauplius body plan, it is surprising that they seem to be inefficient when jumping, which is different from the very efficient larger copepodites. A slow-swimming mode is only displayed by T. longicornis. In this mode, beating of the appendages results in the creation of a strong feeding current that is about 10 times faster than the average translation speed of the nauplius. The nauplius is thus essentially hovering when feeding, which results in a higher feeding efficiency than that of a nauplius cruising through the water

Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants inLARS1

Purpose: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings. Methods: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts. Results: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro. Conclusion: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke