Abstract only Introduction: For older patients with type 2 diabetes, treatments that minimize the risk of hypoglycemia and provide benefits in terms of comorbidities, while optimizing glycemic ...control, are particularly important. Semaglutide, a glucagon-like peptide-1 receptor agonist available as a once-weekly (OW) subcutaneous and once-daily oral formulation, reduces HbA 1c and body weight with a low risk of hypoglycemia. In addition, major adverse cardiovascular events (MACE) were reduced in SUSTAIN 6 (OW semaglutide; significant) and PIONEER 6 (oral semaglutide; not significant) vs placebo. The aim of this post hoc analysis was to evaluate cardiovascular (CV), metabolic and safety outcomes with semaglutide according to age. Methods: Subgroup analyses for semaglutide vs placebo by age as quartiles (≤60 years; >60 years to ≤65; >65 years to ≤70 years; >70 years) were performed for pooled SUSTAIN 6 and PIONEER 6 data in relation to: CV (3-point and individual MACE components), metabolic (change in HbA 1c , body weight) and safety (severe hypoglycemia, serious adverse events SAEs) outcomes. Results: In patients treated with semaglutide (n=3,239) vs placebo (n=3,241), the reduction in MACE and individual components of MACE was consistent across age subgroups (p interaction >0.05 for all; Table ). Minor heterogeneity for change in HbA 1c from baseline was observed with semaglutide vs placebo across the four age subgroups (p interaction =0.01). Weight reduction with semaglutide vs placebo did not differ across age subgroups. Semaglutide (vs placebo) did not result in an increase in severe hypoglycemia or SAEs in any of the age subgroups ( Table ). Conclusions: This post hoc combined analysis of SUSTAIN 6 and PIONEER 6 indicates that the CV and metabolic benefits and the safety profile of semaglutide (vs placebo) align with the drug class and were consistent across age subgroups.
Understanding human immunity to Mycobacterium tuberculosis (Mtb) during different stages of infection is important for development of an effective tuberculosis (TB) vaccine. We aimed to evaluate ...immunity to Mtb infection by measuring immune responses to selected Mtb antigens expressed during different stages of infection over time and to observe sustainability of immunity.
In a cohort study comprising East Greenlanders aged 17-22 years (2012 to 2014) who had either; undetectable Mtb infection, ongoing or prior Mtb infection at enrolment, we measured immunity to 15 antigens over a one-year period. Quantiferon-TB Gold testing (QFT) defined Mtb infection status (undetected/detected). The eligible study population of East Greenlanders aged 17-22 years was identified from the entire population using the Civil Registration System. From the source population 65 participants were selected by stratified random sampling according to information on Mtb infection stage. Retrospective and prospective information on notified TB (including treatment) was obtained through the mandatory TB notification system and was used to characterise Mtb infection stage (ongoing/prior). Immunity to 15 antigens including two QFT antigens, PPD and 12 non-QFT antigens (representing early, constitutive and latent Mtb infection) was assessed by measuring immune responses using whole-blood antigen stimulation and interferon gamma measurement.
Of 65 participants, 54 were considered Mtb-infected. Immunity to Mtb infection fluctuated with high annual risk of conversion (range: 6-69%) and reversion (range: 5-95%). During follow-up, five (8%) participants were notified with TB; neither conversion nor reversion was associated with an increased risk of progressing to TB.
Our findings suggest that human immunity to natural Mtb infection over time is versatile with fluctuations, resulting in high levels of conversion and reversion of immunity, thus human immunity to Mtb is much more dynamic than anticipated. The study findings suggest future use of longitudinal assessment of immune responses when searching for TB vaccine candidate antigens.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • Immunity to promising latent TB vaccine antigens did not reduce risk of TB. • Immunity to latent TB antigens was observed among individuals categorised as not Mtb -infected. • A large ...follow-up study with a clinical outcome in a setting with high TB transmission. • Findings are not influenced by cross-reactions attributed to non tuberculous mycobacteria.
Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically ...recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4, revealed that Tac4
mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16, displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures.
Antigen specific release of IP-10 is the most promising alternative marker to IFN-γ for infection with M. tuberculosis. Compared to Interferon-γ release assays (IGRA), IP-10 is released in high ...levels enabling novel approaches such as field friendly dried blood spots (DBS) and molecular detection.
To develop a robust IP-10 based molecular assay for the diagnosis of infection with M. tubercuolsis from whole blood and DBS.
We developed a one-step probe based multiplex RT-qPCR assay for detecting IP-10 and IFN-γ mRNA expression from whole blood and DBS samples. The assay was validated and applied for the diagnosis of M. tuberculosis infection in DBS samples from 43 patients with confirmed TB, 13 patients with latent TB and 96 presumed uninfected controls. In parallel, IP-10 and INF-γ levels were measured in Quantiferon (QFT-TB) plasma supernatants.
IP-10 mRNA upregulation was detectable at 4 hours after stimulation (6 fold upregulation) peaking at 8 hours (108 fold upregulation). IFN-γ expression occurred in concert but levels were lower (peak 6.7 fold upregulation). IP-10 gene expression level was significantly higher in patients with tuberculosis (median 31.2, IQR 10.7-67.0) and persons with latent tuberculosis infection (LTBI) (41.2, IQR 9.8-64.9) compared to healthy controls (1.6, IQR 1.1-2.4; p<0.0001). The IP-10 mRNA and protein based tests had comparable diagnostic accuracy to QFT-TB, sensitivity (85% and 88% vs 85%) and specificity (96% and 96% vs 97%, p = ns.).
We developed a rapid, robust and accurate molecular immunodiagnostic test for M. tuberculosis infection. By combining DBS based sample acquisition, mail or currier based sample transport with centralized molecular detection, this immunodiagnostic test concept can reduce the local technological requirements everywhere and make it possible to offer highly accurate immunodiagnostic tests in low resource settings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lassen, H., Pedersen, S. A., Frost, H., and Hoff. A. 2013. Fishery management advice with ecosystem considerations. - ICES Journal of Marine Science, 70: 471-479.The European Union Marine Strategy ...Framework Directive (MSFD) includes four descriptors of Good Environmental Status (GES) which are affected by fishing activity. These descriptors are: biodiversity, fish stocks, foodweb, and seabed integrity. This paper shows how these descriptors can be related to variables within an ecological model and how an ecological model can be used to analyse whether the fishing pressure that is estimated based on bioeconomic criteria is within general sustainable limits. The paper presents an example of such an analysis of the Eastern Baltic cod fishery using two models: a bioeconomic model and an ecological model. The models are calibrated based on historic data. The mapping between the descriptors specified by MSFD and variables available for analysis in the models is incomplete, e.g. genetics and spatial structures are not included in the models. The models can be used strategically, providing a qualitative understanding of the anticipated relative changes.
OBJECTIVE
To investigate the efficacy, safety, and tolerability of oral semaglutide added to insulin with or without metformin.
RESEARCH DESIGN AND METHODS
Patients with type 2 diabetes uncontrolled ...on insulin with or without metformin were randomized to oral semaglutide 3 mg (N = 184), 7 mg (N = 182), or 14 mg (N = 181) or to placebo (N = 184) in a 52-week, double-blind trial. End points were change from baseline to week 26 in HbA1c (primary) and body weight (confirmatory secondary). Two estimands were defined: treatment policy (effect regardless of trial product discontinuation or rescue medication) and trial product (effect assuming trial product continuation without rescue medication) in randomized patients.
RESULTS
Oral semaglutide was superior to placebo in reducing HbA1c (estimated treatment difference ETD –0.5% 95% CI –0.7, –0.3, –0.9% –1.1, –0.7, and –1.2% –1.4, –1.0 for 3, 7, and 14 mg, respectively; P < 0.001) and body weight (ETD −0.9 kg 95% CI −1.8, −0.0, −2.0 kg −3.0, −1.0, and −3.3 kg −4.2, −2.3; P = 0.0392 for 3 mg, P ≤ 0.0001 for 7 and 14 mg) at week 26 (treatment policy estimand). Significantly greater dose-dependent HbA1c and body weight reductions versus placebo were achieved with oral semaglutide at weeks 26 and 52 (both estimands). The most frequent adverse event with oral semaglutide was nausea (11.4–23.2% of patients vs. 7.1% with placebo; mostly mild to moderate).
CONCLUSIONS
Oral semaglutide was superior to placebo in reducing HbA1c and body weight when added to insulin with or without metformin in patients with type 2 diabetes. The safety profile was consistent with other glucagon-like peptide 1 receptor agonists.
Summary Forty-seven Mycobacterium tuberculosis genes from the ‘regions of difference’ RD2-7, RD9-13 and RD15 were cloned and expressed, and the purified recombinant proteins were screened for their ...serodiagnostic potential. Evaluation of six selected proteins in serum samples from Danish resident tuberculosis patients and healthy controls led to identification of Rv0222 as the most promising serodiagnostic antigen. Recognition of the Rv0222 was compared with the 38 kDa protein and a fusion protein of the RD1 proteins ESAT-6 and CFP10 in a serum panel from pulmonary tuberculosis (TB) patients from Uganda. The highest overall sensitivity was observed for Rv0222 compared to BCG-vaccinated non-endemic healthy controls as well as symptomatic endemic controls. Importantly, Rv0222 identified human immuno deficiency (HIV) virus-positive patients and HIV-negative patients with the same overall sensitivity. The results emphasize the importance of cut-off values in TB endemic regions based on endemic control individuals to diagnose active TB, and identify Rv0222 as a promising new antigen for serodiagnosis of TB in both HIV-negative and HIV-positive patients.
Abstract
Approximately one third of the world’s population is infected with Mycobacterium tuberculosis. Developing novel vaccines to protect against pulmonary tuberculosis is a public health ...priority. In this study, a Hybrid 1 (H1) subunit vaccine containing a recombinant fusion protein of Ag85B and ESAT-6 was paired with a two-component CAF01 liposomal adjuvant system developed and manufactured by Statens Serum Institut. A phase I clinical study was performed to evaluate H1:CAF01 in healthy non-BCG vaccinated adult male and female subjects between the ages of 18 and 55 years old. The subjects were randomized into four groups including H1 alone or H1 with 125/25µg, 313/125µg or 625/125µg CAF01 and were vaccinated on study days 0 and 56. PBMCs harvested approximately 150 weeks post vaccination were used to assess antigen specific responses by a 13-color intracellular cytokine staining assay. Vaccination with H1:CAF01 resulted in statistically significant Ag85B-specific CD4 polyfunctional CD154+ T cells compared to H1 alone. ESAT-6 stimulation resulted in detection of CD4 polyfunctional CD154+ T cells responses that were not elevated to a statistically significant extent compared to H1 alone. This is the first demonstration of the persistence of an antigen-specific cellular immune response up to 3 years after vaccination in a clinical trial using H1:CAF01 vaccination.
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