1,085 research outputs found
Association of Sodium-Glucose Cotransporter 2 Inhibitor vs Dipeptidyl Peptidase-4 Inhibitor Use With Risk of Incident Obstructive Airway Disease and Exacerbation Events Among Patients With Type 2 Diabetes in Hong Kong
Importance
Patients with diabetes are at higher risk for obstructive airway disease (OAD). In recent meta-analyses of post hoc analyses of cardiorenal trials, sodium-glucose cotransporter 2 inhibitors (SGLT2Is) were suggested to reduce the risk of OAD adverse events. However, a clinical investigation of this association is warranted.
Objective
This study aimed to investigate the association of SGLT2I use vs dipeptidyl peptidase-4 inhibitor (DPP4I) use with OAD incidence and exacerbation events in patients with type 2 diabetes.
Design, Setting, and Participants
This retrospective population-based cohort study used electronic health data from a territory-wide electronic medical database in Hong Kong. Data were collected for patients with type 2 diabetes who were prescribed SGLT2Is or DPP4Is between January 1, 2015, and December 31, 2018. Patients were followed for a median of 2.2 years between January 1, 2015, and December 31, 2020. A prevalent new-user design was adopted to match patients based on previous exposure to the study drugs. Propensity score matching was used to balance baseline characteristics.
Exposures
Patients with type 2 diabetes using SGLT2Is (exposure of interest) or DPP4Is (active comparator).
Main Outcomes and Measures
The main outcomes were the first incidence of OAD and the count of OAD exacerbations. The risk of incident OAD was estimated using a Cox proportional hazards regression model. The rate of exacerbations was estimated using zero-inflated Poisson regression. Statistical analysis was performed on November 13, 2022.
Results
This study included 30 385 patients. The propensity score–matched non-OAD cohort (incidence analysis) consisted of 5696 SGLT2I users and 22 784 DPP4I users, while the matched OAD cohort (exacerbations analysis) comprised 381 SGLT2I users and 1524 DPP4I users. At baseline, 56% of patients in the non-OAD cohort were men and the mean (SD) age was 61.2 (9.9) years; 51% of patients in the OAD cohort were men and the mean age was 62.2 (10.8) years. Compared with DPP4I use, SGLT2I use was associated with a lower risk of incident OAD (hazard ratio, 0.65 [95% CI, 0.54-0.79]; P < .001) and a lower rate of exacerbations (rate ratio, 0.54 [95% CI, 0.36-0.83]; P = .01). The associations were consistent in sex subgroup analysis.
Conclusions and Relevance
The findings of this retrospective cohort study of patients with type 2 diabetes in Hong Kong suggest that SGLT2I use was associated with a reduced risk of incident OAD and a lower rate of exacerbations in a clinical setting compared with DPP4I use. These findings further suggest that SGLT2Is may provide additional protective effects against OAD for patients with type 2 diabetes and that further investigation is warranted
Characterization of an Italian founder mutation in the RING-finger domain of BRCA1
The identification of founder mutations in cancer predisposing genes is important to improve risk assessment in geographically defined populations, since it may provide specific targets resulting in cost-effective genetic testing. Here, we report the characterization of the BRCA1 c.190T>C (p.Cys64Arg) mutation, mapped to the RING-finger domain coding region, that we detected in 43 hereditary breast/ovarian cancer (HBOC) families, for the large part originating from the province of Bergamo (Northern Italy). Haplotype analysis was performed in 21 families, and led to the identification of a shared haplotype extending over three BRCA1-associated marker loci (0.4 cM). Using the DMLE+2.2 software program and regional population demographic data, we were able to estimate the age of the mutation to vary between 3,100 and 3,350 years old. Functional characterization of the mutation was carried out at both transcript and protein level. Reverse transcriptase-PCR analysis on lymphoblastoid cells revealed expression of full length mRNA from the mutant allele. A green fluorescent protein (GFP)-fragment reassembly assay showed that the p.Cys64Arg substitution prevents the binding of the BRCA1 protein to the interacting protein BARD1, in a similar way as proven deleterious mutations in the RING-domain. Overall, 55 of 83 (66%) female mutation carriers had a diagnosis of breast and/or ovarian cancer. Our observations indicate that the BRCA1 c.190T>C is a pathogenic founder mutation present in the Italian population. Further analyses will evaluate whether screening for this mutation can be suggested as an effective strategy for the rapid identification of at-risk individuals in the Bergamo area
Potentials of Mean Force for Protein Structure Prediction Vindicated, Formalized and Generalized
Understanding protein structure is of crucial importance in science, medicine
and biotechnology. For about two decades, knowledge based potentials based on
pairwise distances -- so-called "potentials of mean force" (PMFs) -- have been
center stage in the prediction and design of protein structure and the
simulation of protein folding. However, the validity, scope and limitations of
these potentials are still vigorously debated and disputed, and the optimal
choice of the reference state -- a necessary component of these potentials --
is an unsolved problem. PMFs are loosely justified by analogy to the reversible
work theorem in statistical physics, or by a statistical argument based on a
likelihood function. Both justifications are insightful but leave many
questions unanswered. Here, we show for the first time that PMFs can be seen as
approximations to quantities that do have a rigorous probabilistic
justification: they naturally arise when probability distributions over
different features of proteins need to be combined. We call these quantities
reference ratio distributions deriving from the application of the reference
ratio method. This new view is not only of theoretical relevance, but leads to
many insights that are of direct practical use: the reference state is uniquely
defined and does not require external physical insights; the approach can be
generalized beyond pairwise distances to arbitrary features of protein
structure; and it becomes clear for which purposes the use of these quantities
is justified. We illustrate these insights with two applications, involving the
radius of gyration and hydrogen bonding. In the latter case, we also show how
the reference ratio method can be iteratively applied to sculpt an energy
funnel. Our results considerably increase the understanding and scope of energy
functions derived from known biomolecular structures
K pi vector form factor constrained by tau ---> K pi nu_tau and K_l3 decays
Dispersive representations of the Kpi vector and scalar form factors are used
to fit the spectrum of tau ---> K pi nu_tau obtained by the Belle collaboration
incorporating constraints from results for K_l3 decays. The slope and curvature
of the vector form factor are obtained directly from the data through the use
of a three-times-subtracted dispersion relation. We find and . From
the pole position on the second Riemann sheet the mass and width of the
are found to be ~MeV and
~MeV. The phase-space integrals needed for
K_l3 decays are calculated as well. Furthermore, the Kpi isospin-1/2 P-wave
threshold parameters are derived from the phase of the vector form factor. For
the scattering length and the effective range we find respectively
and .Comment: 22 pages, 4 figure
Weinberg like sum rules revisited
The generalized Weinberg sum rules containing the difference of isovector
vector and axial-vector spectral functions saturated by both finite and
infinite number of narrow resonances are considered. We summarize the status of
these sum rules and analyze their overall agreement with phenomenological
Lagrangians, low-energy relations, parity doubling, hadron string models, and
experimental data.Comment: 31 pages, noticed misprints are corrected, references are added, and
other minor corrections are mad
Charged-Higgs phenomenology in the Aligned two-Higgs-doublet model
The alignment in flavour space of the Yukawa matrices of a general
two-Higgs-doublet model results in the absence of tree-level flavour-changing
neutral currents. In addition to the usual fermion masses and mixings, the
aligned Yukawa structure only contains three complex parameters, which are
potential new sources of CP violation. For particular values of these three
parameters all known specific implementations of the model based on discrete
Z_2 symmetries are recovered. One of the most distinctive features of the
two-Higgs-doublet model is the presence of a charged scalar. In this work, we
discuss its main phenomenological consequences in flavour-changing processes at
low energies and derive the corresponding constraints on the parameters of the
aligned two-Higgs-doublet model.Comment: 46 pages, 19 figures. Version accepted for publication in JHEP.
References added. Discussion slightly extended. Conclusions unchange
Planck intermediate results. XLI. A map of lensing-induced B-modes
The secondary cosmic microwave background (CMB) -modes stem from the
post-decoupling distortion of the polarization -modes due to the
gravitational lensing effect of large-scale structures. These lensing-induced
-modes constitute both a valuable probe of the dark matter distribution and
an important contaminant for the extraction of the primary CMB -modes from
inflation. Planck provides accurate nearly all-sky measurements of both the
polarization -modes and the integrated mass distribution via the
reconstruction of the CMB lensing potential. By combining these two data
products, we have produced an all-sky template map of the lensing-induced
-modes using a real-space algorithm that minimizes the impact of sky masks.
The cross-correlation of this template with an observed (primordial and
secondary) -mode map can be used to measure the lensing -mode power
spectrum at multipoles up to . In particular, when cross-correlating with
the -mode contribution directly derived from the Planck polarization maps,
we obtain lensing-induced -mode power spectrum measurement at a significance
level of , which agrees with the theoretical expectation derived
from the Planck best-fit CDM model. This unique nearly all-sky
secondary -mode template, which includes the lensing-induced information
from intermediate to small () angular scales, is
delivered as part of the Planck 2015 public data release. It will be
particularly useful for experiments searching for primordial -modes, such as
BICEP2/Keck Array or LiteBIRD, since it will enable an estimate to be made of
the lensing-induced contribution to the measured total CMB -modes.Comment: 20 pages, 12 figures; Accepted for publication in A&A; The B-mode map
is part of the PR2-2015 Cosmology Products; available as Lensing Products in
the Planck Legacy Archive http://pla.esac.esa.int/pla/#cosmology; and
described in the 'Explanatory Supplement'
https://wiki.cosmos.esa.int/planckpla2015/index.php/Specially_processed_maps#2015_Lensing-induced_B-mode_ma
The Effect of Insecticide Synergists on the Response of Scabies Mites to Pyrethroid Acaricides
Synergists are commonly used in combination with pesticides to suppress metabolism-based resistance and increase the efficacy of the agents. They are also useful as tools for laboratory investigation of specific resistance mechanisms based on their ability to inhibit specific metabolic pathways. To determine the role of metabolic degradation as a mechanism for acaricide resistance in human scabies, PBO (piperonyl butoxide), DEF (S,S,S-tributyl phosphorotrithioate) and DEM (diethyl maleate) were used with permethrin as synergists in a bioassay of mite killing. A statistically significant difference in survival time of permethrin-resistant Sarcoptes scabiei variety canis was noted when any of the three synergists were used in combination with permethrin compared to survival time of mites exposed to permethrin alone (p<0.0001). These results indicate the potential utility of synergists in reversing tolerance to pyrethroid-based acaricides (i.e. the addition of synergists to permethrin-containing topical acaricide cream commonly used to treat scabies). To further verify specific metabolic pathways being inhibited by these synergists, enzyme assays were developed to measure esterase, glutathione S-transferase (GST) and cytochrome P450 monooxygenase activity in scabies mites. Results of in vitro enzyme inhibition experiments showed lower levels of esterase activity with DEF; lower levels of GST activity with DEM and lower levels of cytochrome monooxygenase activity with PBO. These findings indicate a metabolic mechanism as mediating pyrethroid resistance in scabies mites
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