In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. ...More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.
In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.
Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval CI, 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups.
Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. (Funded by AstraZeneca; DAPA-HF ClinicalTrials.gov number, NCT03036124.).
Adjuvant chemotherapy (ACT) for breast cancer improves relapse-free survival (BCRFS) and overall survival. Differences in terms of efficacy and toxicity could partly be explained by the significant ...interpatient variability in pharmacokinetics which cannot be captured by dosing according to body surface area. Consequently, tailored dosing was prospectively evaluated in the PANTHER trial.
PANTHER is a multicenter, open-label, randomized phase III trial which compared tailored, dose-dense (DD) epirubicin/cyclophosphamide (E/C) and tailored docetaxel (D) (tDD) with standard interval 5-fluorouracil/E/C and D. The primary end point was BCRFS and the primary efficacy analysis has been previously published. In this secondary analysis, we aimed to retrospectively explore the concept of dose tailoring. Our two hypotheses were that BCRFS would not vary depending on the cumulative administered epirubicin dose; and that dose tailoring would lead to appropriate dosing and improved outcomes for obese patients, who are known to have worse prognosis and increased toxicity after DD ACT.
Patients treated with tDD had similar BCRFS regardless of the cumulative epirubicin dose (P = 0.495), while obese patients in this group body mass index (BMI) ≥30 had improved BCRFS compared with nonobese ones (BMI <30) hazard ratio (HR) = 0.51, 95% confidence interval (CI) 0.30–0.89, P = 0.02. Moreover, tDD was associated with improved BCRFS compared with standard treatment only in obese patients (HR = 0.49, 95% CI 0.26–0.90, P = 0.022) but not in nonobese ones (HR = 0.79, 95% CI 0.60–1.04, P = 0.089). The differences were not formally statistically significant (P for interaction 0.175). There were no differences in terms of toxicity across the epirubicin dose levels or the BMI groups.
Dose tailoring is a feasible strategy that can potentially improve outcomes in obese patients without increasing toxicity and should be pursued in further clinical studies.
NCT00798070.
The purpose of the study was to evaluate and compare the prevalence and antimicrobial resistance of
in conventional and organic pigs from France and Sweden. Fecal or colon samples were collected at ...farms or at slaughterhouses and cultured for
. The minimum inhibitory concentrations of ciprofloxacin, nalidixic acid, streptomycin, tetracycline, erythromycin, and gentamicin were determined by microdilution for a total of 263 French strains from 114 pigs from 50 different farms and 82 Swedish strains from 144 pigs from 54 different farms. Erythromycin resistant isolates were examined for presence of the emerging rRNA methylase
(B) gene. The study showed that within the colon samples obtained in each country there was no significant difference in prevalence of
between pigs in organic and conventional productions France: conventional: 43/58 (74%); organic: 43/56 (77%) and Sweden: conventional: 24/36 (67%); organic: 20/36 (56%). In France, but not in Sweden, significant differences of percentages of resistant isolates were associated with production type (tetracycline, erythromycin) and the number of resistances was significantly higher for isolates from conventional pigs. In Sweden, the number of resistances of fecal isolates was significantly higher compared to colon isolates. The
(B) gene was not detected in the 87 erythromycin resistant strains tested.
One of the major goals of pharmacogenetics is to elucidate mechanisms and identify patients at increased risk of adverse events (AEs). To date, however, there have been only a few successful examples ...of this type of approach. In this paper, we describe a retrospective case-control pharmacogenetic study of an AE of unknown mechanism, characterized by elevated levels of serum alanine aminotransferase (ALAT) during long-term treatment with the oral direct thrombin inhibitor ximelagatran. The study was based on 74 cases and 130 treated controls and included both a genome-wide tag single nucleotide polymorphism and large-scale candidate gene analysis. A strong genetic association between elevated ALAT and the MHC alleles DRB1(*)07 and DQA1(*)02 was discovered and replicated, suggesting a possible immune pathogenesis. Consistent with this hypothesis, immunological studies suggest that ximelagatran may have the ability to act as a contact sensitizer, and hence be able to stimulate an adaptive immune response.
Wheat‐dependent exercise‐induced anaphylaxis (WDEIA) is characterized by anaphylactic reactions after wheat ingestion and physical exercise. IgE antibodies to recombinant ω5‐gliadin are detectable in ...a majority of WDEIA patients, but other wheat allergens may also play a role in elicitation of WDEIA. Here, we performed a comprehensive analysis of IgE reactivity to different wheat proteins in 17 patients with confirmed WDEIA by ImmunoCAP research prototypes and a semi‐quantitative microarray immunoassay with α/β/γ‐gliadin, high‐molecular‐weight (HMW) glutenin, alpha‐amylase inhibitor (AAI) dimer, and wheat lipid transfer protein (LTP). By ImmunoCAP, IgE to recombinant ω5‐gliadin was detectable in 14/17 patients (82%), to α/β/γ‐gliadin in 82% including the three patients lacking IgE to ω5‐gliadin, and to HMW glutenin in 59%. The microarray revealed specifically γ‐gliadin as the second most important allergen. These results demonstrate the additional diagnostic value of α/β‐ and γ‐gliadin in particular in ω5‐gliadin‐negative patients in the diagnosis of WDEIA.
The genetic variation in a partially asexual organism is investigated by two models suited for different time scales. Only selectively neutral variation is considered. Model 1 shows, by the use of a ...coalescence argument, that three sexually derived individuals per generation are sufficient to give a population the same pattern of allelic variation as found in fully sexually reproducing organisms. With less than one sexual event every third generation, the characteristic pattern expected for asexual organisms appear, with strong allelic divergence between the gene copies in individuals. At intermediary levels of sexuality, a complex situation reigns. The pair‐wise allelic divergence under partial sexuality exceeds, however, always the corresponding value under full sexuality. These results apply to large populations with stable reproductive systems. In a more general framework, Model 2 shows that a small number of sexual individuals per generation is sufficient to make an apparently asexual population highly genotypically variable. The time scale in terms of generations needed to produce this effect is given by the population size and the inverse of the rate of sexuality.
Global warming is causing Atlantification of water masses and concomitant changes in food webs in the Barents Sea region. To determine whether changes that have been documented at lower trophic ...levels are impacting the diet of ringed seals (
Pusa hispida
) gastrointestinal tracts (GITs) from 99 coastal-feeding ringed seals, collected in western Spitsbergen, Svalbard, were analysed via identification of hard-parts. The study animals were shot in spring (
n
= 30; April–July) or autumn (
n
= 69; August–October) during four consecutive years (2014–2017). Thirty different prey types were identified, but most seals (55.6%) had consumed between 2 and 4 different types of prey. Polar cod (
Boreogadus saida
) dominated the diet of the ringed seals in terms of relative biomass (
B
i
= 60.0%) and frequency of occurrence (
FO
i
= 86.9%), followed by pricklebacks (Stichaeidae;
B
i
= 23.4%;
FO
i
= 79.8%). Redundancy analysis (RDA) revealed that year was the only significant predictor explaining variance in autumn diet composition (RDA,
F
3
= 4.96,
AIC
= − 76.49,
p
≤ 0.0050; blubber content and maturity/sex group were not significant). Blue whiting (
Micromesistius poutassou
) occurred in the diet in small quantities; this Atlantic fish species has not previously been documented in the ringed seals’ diet. Atlantic cod (
Gadus morhua
) had the highest
B
i
(9.2%) among Atlantic prey types. However, despite major changes in the last decade in the fish and zooplankton community in western Svalbard, and consumption of a few Atlantic prey types, the ringed seals’ diet in Svalbard continues to be dominated by Arctic prey, especially polar cod.
The aim of this study was to evaluate whether the HER2 expression in breast cancer is retained in metastases. The HER2 expression in primary tumours and the corresponding lymph node metastases were ...evaluated in parallel samples from 47 patients. The HercepTest was used for immunohistochemical analyses of HER2 overexpression in all cases. CISH/FISH was used for analysis of gene amplification in some cases. HER2 overexpression (HER2-scores 2+ or 3+) was found in 55% of both the primary tumours and of the lymph node metastases. There were only small changes in the HER2-scores; six from 1+ to 0 and one from 3+ to 2+ when the metastases were compared to the corresponding primary tumours. However, there were no cases with drastic changes in HER2 expression between the primary tumours and the corresponding lymph node metastases. The literature was reviewed for similar investigations, and it is concluded that breast cancer lymph node metastases generally overexpress HER2 to the same extent as the corresponding primary tumours. This also seems to be the case when distant metastases are considered. It has been noted that not all patients with HER2 overexpression respond to HER2-targeted Trastuzumab treatment. The stability in HER2 expression is encouraging for efforts to develop complementary forms of therapy, for example, therapy with radionuclide-labelled Trastuzumab.
This paper reports an investigation of the dynamic behavior of a GaN-HEMT, which is subjected to high reverse gate voltage pulses. These stress conditions are typical for robust LNAs under RF input ...overdrive and their quick recovery to the initial operating state is crucial but scarcely investigated. It was found that trapping effects similar to those in power amplifiers may play a major role in the impairment and recovery process of GaN HEMT-based LNAs with Fe-doping in the buffer. The interaction with traps and the resulting adverse effects on the device operation were found to be in the range of microseconds. Measurements at elevated temperatures suggest that the recovery time of the transistor is mainly governed by the emission of occupied traps, which takes place in the order of milliseconds. The characterization method is suited to predict the transient effects of LNAs under input overdrive.
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