Aims/hypothesis
Individuals with type 2 diabetes have aberrant intestinal microbiota. However, recent studies suggest that metformin alters the composition and functional potential of gut microbiota, ...thereby interfering with the diabetes-related microbial signatures. We tested whether specific gut microbiota profiles are associated with prediabetes (defined as fasting plasma glucose of 6.1–7.0 mmol/l or HbA
1c
of 42–48 mmol/mol 6.0–6.5%) and a range of clinical biomarkers of poor metabolic health.
Methods
In the present case–control study, we analysed the gut microbiota of 134 Danish adults with prediabetes, overweight, insulin resistance, dyslipidaemia and low-grade inflammation and 134 age- and sex-matched individuals with normal glucose regulation.
Results
We found that five bacterial genera and 36 operational taxonomic units (OTUs) were differentially abundant between individuals with prediabetes and those with normal glucose regulation. At the genus level, the abundance of
Clostridium
was decreased (mean log
2
fold change −0.64 (SEM 0.23),
p
adj
= 0.0497), whereas the abundances of
Dorea
,
Ruminococcus
,
Sutterella
and
Streptococcus
were increased (mean log
2
fold change 0.51 (SEM 0.12),
p
adj
= 5 × 10
−4
; 0.51 (SEM 0.11),
p
adj
= 1 × 10
−4
; 0.60 (SEM 0.21),
p
adj
= 0.0497; and 0.92 (SEM 0.21),
p
adj
= 4 × 10
−4
, respectively). The two OTUs that differed the most were a member of the order Clostridiales (OTU 146564) and
Akkermansia muciniphila
, which both displayed lower abundance among individuals with prediabetes (mean log
2
fold change −1.74 (SEM 0.41),
p
adj
= 2 × 10
−3
and −1.65 (SEM 0.34),
p
adj
= 4 × 10
−4
, respectively). Faecal transfer from donors with prediabetes or screen-detected, drug-naive type 2 diabetes to germfree Swiss Webster or conventional C57BL/6 J mice did not induce impaired glucose regulation in recipient mice.
Conclusions/interpretation
Collectively, our data show that individuals with prediabetes have aberrant intestinal microbiota characterised by a decreased abundance of the genus
Clostridium
and the mucin-degrading bacterium
A. muciniphila
. Our findings are comparable to observations in overt chronic diseases characterised by low-grade inflammation.
Background
Solid‐organ transplantation (SOT) has become commonly used in children and is associated with excellent survival rates into adulthood. Data regarding long‐term respiratory outcomes ...following pediatric transplantation are lacking. We aimed to describe the prevalence and nature of respiratory pathology following pediatric heart, kidney, and liver transplant, and identify potential risk factors for respiratory complications.
Methods
Retrospective review involving all children under active follow‐up at the provincial transplant service in British Columbia, Canada, following SOT.
Results
Of 118 children, 33% experienced respiratory complications, increasing to 54% in heart transplant recipients. Chronic or recurrent cough with persistent chest x‐ray changes was the most common clinical picture, and most infections were with nonopportunistic organisms typically found in otherwise healthy children. A history of respiratory illness before transplant was significantly associated with risk of posttransplant respiratory complications. Eight percentage8% were diagnosed with bronchiectasis, which was more common in recipients of heart and kidney transplant. Bronchiectasis was associated with recurrent hospital admissions with lower respiratory tract infections, treatment of acute rejection episodes, and treatment with sirolimus.
Interpretation
Respiratory morbidity is common after pediatric SOT, and bronchiectasis rates were disproportionately high in this patient group. We hypothesize that this relates to recurrent infections resulting from iatrogenic immunosuppression. Direct pulmonary toxicity from immunosuppression drugs may also be contributory. A high index of suspicion for respiratory complications is needed following childhood SOT, particularly in those with a history of respiratory disease before transplant, experiencing recurrent or severe respiratory tract infections, or exposed to intensified immunosuppression.
An airfoil optimization method for wind turbine applications that controls the loss in performance due to leading edge contamination is developed and tested. The method uses the ...class‐shape‐transformation technique to parametrize the airfoil geometry and uses an adjusted version of the panel code XFOIL to calculate the aerodynamic performance. To find optimal airfoil shapes, the derivative‐free Covariance Matrix Adaptation Evolution Strategy is used in combination with an adaptive penalty function. The method is tested for the design of airfoils for the outer part of a megawatt‐class wind turbine rotor blade, and the results are compared with airfoils from Delft University. It is found that the method is able to automatically create airfoils with equal or improved performance compared with the Delft designs. For the tested application, the adjustments performed to the XFOIL code improve the maximum lift, post stall, and the overall drag predictions.
A
bstract
In this work, we use an extension of the quantization condition, given in ref.
1
, to numerically explore the finite-volume spectrum of three relativistic particles, in the case that ...two-particle subsets are either resonant or bound. The original form of the relativistic three-particle quantization condition was derived under a technical assumption on the two- particle K matrix that required the absence of two-particle bound states or narrow two- particle resonances. Here we describe how this restriction can be lifted in a simple way using the freedom in the definition of the K-matrix-like quantity that enters the quantization condition. With this in hand, we extend previous numerical studies of the quantization condition to explore the finite-volume signature for a variety of two- and three-particle interactions. We determine the spectrum for parameters such that the system contains both dimers (two-particle bound states) and one or more trimers (in which all three particles are bound), and also for cases where the two-particle subchannel is resonant. We also show how the quantization condition provides a tool for determining infinite-volume dimer- particle scattering amplitudes for energies below the dimer breakup. We illustrate this for a series of examples, including one that parallels physical deuteron-nucleon scattering. All calculations presented here are restricted to the case of three identical scalar particles.
Growth differentiation factor 15 (GDF15; also known as MIC-1) is a divergent member of the TGF-β superfamily and is associated with body-weight regulation in humans and rodents. However, the cognate ...receptor of GDF15 is unknown. Here we show that GDF15 binds specifically to GDNF family receptor α-like (GFRAL) with high affinity, and that GFRAL requires association with the coreceptor RET to elicit intracellular signaling in response to GDF15 stimulation. We also found that GDF15-mediated reductions in food intake and body weight of mice with obesity were abolished in GFRAL-knockout mice. We further found that GFRAL expression was limited to hindbrain neurons and not present in peripheral tissues, which suggests that GDF15-GFRAL-mediated regulation of food intake is by a central mechanism. Lastly, given that GDF15 did not increase energy expenditure in treated mice with obesity, the anti-obesity actions of the cytokine are likely driven primarily by a reduction in food intake.
Summary
Probabilistically formulated inverse problems can be solved using Monte Carlo-based sampling methods. In principle, both advanced prior information, based on for example, complex ...geostatistical models and non-linear forward models can be considered using such methods. However, Monte Carlo methods may be associated with huge computational costs that, in practice, limit their application. This is not least due to the computational requirements related to solving the forward problem, where the physical forward response of some earth model has to be evaluated. Here, it is suggested to replace a numerical complex evaluation of the forward problem, with a trained neural network that can be evaluated very fast. This will introduce a modeling error that is quantified probabilistically such that it can be accounted for during inversion. This allows a very fast and efficient Monte Carlo sampling of the solution to an inverse problem. We demonstrate the methodology for first arrival traveltime inversion of crosshole ground penetrating radar data. An accurate forward model, based on 2-D full-waveform modeling followed by automatic traveltime picking, is replaced by a fast neural network. This provides a sampling algorithm three orders of magnitude faster than using the accurate and computationally expensive forward model, and also considerably faster and more accurate (i.e. with better resolution), than commonly used approximate forward models. The methodology has the potential to dramatically change the complexity of non-linear and non-Gaussian inverse problems that have to be solved using Monte Carlo sampling techniques.
To test the hypothesis that lower extremity progressive resistance training (PRT) can improve muscle strength and functional capacity in patients with multiple sclerosis (MS) and to evaluate whether ...the improvements are maintained after the trial.
The present study was a 2-arm, 12-week, randomized controlled trial including a poststudy follow-up period of 12 weeks. Thirty-eight moderately impaired patients with MS were randomized to a PRT exercise group (n = 19) or a control group (n = 19). The exercise group completed a biweekly 12-week lower extremity PRT program and was afterward encouraged to continue training. After the trial, the control group completed the PRT intervention. Both groups were tested before and after 12 weeks of the trial and at 24 weeks (follow-up), where isometric muscle strength of the knee extensors (KE MVC) and functional capacity (FS; combined score of 4 tests) were evaluated.
KE MVC and FS improved after 12 weeks of PRT in the exercise group (KE MVC: 15.7% 95% confidence interval 4.3-27.0, FS: 21.5% 95% confidence interval 17.0-26.1; p < 0.05), and the improvements were better than in the control group (p < 0.05). The improvements of KE and FS in the exercise group persisted at follow-up after 24 weeks. Also, the exercise effects were reproduced in the control group during the 12-week posttrial PRT period.
Twelve weeks of intense progressive resistance training of the lower extremities leads to improvements of muscle strength and functional capacity in patients with multiple sclerosis, the effects persisting after 12 weeks of self-guided physical activity.
The present study provides level III evidence supporting the hypothesis that lower extremity progressive resistance training can improve muscle strength and functional capacity in patients with multiple sclerosis.
We present the first detailed elemental abundances in the ultra-faint Magellanic satellite galaxies Carina II (Car II) and Carina III (Car III). With high-resolution Magellan/MIKE spectroscopy, we ...determined the abundances of nine stars in Car II, including the first abundances of an RR Lyrae star in an ultra-faint dwarf galaxy (UFD), and two stars in Car III. The chemical abundances demonstrate that both systems are clearly galaxies and not globular clusters. The stars in these galaxies mostly display abundance trends matching those of other similarly faint dwarf galaxies: enhanced but declining /Fe ratios, iron-peak elements matching the stellar halo, and unusually low neutron-capture element abundances. One star displays a low outlying Sc/Fe = −1.0. We detect a large Ba scatter in Car II, likely due to inhomogeneous enrichment by low-mass asymptotic giant branch star winds. The most striking abundance trend is for Mg/Ca in Car II, which decreases from +0.4 to −0.4 and indicates clear variation in the initial progenitor masses of enriching core-collapse supernovae. So far, the only UFDs displaying a similar Mg/Ca trend are likely satellites of the Large Magellanic Cloud. We find two stars with Fe/H ≤ −3.5 whose abundances likely trace the first generation of metal-free Population III stars and are well fit by Population III core-collapse supernova yields. An appendix describes our new abundance uncertainty analysis that propagates line-by-line stellar parameter uncertainties.
The goal of this study was to evaluate the utility of urinary metabolomics for noninvasive diagnosis of T cell–mediated rejection (TCMR) in pediatric kidney transplant recipients. Urine samples (n = ...277) from 57 patients with surveillance or indication kidney biopsies were assayed for 134 unique metabolites by quantitative mass spectrometry. Samples without TCMR (n = 183) were compared to borderline tubulitis (n = 54) and TCMR (n = 30). Partial least squares discriminant analysis identified distinct classifiers for TCMR (area under receiver operating characteristic curve AUC = 0.892; 95% confidence interval CI 0.827–0.957) and borderline tubulitis (AUC = 0.836; 95% CI 0.781–0.892), respectively. Application of the TCMR classifier to borderline tubulitis samples yielded a discriminant score (−0.47 ± 0.33) mid‐way between TCMR (−0.20 ± 0.34) and No TCMR (−0.80 ± 0.32) (p < 0.001 for all comparisons). Discriminant scoring for combined borderline/TCMR versus No TCMR (AUC = 0.900; 95% CI 0.859–0.940) applied to a validation cohort robustly distinguished between samples with (−0.08 ± 0.52) and without (−0.65 ± 0.54, p < 0.001) borderline/TCMR (p < 0.001). The TCMR discriminant score was driven by histological t‐score, ct‐score, donor‐specific antibody and biopsy indication, and was unaffected by renal function, interstitial or microcirculatory inflammation, interstitial fibrosis or pyuria. These preliminary findings suggest that urinary metabolomics is a sensitive, specific and noninvasive tool for TCMR identification that is superior to serum creatinine, with minimal confounding by other allograft injury processes.
This study identifies patterns of urinary metabolites associated with the presence and severity of T cell‐mediated rejection, highlighting the potential utility of urinary metabolomics for noninvasive monitoring.
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