Profiles of disordered eating behaviour in type 1 diabetes using the DEPS-R and behaviour and glycaemic outcomes in a real-life setting.

AIMS: The Diabetes Eating Problems Survey - Revised (DEPS-R) is commonly used to assess disordered eating behaviour (DEB) in individuals with type 1 diabetes and has advantages compared to other measures not specifically tailored to diabetes. A score ≥20 on the DEPS-R is used to indicate clinically significant DEB; however, it does not distinguish between eating disorder (ED) phenotypes necessary to guide treatment decisions, limiting clinical utility. METHODS: The current study used latent class analysis to identify distinct person-centred profiles of DEB in adults with type 1 diabetes using the DEPS-R. Analysis of Variance with Games Howell post-hoc comparisons was then conducted to examine the correspondence between the profiles and binge eating, insulin restriction and glycaemic control (HbA1c, mean blood glucose, and percent time spent in hyperglycaemia) during 3 days of assessment in a real-life setting. RESULTS: Latent class analysis indicated a 4-class solution, with patterns of item endorsement suggesting the following profiles: Bulimia, Binge Eating, Overeating and Low Pathology. Differences in binge eating, insulin restriction and glycaemic control were observed between profiles during 3 days of at-home assessment. The Bulimia profile was associated with highest HbA1c and 3-day mean blood glucose. CONCLUSIONS: There are common patterns of responses on the DEPS-R that appear to reflect different ED phenotypes. Profiles based on the DEPS-R corresponded with behaviour in the real-life setting as expected and were associated with different glycaemic outcomes. Results may have implications for the use of the DEPS-R in research and clinical settings.

Long-term health outcomes associated with hydration status.

Body water balance is determined by fundamental homeostatic mechanisms that maintain stable volume, osmolality and the composition of extracellular and intracellular fluids. Water balance is maintained by multiple mechanisms that continuously match water losses through urine, the skin, the gastrointestinal tract and respiration with water gains achieved through drinking, eating and metabolic water production. Hydration status is determined by the state of the water balance. Underhydration occurs when a decrease in body water availability, due to high losses or low gains, stimulates adaptive responses within the water balance network that are aimed at decreasing losses and increasing gains. This stimulation is also accompanied by cardiovascular adjustments. Epidemiological and experimental studies have linked markers of low fluid intake and underhydration - such as increased plasma concentration of vasopressin and sodium, as well as elevated urine osmolality - with an increased risk of new-onset chronic diseases, accelerated aging and premature mortality, suggesting that persistent activation of adaptive responses may be detrimental to long-term health outcomes. The causative nature of these associations is currently being tested in interventional trials. Understanding of the physiological responses to underhydration may help to identify possible mechanisms that underlie potential adverse, long-term effects of underhydration and inform future research to develop preventative and treatment approaches to the optimization of hydration status.

Mast cell activation and degranulation in acute artery injury: A target for post-operative therapy.

The increasing incidence of cardiovascular disease (CVD) has led to a significant ongoing need to address this surgically through coronary artery bypass grafting (CABG) and percutaneous coronary interventions (PCI). From this, there continues to be a substantial burden of mortality and morbidity due to complications arising from endothelial damage, resulting in restenosis. Whilst mast cells (MC) have been shown to have a causative role in atherosclerosis and other vascular diseases, including restenosis due to vein engraftment; here, we demonstrate their rapid response to arterial wire injury, recapitulating the endothelial damage seen in PCI procedures. Using wild-type mice, we demonstrate accumulation of MC in the femoral artery post-acute wire injury, with rapid activation and degranulation, resulting in neointimal hyperplasia, which was not observed in MC-deficient KitW-sh/W-sh mice. Furthermore, neutrophils, macrophages, and T cells were abundant in the wild-type mice area of injury but reduced in the KitW-sh/W-sh mice. Following bone-marrow-derived MC (BMMC) transplantation into KitW-sh/W-sh mice, not only was the neointimal hyperplasia induced, but the neutrophil, macrophage, and T-cell populations were also present in these transplanted mice. To demonstrate the utility of MC as a target for therapy, we administered the MC stabilizing drug, disodium cromoglycate (DSCG) immediately following arterial injury and were able to show a reduction in neointimal hyperplasia in wild-type mice. These studies suggest a critical role for MC in inducing the conditions and coordinating the detrimental inflammatory response seen post-endothelial injury in arteries undergoing revascularization procedures, and by targeting the rapid MC degranulation immediately post-surgery with DSCG, this restenosis may become a preventable clinical complication.

Exploration of model misspecification in latent class methods for longitudinal data: Correlation structure matters.

Modeling longitudinal trajectories and identifying latent classes of trajectories is of great interest in biomedical research, and software to identify latent classes of such is readily available for latent class trajectory analysis (LCTA), growth mixture modeling (GMM) and covariance pattern mixture models (CPMM). In biomedical applications, the level of within-person correlation is often non-negligible, which can impact the model choice and interpretation. LCTA does not incorporate this correlation. GMM does so through random effects, while CPMM specifies a model for within-class marginal covariance matrix. Previous work has investigated the impact of constraining covariance structures, both within and across classes, in GMMs-an approach often used to solve convergence problems. Using simulation, we focused specifically on how misspecification of the temporal correlation structure and strength, but correct variances, impacts class enumeration and parameter estimation under LCTA and CPMM. We found (1) even in the presence of weak correlation, LCTA often does not reproduce original classes, (2) CPMM performs well in class enumeration when the correct correlation structure is selected, and (3) regardless of misspecification of the correlation structure, both LCTA and CPMM give unbiased estimates of the class trajectory parameters when the within-individual correlation is weak and the number of classes is correctly specified. However, the bias increases markedly when the correlation is moderate for LCTA and when the incorrect correlation structure is used for CPMM. This work highlights the importance of correlation alone in obtaining appropriate model interpretations and provides insight into model choice.

Middle-age high normal serum sodium as a risk factor for accelerated biological aging, chronic diseases, and premature mortality.

BACKGROUND: It is known that some people age faster than others, some people live into old age disease-free, while others develop age-related chronic diseases. With a rapidly aging population and an emerging chronic diseases epidemic, finding mechanisms and implementing preventive measures that could slow down the aging process has become a new challenge for biomedical research and public health. In mice, lifelong water restriction shortens the lifespan and promotes degenerative changes. Here, we test the hypothesis that optimal hydration may slow down the aging process in humans. METHODS: We performed a cohort analysis of data from the Atherosclerosis Risk in Communities study with middle-age enrollment (45-66 years, n = 15,752) and 25 years follow-up. We used serum sodium, as a proxy for hydration habits. To estimate the relative speed of aging, we calculated the biological age (BA) from age-dependent biomarkers and assessed risks of chronic diseases and premature mortality. FINDINGS: The analysis showed that middle age serum sodium >142 mmol/l is associated with a 39% increased risk to develop chronic diseases (hazard ratio [HR] = 1.39, 95% confidence interval [CI]:1.18-1.63) and >144 mmol/l with 21% elevated risk of premature mortality (HR = 1.21, 95% CI:1.02-1.45). People with serum sodium >142 mmol/l had up to 50% higher odds to be older than their chronological age (OR = 1.50, 95% CI:1.14-1.96). A higher BA was associated with an increased risk of chronic diseases (HR = 1.70, 95% CI:1.50-1.93) and premature mortality (HR = 1.59, 95% CI 1.39-1.83). INTERPRETATION: People whose middle-age serum sodium exceeds 142 mmol/l have increased risk to be biologically older, develop chronic diseases and die at younger age. Intervention studies are needed to confirm the link between hydration and aging. FUNDING: This work was funded by Intramural Research program of the National Heart, Lung, and Blood Institute (NHLBI). The ARIC study has been funded in whole or in part with federal funds from the NHLBI; the National Institutes of Health (NIH); and the Department of Health and Human Services.

Solvent effect on the Spectra of Methylene Green and Methylene Blue.

This investigation focuses on dyes that differ only in the nitro substituent. The NO2 group leads to a strong hardening of the fluorescence at 298 K. In methylene green (MG) the excitation energy migrates to the system of triplet states. This non-radiative process causes the MG fuorescence absent or too low compared to methylene blue (MB). Moreover, laser-induced fluorescence is completely absent for MG in the investigated solvents. However, at liquid nitrogen temperature, we recorded fluorescence for MG in ethanol 250 times higher than at room temperature and phosphorescence too. The intensity of the MB fluorescence band in ethanol at 77 K is 6 times higher than at room temperature. According to the results of this study, the lifetime in the excited state decreases in the following order: isopropanol > acetonitrile≈ethanol≈dimethyl sulfoxide > > water for MG and chloroform > acetonitrile≈ethanol≈dimethyl sulfoxide > > water≈isopropanol for MB. In addition, MG has phosphorescence in ethanol at 780 nm (12,800 cm-1) and in chloroform at 810 nm (12,300 cm-1).

Amorphous FeCoCrSiB Ribbons with Tailored Anisotropy for the Development of Magnetic Elements for High Frequency Applications.

The ferromagnetic resonance (FMR) in the frequency range of 0.5 to 12.5 GHz has been investigated as a function of external magnetic field for rapidly quenched Fe3Co67Cr3Si15B12 amorphous ribbons with different features of the effective magnetic anisotropy. Three states of the ribbons were considered: as-quenched without any treatment; after relaxation annealing without stress at the temperature of 350 °C during 1 h; and after annealing under specific stress of 230 MPa at the temperature of 350 °C during 1 h. For FMR measurements, we adapted a technique previously proposed and tested for the case of microwires. Here, amorphous ribbons were studied using the sample holder based on a commercial SMA connector. On the basis of the measurements of the reflection coefficient S11, the total impedance including its real and imaginary components was determined to be in the frequency range of 0.5 to 12.5 GHz. In order to confirm the validity of the proposed technique, FMR was also measured by the certified cavity perturbation technique using a commercial Bruker spectrometer operating at X-band frequency of 9.39 GHz. As part of the characterization of the ribbons used for microwave measurements, comparative analysis was performed of X-ray diffraction, optical microscopy, transmission electron microscopy, inductive magnetic hysteresis loops, vibrating sample magnetometry, magneto-optical Kerr effect (including magnetic domains) and magnetoimpedance data for of all samples.

Middle age serum sodium levels in the upper part of normal range and risk of heart failure.

AIMS: With increasing prevalence of heart failure (HF) owing to the ageing population, identification of modifiable risk factors is important. In a mouse model, chronic hypohydration induced by lifelong water restriction promotes cardiac fibrosis. Hypohydration elevates serum sodium. Here, we evaluate the association of serum sodium at middle age as a measure of hydration habits with risk to develop HF. METHODS AND RESULTS: We analysed data from Atherosclerosis Risk in Communities study with middle age enrolment (45-66 years) and 25 years of follow-up. Participants without water balance dysregulation were selected: serum sodium within normal range (135-146 mmol/L), not diabetic, not obese and free of HF at baseline (N = 11 814). In time-to-event analysis, HF risk was increased by 39% if middle age serum sodium exceeded 143 mmol/L corresponding to 1% body weight water deficit [hazard ratio 1.39, 95% confidence interval (CI) 1.14-1.70]. In a retrospective case-control analysis performed on 70- to 90-year-old attendees of Visit 5 (N = 4961), serum sodium of 142.5-143 mmol/L was associated with 62% increase in odds of left ventricular hypertrophy (LVH) diagnosis [odds ratio (OR) 1.62, 95% CI 1.03-2.55]. Serum sodium above 143 mmol/L was associated with 107% increase in odds of LVH (OR 2.07, 95% CI 1.30-3.28) and 54% increase in odds of HF (OR 1.54, 95% CI 1.06-2.23). As a result, prevalence of HF and LVH was increased among 70- to 90-year-old participants with higher middle age serum sodium. CONCLUSION: Middle age serum sodium above 142 mmol is a risk factor for LVH and HF. Maintaining good hydration throughout life may slow down decline in cardiac function and decrease prevalence of HF.

The theoretical modeling of the dynamic compaction process of forest soil.

Due to the growing demand for timber, forest soils are increasingly exposed to mechanical disturbances, caused by forestry equipment. Even though using skidding machines to transport wood is detrimental to the physical state of the soil, this method remains the most common. Hence, there is a need to model the impact of skidding systems on the upper (fertile) layer of the soil. This study aims to develop such a model using the D'Alembert principle, the method of Laplace transforms, and a modified Kelvin-Voigt model. The work shows that subdividing the tractor-bundle-soil system makes it possible to consider the dynamic effect of the vibrating tractor on the soil and soil's ability to undergo deformation separately. In addition, the study developed individual models for the first subsystem that determine vibration effects on soil caused by an unloaded tractor and two loaded skidding systems using different methods of semi-suspended skidding. The present findings can be used to predict the degree of dynamic soil compaction without conducting direct on-site experiments and thus minimize the negative impact of forestry operations on the local ecosystem. The current data also allow simplifying design models for complex forwarders.

Global Expansion of Linezolid-Resistant Coagulase-Negative Staphylococci.

Coagulase-negative staphylococci (CoNS) for a long time were considered avirulent constituents of the human and warm-blooded animal microbiota. However, at present, S. epidermidis, S. haemolyticus, and S. hominis are recognized as opportunistic pathogens. Although linezolid is not registered for the treatment of CoNS infections, it is widely used off-label, promoting emergence of resistance. Bioinformatic analysis based on maximum-likelihood phylogeny and Bayesian clustering of the CoNS genomes obtained in the current study and downloaded from public databases revealed the existence of international linezolid-resistant lineages, each of which probably had a common predecessor. Linezolid-resistant S. epidermidis sequence-type (ST) 2 from Russia, France, and Germany formed a compact group of closely related genomes with a median pairwise single nucleotide polymorphism (SNP) difference of fewer than 53 SNPs, and a common ancestor of this lineage appeared in 1998 (1986-2006) before introduction of linezolid in practice. Another compact group of linezolid-resistant S. epidermidis was represented by ST22 isolates from France and Russia with a median pairwise SNP difference of 40; a common ancestor of this lineage appeared in 2011 (2008-2013). Linezolid-resistant S. hominis ST2 from Russia, Germany, and Brazil also formed a group with a high-level genome identity with median 25.5 core-SNP differences; the appearance of the common progenitor dates to 2003 (1996-2012). Linezolid-resistant S. hominis isolates from Russia demonstrated associated resistance to teicoplanin. Analysis of a midpoint-rooted phylogenetic tree of the group confirmed the genetic proximity of Russian and German isolates; Brazilian isolates were phylogenetically distant. repUS5-like plasmids harboring cfr were detected in S. hominis and S. haemolyticus.

Structure-based insights into evolution of rhodopsins.

Rhodopsins, most of which are proton pumps generating transmembrane electrochemical proton gradients, span all three domains of life, are abundant in the biosphere, and could play a crucial role in the early evolution of life on earth. Whereas archaeal and bacterial proton pumps are among the best structurally characterized proteins, rhodopsins from unicellular eukaryotes have not been well characterized. To fill this gap in the current understanding of the proton pumps and to gain insight into the evolution of rhodopsins using a structure-based approach, we performed a structural and functional analysis of the light-driven proton pump LR (Mac) from the pathogenic fungus Leptosphaeria maculans. The first high-resolution structure of fungi rhodopsin and its functional properties reveal the striking similarity of its membrane part to archaeal but not to bacterial rhodopsins. We show that an unusually long N-terminal region stabilizes the protein through direct interaction with its extracellular loop (ECL2). We compare to our knowledge all available structures and sequences of outward light-driven proton pumps and show that eukaryotic and archaeal proton pumps, most likely, share a common ancestor.

STAT3 modulates reprogramming efficiency of human somatic cells; insights from autosomal dominant Hyper IgE syndrome caused by STAT3 mutations.

Human induced pluripotent stem cell (iPSC) technology has opened exciting opportunities for stem-cell-based therapy. However, its wide adoption is precluded by several challenges including low reprogramming efficiency and potential for malignant transformation. Better understanding of the molecular mechanisms of the changes that cells undergo during reprograming is needed to improve iPSCs generation efficiency and to increase confidence for their clinical use safety. Here, we find that dominant negative mutations in STAT3 in patients with autosomal-dominant hyper IgE (Job's) syndrome (AD-HIES) result in greatly reduced reprograming efficiency of primary skin fibroblasts derived from skin biopsies. Analysis of normal skin fibroblasts revealed upregulation and phosphorylation of endogenous signal transducer and activator of transcription 3 (STAT3) and its binding to the NANOG promoter following transduction with OKSM factors. This coincided with upregulation of NANOG and appearance of cells expressing pluripotency markers. Upregulation of NANOG and number of pluripotent cells were greatly reduced throughout the reprograming process of AD-HIES fibroblasts that was restored by over-expression of functional STAT3. NANOGP8, the human-specific NANOG retrogene that is often expressed in human cancers, was also induced during reprogramming, to very low but detectable levels, in a STAT3-dependent manner. Our study revealed the critical role of endogenous STAT3 in facilitating reprogramming of human somatic cells.

Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome.

There are more than 7000 described rare diseases, most lacking specific treatment. Autosomal-dominant hyper-IgE syndrome (AD-HIES, also known as Job's syndrome) is caused by mutations in STAT3. These patients present with immunodeficiency accompanied by severe nonimmunological features, including skeletal, connective tissue, and vascular abnormalities, poor postinfection lung healing, and subsequent pulmonary failure. No specific therapies are available for these abnormalities. Here, we investigated underlying mechanisms in order to identify therapeutic targets. Histological analysis of skin wounds demonstrated delayed granulation tissue formation and vascularization during skin-wound healing in AD-HIES patients. Global gene expression analysis in AD-HIES patient skin fibroblasts identified deficiencies in a STAT3-controlled transcriptional network regulating extracellular matrix (ECM) remodeling and angiogenesis, with hypoxia-inducible factor 1α (HIF-1α) being a major contributor. Consistent with this, histological analysis of skin wounds and coronary arteries from AD-HIES patients showed decreased HIF-1α expression and revealed abnormal organization of the ECM and altered formation of the coronary vasa vasorum. Disease modeling using cell culture and mouse models of angiogenesis and wound healing confirmed these predicted deficiencies and demonstrated therapeutic benefit of HIF-1α-stabilizing drugs. The study provides mechanistic insights into AD-HIES pathophysiology and suggests potential treatment options for this rare disease.

Generation of human induced pluripotent stem cells (NIHTVBi004-A, NIHTVBi005-A, NIHTVBi006-A, NIHTVBi007-A, NIHTVBi008-A) from 5 CADASIL patients with NOTCH3 mutation.

We have successfully generated induced pluripotent stem cell (iPSC) lines derived from peripheral blood mononuclear cells of five patients with Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). These cells carry the genetic NOTCH3 mutation present in their parental cells. These iPSC cells exhibited normal karyotype and phenotype, which were sustained through propagation. Furthermore, these iPSCs displayed the capacity of differentiating toward the three germ layers in vitro.

Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease.

RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1-7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1-/- mice died postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.

Generation of human induced pluripotent stem cell lines (NIHTVBi011-A, NIHTVBi012-A, NIHTVBi013-A) from autosomal dominant Hyper IgE syndrome (AD-HIES) patients carrying STAT3 mutation.

Autosomal dominant Hyper IgE syndrome (AD-HIES), a rare immune deficiency affecting fewer than one per million people, is caused by heterozygous deleterious mutations in STAT3. STAT3 signaling plays crucial roles in basic cellular functions affecting broad aspects of cellular homeostasis. Accordingly, in addition to immunological deficits, patients experience severe multisystem non-immunological features. Human induced pluripotent stem cells (hiPSC) are well established as in vivo disease models for various human pathologies. We describe the generation of iPSC from three AD-HIES patients. These iPSCs express pluripotency markers, differentiate into three germ layers, have normal karyotype and similar genome identity to parental cells.

Efficacy of a Goal Setting and Implementation Planning Intervention on Firefighters' Cardiorespiratory Fitness.

Bycura, DK, Dmitrieva, NO, Santos, AC, Waugh, KL, and Ritchey, KM. Efficacy of a Goal Setting and Implementation Planning Intervention on Firefighters' Cardiorespiratory Fitness. J Strength Cond Res 33(11): 3151-3161, 2019-The purpose of this study was to assess the effectiveness of a goal setting and implementation planning (GSIP) intervention on cardiorespiratory fitness among firefighters. Male career firefighters (N = 20) from a large municipal fire department were assigned to an intervention arm (n = 12) or passive control arm (n = 8) of a 14-week study involving cardiorespiratory exercise. The intervention consisted of GSIP coaching at baseline and support throughout the study. Cardiorespiratory fitness was assessed through a standardized physical protocol for firefighters (Candidate Physical Ability Test) at baseline, at 6 weeks, and at 14 weeks time points, using the Cosmed K4b portable metabolic system to measure physiological variables. Using intention-to-treat principles, we employed a 2-level multilevel model to examine the effect of intervention group on intercept and change over time on primary outcomes of interest: oxygen transport and utilization (VO2), heart rate (HR), and respiratory exchange ratio (R). Results demonstrated that the intervention and control groups both exhibited a significant increase in VO2 (B = 0.143, SE = 0.025, p < 0.001) and a decline in R (B = -0.003. SE = 0.001, p < 0.01) over the course of the study. Although both groups exhibited improvements on 2 of the 3 cardiorespiratory outcomes, subjects assigned to the intervention did not exhibit superior outcomes when compared to the control group. Given the improvements we observed in 2 out of 3 outcomes across both conditions, future research may consider testing effectiveness of interventions consisting of functional training exercises that closely translate to firefighting tasks over time periods sufficient to elicit aerobic metabolic adaptations.

Suboptimal hydration remodels metabolism, promotes degenerative diseases, and shortens life.

With increased life expectancy worldwide, there is an urgent need for improving preventive measures that delay the development of age-related degenerative diseases. Here, we report evidence from mouse and human studies that this goal can be achieved by maintaining optimal hydration throughout life. We demonstrate that restricting the amount of drinking water shortens mouse lifespan with no major warning signs up to 14 months of life, followed by sharp deterioration. Mechanistically, water restriction yields stable metabolism remodeling toward metabolic water production with greater food intake and energy expenditure, an elevation of markers of inflammation and coagulation, accelerated decline of neuromuscular coordination, renal glomerular injury, and the development of cardiac fibrosis. In humans, analysis of data from the Atherosclerosis Risk in Communities (ARIC) study revealed that hydration level, assessed at middle age by serum sodium concentration, is associated with markers of coagulation and inflammation and predicts the development of many age-related degenerative diseases 24 years later. The analysis estimates that improving hydration throughout life may greatly decrease the prevalence of degenerative diseases, with the most profound effect on dementia, heart failure (HF), and chronic lung disease (CLD), translating to the development of these diseases in 3 million fewer people in the United States alone.