MicroRNA-194 modulates glucose metabolism and its skeletal muscle expression is reduced in diabetes

BACKGROUND: The regulation of microRNAs (miRNAs) at different stages of the progression of type 2 diabetes mellitus (T2DM) and their role in glucose homeostasis was investigated. METHODS: Microarrays were used to assess miRNA expression in skeletal muscle biopsies taken from healthy individuals and patients with pre-diabetes or T2DM, and insulin resistant offspring of rat dams fed a high fat diet during pregnancy. RESULTS: Twenty-three miRNAs were differentially expressed in patients with T2DM, and 7 in the insulin resistant rat offspring compared to their controls. Among these, only one miRNA was similarly regulated: miR-194 expression was significantly reduced by 25 to 50% in both the rat model and in human with pre-diabetes and established diabetes. Knockdown of miR-194 in L6 skeletal muscle cells induced an increase in basal and insulin-stimulated glucose uptake and glycogen synthesis. This occurred in conjunction with an increased glycolysis, indicated by elevated lactate production. Moreover, oxidative capacity was also increased as we found an enhanced glucose oxidation in presence of the mitochondrial uncoupler FCCP. When miR-194 was down-regulated in vitro, western blot analysis showed an increased phosphorylation of AKT and GSK3β in response to insulin, and an increase in expression of proteins controlling mitochondrial oxidative phosphorylation. CONCLUSIONS: Type 2 diabetes mellitus is associated with regulation of several miRNAs in skeletal muscle. Interestingly, miR-194 was a unique miRNA that appeared regulated across different stages of the disease progression, from the early stages of insulin resistance to the development of T2DM. We have shown miR-194 is involved in multiple aspects of skeletal muscle glucose metabolism from uptake, through to glycolysis, glycogenesis and glucose oxidation, potentially via mechanisms involving AKT, GSK3 and oxidative phosphorylation. MiR-194 could be down-regulated in patients with early features of diabetes as an adaptive response to facilitate tissue glucose uptake and metabolism in the face of insulin resistance

Some Model Theory of Free Groups

There are two main sets of results, both pertaining to the model theory of free groups. In the first set of results, we prove that non-abelian free groups of finite rank at least 3 or of countable rank are not A-homogeneous. We then build on the proof of this result to show that two classes of groups, namely finitely generated free groups and finitely generated elementary free groups, fail to form A-Fraisse classes and that the class of non-abelian limit groups fails to form a strong A-Fraisse class. The second main result is that if a countable group is elementarily equivalent to a non-abelian free group and all of its finitely generated abelian subgroups are cyclic, then the group is a union of a chain of regular NTQ groups (i.e., hyperbolic towers)

Factors Affecting Patient Reported Outcomes Following Tibial Plateau Fracture

Background/Objective:  Tibial Plateau Fractures (TPFs) account for ~1% of all fractures and ~8% of all fractures in the elderly. Despite the frequency and severity of TPFs there is a paucity of data evaluating factors that affect patient recovery after injury and surgical fixation. We hypothesized that patient reported outcomes are modulated by several variables including patient demographics, comorbidities, injury characteristics, and Social Determinants of Health (SDH).   Methods:  In this retrospective cohort study, we collected the interval patient reported outcome scores (PROs) of patients with TPFs treated with open reduction internal fixation occurring between February 2013 and November 2020. PROs included 1) Visual Analog Scale (VAS) pain scores, 2) Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference (PI) scores, and 3) Physical Function (PF) survey scores. Patient demographics, comorbidities, fracture characteristics, insurance status, and area deprivation index (ADI) of the patient’s residence were collected via electronic medical record review. Bivariate analyses of PRO scores to the aforementioned factors were performed using generalized estimating equations to account for participant repeated measures, with p<0.05 being considered significant.  Results:  196 patients were evaluated with >1 year follow-up. It was determined that patients’ insurance status affected their VAS (p0<.001), PI (p<0.001), and PF (p<0.001) scores. Patient ADI affected VAS (p<0.001) and PI (p=0.0026), with increased ADI scores resulting in worse PROs. Diabetes and depression were found to negatively impact VAS (p=0.010 & 0.008 respectively) and PI (p=0.0044 & 0.0048, respectively). Additionally, age and sex both influence VAS (p=0.0006 & 0.0033, respectively), and compartment syndrome was associated with decreased PF (p=0.0206).   Conclusion and Potential Impact:  To our knowledge, this is the first investigation to evaluate the effect of SDH on patient recovery following surgical fixation of TPFs—suggesting that insurance status and residence ADI scores are associated with worsened PROs. Further investigation is necessary to identify if these factors are independent of other covariates.&nbsp

Utility of Plasma Protein Biomarkers and Mid-Infrared Spectroscopy for Diagnosing Fracture-Related Infections: A Pilot Study.

OBJECTIVES: To compare a large panel of plasma protein inflammatory biomarkers and mid-infrared (MIR) spectral patterns between patients with confirmed fracture related infections (FRIs) and controls without infection. DESIGN: Prospective case-control. SETTING: Academic, level 1 trauma center. PATIENTS: Thirteen patients meeting confirmatory FRI criteria were matched to 13 controls based on age, time after surgery, and fracture region. INTERVENTION: Plasma levels of 49 proteins were measured using enzyme-linked immunosorbent assay (ELISA) techniques. Fourier transform infrared (FTIR) spectroscopy of dried films was used to obtain MIR spectra of plasma samples. MAIN OUTCOME MEASUREMENTS: Plasma protein levels and MIR spectra of samples. RESULTS: Multivariate analysis-based predictive model developed utilizing ELISA-based biomarkers had sensitivity, specificity, and accuracy of 69.2±0.0%, 99.9±1.0%, and 84.5±0.6%, respectively, with PDGF-AB/BB, CRP, and MIG selected as the minimum number of variables explaining group differences (P CONCLUSIONS: This pilot study demonstrates the feasibility of using a select panel of plasma proteins and FTIR spectroscopy to diagnose FRI. The preliminary data suggest that measurement of these select proteins and MIR spectra may be potential clinical tools to detect FRI. Further investigation of these biomarkers in a larger cohort of patients is warranted. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence

Mass calibration of optically selected DES clusters using a measurement of CMB-cluster lensing with SPTpol data

We use cosmic microwave background (CMB) temperature maps from the 500 deg2 SPTpol survey to measure the stacked lensing convergence of galaxy clusters from the Dark Energy Survey (DES) Year-3 redMaPPer (RM) cluster catalog. The lensing signal is extracted through a modified quadratic estimator designed to be unbiased by the thermal Sunyaev-Zel{'}dovich (tSZ) effect. The modified estimator uses a tSZ-free map, constructed from the SPTpol 95 and 150 GHz datasets, to estimate the background CMB gradient. For lensing reconstruction, we employ two versions of the RM catalog: a flux-limited sample containing 4003 clusters and a volume-limited sample with 1741 clusters. We detect lensing at a significance of 8.7 σ (6.7σ) with the flux(volume)-limited sample. By modeling the reconstructed convergence using the Navarro-Frenk-White profile, we find the average lensing masses to be M200m = (1.62 +0.32 −0.25 [stat.] ± 0.04 [sys.]) and (1.28 +0.14 −0.18 [stat.] ±0.03 [sys.])×1014 M⊙for the volume- and flux-limited samples respectively. The systematic error budget is much smaller than the statistical uncertainty and is dominated by the uncertainties in the RM cluster centroids. We use the volume-limited sample to calibrate the normalization of the mass-richness scaling relation, and find a result consistent with the galaxy weak-lensing measurements from DES (Mcclintock et al. 2018)

Dark Energy Survey Year 1 Results: A Precise H0 Measurement from DES Y1, BAO, and D/H Data

We combine Dark Energy Survey Year 1 clustering and weak lensing data with baryon acoustic oscillations and Big Bang nucleosynthesis experiments to constrain the Hubble constant. Assuming a flat ΛCDM model with minimal neutrino mass (Σm υ = 0.06 eV), we find H 0 = 67.4 -1.2+1.1 km s -1 Mpc -1 (68 per cent CL). This result is completely independent of Hubble constant measurements based on the distance ladder, cosmic microwave background anisotropies (both temperature and polarization), and strong lensing constraints. There are now five data sets that: (a) have no shared observational systematics; and (b) each constrains the Hubble constant with fractional uncertainty at the few percent level. We compare these five independent estimates, and find that, as a set, the differences between them are significant at the 2.5σ level (χ 2 /dof = 24/11, probability to exceed = 1.1 per cent). Having set the threshold for consistency at 3σ, we combine all five data sets to arrive at H 0 = 69.3 -0.6+0.4 km s -1 Mpc -

Mass Calibration of Optically Selected des Clusters Using a Measurement of CMB-cluster Lensing with SPTpol Data

We use cosmic microwave background (CMB) temperature maps from the 500 deg 2 SPTpol survey to measure the stacked lensing convergence of galaxy clusters from the Dark Energy Survey (DES) Year-3 redMaPPer (RM) cluster catalog. The lensing signal is extracted through a modified quadratic estimator designed to be unbiased by the thermal Sunyaev-Zel'dovich (tSZ) effect. The modified estimator uses a tSZ-free map, constructed from the SPTpol 95 and 150 GHz data sets, to estimate the background CMB gradient. For lensing reconstruction, we employ two versions of the RM catalog: a flux-limited sample containing 4003 clusters and a volume-limited sample with 1741 clusters. We detect lensing at a significance of 8.7σ(6.7σ) with the flux (volume)-limited sample. By modeling the reconstructed convergence using the Navarro-Frenk-White profile, we find the average lensing masses to be M 200m = (1.62 -0.25+0.32 [stat] ± 0.04 [sys.]) and (1.28 -0.18+0.14 [stat] ± 0.03[sys.])× 10 14 M ⊙ for the volume- and flux-limited samples, respectively. The systematic error budget is much smaller than the statistical uncertainty and is dominated by the uncertainties in the RM cluster centroids. We use the volume-limited sample to calibrate the normalization of the mass-richness scaling relation, and find a result consistent with the galaxy weak-lensing measurements from DES

A measurement of CMB cluster lensing with SPT and DES year 1 data

Clusters of galaxies gravitationally lens the cosmic microwave background (CMB) radiation, resulting in a distinct imprint in the CMB on arcminute scales. Measurement of this effect offers a promising way to constrain the masses of galaxy clusters, particularly those at high redshift. We use CMB maps from the South Pole Telescope Sunyaev–Zel’dovich (SZ) survey to measure the CMB lensing signal around galaxy clusters identified in optical imaging from first year observations of the Dark Energy Survey. The cluster catalogue used in this analysis contains 3697 members with mean redshift of z¯ = 0.45. We detect lensing of the CMB by the galaxy clusters at 8.1σ significance. Using the measured lensing signal, we constrain the amplitude of the relation between cluster mass and optical richness to roughly 17 per cent precision, finding good agreement with recent constraints obtained with galaxy lensing. The error budget is dominated by statistical noise but includes significant contributions from systematic biases due to the thermal SZ effect and cluster miscentring

Single-cell RNA sequencing of intramedullary canal tissue to improve methods for studying fracture repair biology

The ability to study the bone microenvironment of failed fracture healing may lead to biomarkers for fracture nonunion. Herein the authors describe a technique for isolating individual cells suitable for single-cell RNA sequencing analyses from intramedullary canal tissue collected by reaming during surgery. The purpose was to detail challenges and solutions inherent to the collection and processing of intramedullary canal tissue samples. The authors then examined single-cell RNA sequencing data from fresh and reanimated samples to demonstrate the feasibility of this approach for prospective studies

Polytraumatized patient lower extremity nonunion development: Raw data

In this article we report data collected to evaluate the pathomechanistic effect of acute anaerobic metabolism in the polytraumatized patient and its subsequent effect on fracture nonunion; see "Base Deficit ≥6 within 24 Hours of Injury is a Risk Factor for Fracture Nonunion in the Polytraumatized Patient" (Sardesai et al., 2021) [1]. Data was collected on patients age ≥16 with an Injury Severity Score (ISS) >16 that presented between 2013-2018 who sustained a fracture of the tibia or femur distal to the femoral neck. Patients presenting to our institution greater than 24 hours post-injury and those with less than three months follow-up were excluded. Medical charts were reviewed to collect patient demographic information and known nonunion risk-factors, including smoking, alcohol use, and diabetes. In addition, detailed injury characteristics to quantify injury magnitude including ISS, Glasgow Coma Scale (GCS) at admission, and ICU length of stay were recorded. ISS values were obtained from our institutional trauma database where they are entered by individuals trained in ISS calculations. Associated fracture-related features including fracture location, soft-tissue injury (open vs. closed fracture), vascular injury, and compartment syndrome were recorded. Finally, vital signs, base deficit (BD), and blood transfusions over 24 hours from admission were recorded. We routinely measure BD and less consistently measure serum lactate in trauma patients at the time of presentation or during resuscitation. BD values are automatically produced by our laboratory with any arterial blood gas order, and we recorded BD values from the medical record. Clinical notes and radiographs were reviewed to confirm fracture union versus nonunion and assess for deep infection at the fracture site. Patients were categorized as having a deep infection if they were treated operatively for the infection prior to fracture healing or classification as a nonunion. Nonunion was defined by failure of progressive healing on sequential radiographs and/or surgical treatment for nonunion repair at least six months post-injury