Augmentation of Rotator Cuff Repair With Soft Tissue Scaffolds

Background Tears of the rotator cuff are one of the most common tendon disorders. Treatment often includes surgical repair, but the rate of failure to gain or maintain healing has been reported to be as high as 94%. This has been substantially attributed to the inadequate capacity of tendon to heal once damaged, particularly to bone at the enthesis. A number of strategies have been developed to improve tendon-bone healing, tendon-tendon healing, and tendon regeneration. Scaffolds have received considerable attention for replacement, reconstruction, or reinforcement of tendon defects but may not possess situation-specific or durable mechanical and biological characteristics. Purpose To provide an overview of the biology of tendon-bone healing and the current scaffolds used to augment rotator cuff repairs. Study Design Systematic review; Level of evidence, 4. Methods A preliminary literature search of MEDLINE and Embase databases was performed using the terms rotator cuff scaffolds, rotator cuff augmentation, allografts for rotator cuff repair, xenografts for rotator cuff repair, and synthetic grafts for rotator cuff repair. Results The search identified 438 unique articles. Of these, 214 articles were irrelevant to the topic and were therefore excluded. This left a total of 224 studies that were suitable for analysis. Conclusion A number of novel biomaterials have been developed into biologically and mechanically favorable scaffolds. Few clinical trials have examined their effect on tendon-bone healing in well-designed, long-term follow-up studies with appropriate control groups. While there is still considerable work to be done before scaffolds are introduced into routine clinical practice, there does appear to be a clear indication for their use as an interpositional graft for large and massive retracted rotator cuff tears and when repairing a poor-quality degenerative tendon

A self-similar solution for thermal disc winds

We derive a self-similar description for the 2D streamline topology and flow structure of an axi-symmetric, thermally driven wind originating from a disc in which the density is a power law function of radius. Our scale-free solution is strictly only valid in the absence of gravity or centrifugal support; comparison with 2D hydrodynamic simulations of winds from Keplerian discs however demonstrates that the scale-free solution is a good approximation also in the outer regions of such discs, and can provide a reasonable description even for launch radii well within the gravitational radius of the flow. Although other authors have considered the flow properties along streamlines whose geometry has been specified in advance, this is the first isothermal calculation in which the flow geometry and variation of flow variables along streamlines is determined self-consistently. It is found that the flow trajectory is very sensitive to the power-law index of radial density variation in the disc: the steeper the density gradient, the stronger is the curvature of streamlines close to the flow base that is required in order to maintain momentum balance perpendicular to the flow. Steeper disc density profiles are also associated with more rapid acceleration, and a faster fall-off of density, with height above the disc plane. The derivation of a set of simple governing equations for the flow structure of thermal winds from the outer regions of power law discs offers the possibility of deriving flow observables without having to resort to hydrodynamical simulation.This work has been partially supported by the DISCSIM project, grant agreement 341137 funded by the European Research Council under ERC- 2013-ADG. RDA acknowledges support from STFC through an Advanced Fellowship (ST/G00711X/1), and from the Leverhulme Trust through a Philip Leverhulme Prize. Astrophysical research at the University of Leicester is supported by an STFC Consolidated Grant (ST/K001000/1). This research used the ALICE High Performance Computing Facility at the University of Leicester. Some resources on ALICE form part of the DiRAC Facility jointly funded by STFC and the Large Facilities Capital Fund of BIS. This work also used the DiRAC Complexity system, operated by the University of Leicester IT Services, which forms part of the STFC DiRAC HPC Facility (http://www.dirac.ac.uk). This equipment is funded by BIS National E-Infrastructure capital grant ST/K000373/1 and STFC DiRAC Operations grant ST/K0003259/1. DiRAC is part of the UK National E-Infrastructure.This is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/mnras/stw117

The anti-fibrotic effect of inhibition of TGFβ-ALK5 signalling in experimental pulmonary fibrosis in mice is attenuated in the presence of concurrent γ-herpesvirus infection.

Journal ArticleTGFβ-ALK5 pro-fibrotic signalling and herpesvirus infections have been implicated in the pathogenesis and exacerbation of pulmonary fibrosis. In this study we addressed the role of TGFβ-ALK5 signalling during the progression of fibrosis in a two-hit mouse model of murine γ-herpesvirus 68 (MHV-68) infection on the background of pre-existing bleomycin-induced pulmonary fibrosis. Assessment of total lung collagen levels in combination with ex vivo micro-computed tomography (µCT) analysis of whole lungs demonstrated that MHV-68 infection did not enhance lung collagen deposition in this two-hit model but led to a persistent and exacerbated inflammatory response. Moreover, µCT reconstruction and analysis of the two-hit model revealed distinguishing features of diffuse ground-glass opacities and consolidation superimposed on pre-existing fibrosis that were reminiscent of those observed in acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). Virally-infected murine fibrotic lungs further displayed evidence of extensive inflammatory cell infiltration and increased levels of CCL2, TNFα, IL-1β and IL-10. Blockade of TGFβ-ALK5 signalling attenuated lung collagen accumulation in bleomycin-alone injured mice, but this anti-fibrotic effect was reduced in the presence of concomitant viral infection. In contrast, inhibition of TGFβ-ALK5 signalling in virally-infected fibrotic lungs was associated with reduced inflammatory cell aggregates and increased levels of the antiviral cytokine IFNγ. These data reveal newly identified intricacies for the TGFβ-ALK5 signalling axis in experimental lung fibrosis, with different outcomes in response to ALK5 inhibition depending on the presence of viral infection. These findings raise important considerations for the targeting of TGFβ signalling responses in the context of pulmonary fibrosis.MRCNovartis CASE studentshi

Cerebellar Integrity in the Amyotrophic Lateral Sclerosis - Frontotemporal Dementia Continuum

Amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) are multisystem neurodegenerative disorders that manifest overlapping cognitive, neuropsychiatric and motor features. The cerebellum has long been known to be crucial for intact motor function although emerging evidence over the past decade has attributed cognitive and neuropsychiatric processes to this structure. The current study set out i) to establish the integrity of cerebellar subregions in the amyotrophic lateral sclerosis-behavioural variant frontotemporal dementia spectrum (ALS-bvFTD) and ii) determine whether specific cerebellar atrophy regions are associated with cognitive, neuropsychiatric and motor symptoms in the patients. Seventy-eight patients diagnosed with ALS, ALS-bvFTD, behavioural variant frontotemporal dementia (bvFTD), most without C9ORF72 gene abnormalities, and healthy controls were investigated. Participants underwent cognitive, neuropsychiatric and functional evaluation as well as structural imaging using voxel-based morphometry (VBM) to examine the grey matter subregions of the cerebellar lobules, vermis and crus. VBM analyses revealed: i) significant grey matter atrophy in the cerebellum across the whole ALS-bvFTD continuum; ii) atrophy predominantly of the superior cerebellum and crus in bvFTD patients, atrophy of the inferior cerebellum and vermis in ALS patients, while ALS-bvFTD patients had both patterns of atrophy. Post-hoc covariance analyses revealed that cognitive and neuropsychiatric symptoms were particularly associated with atrophy of the crus and superior lobule, while motor symptoms were more associated with atrophy of the inferior lobules. Taken together, these findings indicate an important role of the cerebellum in the ALS-bvFTD disease spectrum, with all three clinical phenotypes demonstrating specific patterns of subregional atrophy that associated with different symptomology

A new potential energy surface for OH(A 2Σ+)–Kr: The van der Waals complex and inelastic scattering

New ab initio studies of the OH(A(2)Σ(+))-Kr system reveal significantly deeper potential energy wells than previously believed, particularly for the linear configuration in which Kr is bound to the oxygen atom side of OH(A(2)Σ(+)). In spite of this difference with previous work, bound state calculations based on a new RCCSD(T) potential energy surface yield an energy level structure in reasonable accord with previous studies. However, the new calculations suggest the need for a reassignment of the vibrational levels of the electronically excited complex. Quantum mechanical and quasi-classical trajectory scattering calculations are also performed on the new potential energy surface. New experimental measurements of rotational inelastic scattering cross sections are reported, obtained using Zeeman quantum beat spectroscopy. The values of the rotational energy transfer cross sections measured experimentally are in good agreement with those derived from the dynamical calculations on the new adiabatic potential energy surface

Mortality of Patients with Hematological Malignancy after Admission to the Intensive Care Unit

Background: The admission of patients with malignancies to an intensive care unit (ICU) still remains a matter of substantial controversy. The identification of factors that potentially influence the patient outcome can help ICU professionals make appropriate decisions. Patients and Methods: 90 adult patients with hematological malignancy (leukemia 47.8%, high-grade lymphoma 50%) admitted to the ICU were analyzed retrospectively in this single-center study considering numerous variables with regard to their influence on ICU and day-100 mortality. Results: The median simplified acute physiology score (SAPS) II at ICU admission was 55 (ICU survivors 47 vs. 60.5 for non-survivors). The overall ICU mortality rate was 45.6%. With multivariate regression analysis, patients admitted with sepsis and acute respiratory failure had a significantly increased ICU mortality (sepsis odds ratio (OR) 9.12, 95% confidence interval (CI) 1.1-99.7, p = 0.04; respiratory failure OR 13.72, 95% CI 1.39-136.15, p = 0.025). Additional factors associated with an increased mortality were: high doses of catecholamines (ICU: OR 7.37, p = 0.005; day 100: hazard ratio (HR) 2.96, p < 0.0001), renal replacement therapy (day 100: HR 1.93, p = 0.026), and high SAPS II (ICU: HR 1.05, p = 0.038; day 100: HR 1.2, p = 0.027). Conclusion: The decision for or against ICU admission of patients with hematological diseases should become increasingly independent of the underlying malignant disease

Disease Progression Modelling in Chronic Obstructive Pulmonary Disease (COPD)

RATIONALE: The decades-long progression of Chronic Obstructive Pulmonary Disease (COPD) renders identifying different trajectories of disease progression challenging. OBJECTIVES: To identify subtypes of COPD patients with distinct longitudinal progression patterns using a novel machine-learning tool called "Subtype and Stage Inference (SuStaIn)", and to evaluate the utility of SuStaIn for patient stratification in COPD. METHODS: We applied SuStaIn to cross-sectional CT imaging markers in 3698 GOLD1-4 patients and 3479 controls from the COPDGene study to identify COPD patient subtypes. We confirmed the identified subtypes and progression patterns using ECLIPSE data. We assessed the utility of SuStaIn for patient stratification by comparing SuStaIn subtypes and stages at baseline with longitudinal follow-up data. MEASUREMENTS AND MAIN RESULTS: We identified two trajectories of disease progression in COPD: a "Tissue→Airway" subtype (n=2354, 70.4%) in which small airway dysfunction and emphysema precede large-airway wall abnormalities, and an "Airway→Tissue" subtype (n=988, 29.6%) in which large-airway wall abnormalities precede emphysema and small airway dysfunction. Subtypes were reproducible in ECLIPSE. Baseline stage in both subtypes correlated with future FEV1/FVC decline (r=-0.16 (p<0.001) in the Tissue→Airway group; r=-0.14 (p=0.011) in the Airway→Tissue group). SuStaIn placed 30% of smokers with normal lung function at non-baseline stages suggesting imaging changes consistent with early COPD. Individuals with early changes were 2.5 times more likely to meet COPD diagnostic criteria at follow-up. CONCLUSIONS: We demonstrate two distinct patterns of disease progression in COPD using SuStaIn, likely representing different endotypes. One-third of healthy smokers have detectable imaging changes, suggesting a new biomarker of 'early COPD'

Clinical brca1/2 reversion analysis identifies hotspot mutations and predicted neoantigens associated with therapy resistance

Reversion mutations in BRCA1 or BRCA2 are associated with resistance to PARP inhibitors and platinum. To better understand the nature of these mutations, we collated, codified, and analyzed more than 300 reversions. This identified reversion “hotspots” and “deserts” in regions encoding the N and C terminus, respectively, of BRCA2, suggesting that pathogenic mutations in these regions may be at higher or lower risk of reversion. Missense and splice-site pathogenic mutations in BRCA1/2 also appeared less likely to revert than truncating mutations. Most rever-sions were <100 bp deletions. Although many deletions exhibited microhomology, this was not universal, suggesting that multiple DNA-repair processes cause reversion. Finally, we found that many reversions were predicted to encode immunogenic neopeptides, suggesting a route to the treatment of reverted disease. As well as providing a freely available database for the collation of future reversion cases, these observations have implications for how drug resistance might be managed in BRCA-mutant cancers. SIGNIFICANCE: Reversion mutations in BRCA genes are a major cause of clinical platinum and PARP inhibitor resistance. This analysis of all reported clinical reversions suggests that the position of BRCA2 mutations affects the risk of reversion. Many reversions are also predicted to encode tumor neoantigens, providing a potential route to targeting resistance

New Insights into Properties of Large-N Holographic Thermal QCD at Finite Gauge Coupling at (the Non-Conformal/Next-to) Leading Order in N

In the context of [1]'s string theoretic dual of large-N thermal QCD-like theories at finite gauge/string coupling (as part of the `MQGP' limit of [2]), we discuss the following. First, up to LO in N, using the results of [3], we show that the local T^3 of [2] is the T^2-invariant sLag of [3] in a resolved conifold. This, together with the results of [4], shows that for a (predominantly resolved or deformed) resolved warped deformed conifold, the local T^3 of [2] in the MQGP limit, is the T^2-invariant sLag of [3] justifying the construction of the delocalized SYZ type IIA mirror of the type IIB background of [1]. Then, using the prescription of [5], we obtain the temperature dependence of the thermal (and electrical) conductivity working up to leading order in N (the number of D3-branes), and upon comparison with [6] show that the results mimic a 1+1-dimensional Luttinger liquid with impurities. Further, including sub-leading non-conformal terms in the metric determined by M (the number of fractional D-branes = the number of colors = 3 in the IR after the end of a Seiberg duality cascade), by looking at respectively the scalar, vector and tensor modes of metric perturbations and using [7]'s prescription of constructing appropriate gauge-invariant perturbations, we obtain respectively the speed of sound, the diffusion constant and the shear viscosity \eta (and \eta/s) including the non-conformal O((g_s M^2) (g_s N_f)/N<<1)-corrections, N_f being the number of flavor D7-branes.Comment: 1+75 pages, LaTeX; Some corrections in Tc-related calculations, results unchange