Visualization of bone formation in sheep's middle ear by using fluorochrome sequential labelling (FSL).

One factor for the lacking integration of the middle ear stapes footplate prosthesis or the missing healing of stapes footplate fractures could be the known osteogenic inactivity. In contrast, it was recently demonstrated that titanium prostheses with an applied collagen matrix and immobilised growth factors stimulate osteoblastic activation and differentiation on the stapes footplate. Regarding those findings, the aim of this study was to evaluate the potential of bone regeneration including bone remodeling in the middle ear. Ten one-year-old female merino sheep underwent a middle ear surgery without implantation of middle ear prostheses or any other component for activating bone formation. Post-operatively, four fluorochromes (tetracycline, alizarin complexion, calcein green and xylenol orange) were administered by subcutaneous injection at different time points after surgery (1 day: tetracycline, 7 days: alizarin, 14 days: calcein, 28 days: xylenol). After 12 weeks, the temporal bones including the lateral skull base were extracted and histologically analyzed. Fluorescence microscopy analysis of the entire stapes with the oval niche, but in particular stapes footplate and the Crura stapedis revealed evidence of new bone formation. Calcein was detected in all and xylenol in 60% of the animals. In contrast, tetracycline and alizarin could only be verified in two animals. The authors were able to demonstrate the osseoregenerative potential of the middle ear, in particular of the stapes footplate, using fluorescence sequence labelling.

Quantitative magnetic resonance imaging to aid clinical decision making in autoimmune hepatitis.

Background: In autoimmune hepatitis (AIH), clinical practice and treatment guidelines frequently diverge as a reflection of disease heterogeneity and challenges in achieving standardised care. We sought to explore the utility of multiparametric (mp) MR in patients with AIH, and the impact of this technology on physicians' decision making and intended patient management. Methods: 82 AIH patients, recruited from two sites between June and November 2019 as part of an observational cohort study, underwent non-contrast MRI alongside their standard clinical investigations. Correlations between iron-corrected T1 (cT1) and other markers of disease were investigated alongside the utility of imaging markers to risk stratify patients in biochemical remission. The impact of mpMR on clinical decision making was evaluated using pairwise t-tests. The discriminatory ability of the imaging markers was assessed using area under the receiver operating characteristic curves (AUCs). Findings: cT1 had a significant impact on clinician intended patient management (p<0.0001). cT1 correlated with ALT (p = 0.0005), AST (p<0.001), IgG (p = 0.0005), and liver stiffness (p<0.0001). Patients in deep biochemical remission (N = 11; AST/ALT <50% upper limit of normal [ULN] and IgG <12 g/L) had low cT1, while 7/34 in normal biochemical remission (AST/ALT between 50 and 100% of ULN) had high cT1 and were at risk of disease flare. cT1 measures of disease heterogeneity, ALP and bilirubin made the best predictor of those not in biochemical remission (AUC:0.85). Interpretation: This study investigates the impact of mpMR results on intended clinical management in a real world setting. Findings showed that mpMR demonstrated a significant impact on clinical management of AIH and has the potential to inform patient risk stratification. Funding: This paper presents independent research supported by the Innovate UK grant (104,915).

Parallel spectroscopic ellipsometry for ultra-fast thin film characterization.

Spectroscopic ellipsometer (SE) is an essential optical metrology tool commonly used to characterize thin films and monitor fabrication processes. However, it relies on mechanical rotation of a polarizer or a photo-elastic phase modulator which are limited in speed and prone to errors when handling dynamic processes. The constant trend of micro-electronics dimensions shrinkage and increase of the wafer area necessitates faster and more accurate tools. A fast SE design based on parallel snapshot detection of three signals at different polarizations is proposed and demonstrated. Not relying on mechanical rotation nor serial phase modulation, it is more accurate and can reach acquisition rates of hundreds of measurements per second.

Systematic review with meta-analysis: Nutritional screening and assessment tools in cirrhosis.

BACKGROUND & AIMS: Disease-related malnutrition is common in cirrhosis. Multiple studies have evaluated nutritional screening tools (NSTs, rapid bedside tests targeting who needs assessment) and nutritional assessment tools (NATs, used in diagnosing malnutrition) as predictors of clinical outcome in this population. We performed a systematic review and meta-analysis of this literature with the aim of summarising the varying definitions of malnutrition across studies, the available evidence for NSTs and the ability of NSTs and NATs to predict clinical outcomes in cirrhosis. METHODS: The primary outcome measures were pre- and post-transplant mortality with a range of secondary outcomes. Inclusion: cirrhosis over age 16. Exclusion: >25% with hepatocellular carcinoma, primarily laboratory test-based NATs or lack of screening, assessment or outcome criteria. RESULTS: Eight thousand eight hundred fifty patients were included across 47 studies. Only 3 studies assessed NSTs. Thirty-two definitions for malnutrition were utilised across studies. NATs predicted pre-transplant mortality in 69% of cases that were assessed with a risk ratio (RR) of 2.38 (95% CI 1.96-2.89). NATs were prognostic for post-transplant mortality only 28% of the times they were assessed, with a RR of 3.04 (95% CI 1.51-6.12). CONCLUSIONS: The cirrhosis literature includes limited data on nutrition screening and multiple definitions for what constitutes malnutrition using NATs. Despite this discordance, it is clear that malnutrition is a valuable predictor of pre-transplant mortality almost regardless of how it is defined. We require clinical and research consensus around the definition of malnutrition and the accepted processes and cut-points for nutrition screening and assessment in cirrhosis.

Systematic review of nutrition screening and assessment in inflammatory bowel disease.

BACKGROUND: Malnutrition is prevalent in inflammatory bowel disease (IBD). Multiple nutrition screening (NST) and assessment tools (NAT) have been developed for general populations, but the evidence in patients with IBD remains unclear. AIM: To systematically review the prevalence of abnormalities on NSTs and NATs, whether NSTs are associated with NATs, and whether they predict clinical outcomes in patients with IBD. METHODS: Comprehensive searches performed in Medline, CINAHL Plus and PubMed. Included: English language studies correlating NSTs with NATs or NSTs/NATs with clinical outcomes in IBD. Excluded: Review articles/case studies; use of body mass index/laboratory values as sole NST/NAT; age < 16. RESULTS: Of 16 studies and 1618 patients were included, 72% Crohn's disease and 28% ulcerative colitis. Four NSTs (the Malnutrition Universal Screening Tool, Malnutrition Inflammation Risk Tool (MIRT), Saskatchewan Inflammatory Bowel Disease Nutrition Risk Tool (SaskIBD-NRT) and Nutrition Risk Screening 2002 (NRS-2002) were significantly associated with nutritional assessment measures of sarcopenia and the Subjective Global Assessment (SGA). Three NSTs (MIRT, NRS-2002 and Nutritional Risk Index) were associated with clinical outcomes including hospitalizations, need for surgery, disease flares, and length of stay (LOS). Sarcopenia was the most commonly evaluated NAT associated with outcomes including the need for surgery and post-operative complications. The SGA was not associated with clinical outcomes aside from LOS. CONCLUSION: There is limited evidence correlating NSTs, NATs and clinical outcomes in IBD. Although studies support the association of NSTs/NATs with relevant outcomes, the heterogeneity calls for further studies before an optimal tool can be recommended. The NRS-2002, measures of sarcopenia and developments of novel NSTs/NATs, such as the MIRT, represent key, clinically-relevant areas for future exploration.

Retrospective investigation of the prognostic value of the ß1 integrin expression in patients with head and neck squamous cell carcinoma receiving primary radio(chemo)therapy.

This retrospective study evaluated the expression of ß1 integrins and associated proteins as prognostic markers for primary radio(chemo)therapy outcome of patients with locally advanced head and neck squamous cell carcinomas (HNSCC). Tissue microarrays were prepared from 224 HNSCC patients undergoing curative primary radio(chemo)therapy from 1996 to 2005. Staining intensities of ß1 integrin and its downstream-proteins FAK, phosphorylated FAK as well as the ß1 integrin ECM ligands fibronectin and collagen type-I were determined. Their association to the primary endpoint loco-regional control and the secondary endpoints overall survival and freedom from distant metastasis was analyzed by Cox regression. None of the considered molecular parameters showed a significant association with loco-regional control and freedom from distant metastasis. Patients with p16 positive tumors or tumors with a low intensity of fibronectin showed significantly higher overall survival in univariable regression. In multivariable regression including additional clinical parameters, however, these parameters were not significantly associated with overall survival. Our study in a HNSCC patient cohort treated with primary radio(chemo)therapy does not reveal a prognostic value of ß1 integrin expression.

Predicting Hepatic Encephalopathy-Related Hospitalizations Using a Composite Assessment of Cognitive Impairment and Frailty in 355 Patients With Cirrhosis.

INTRODUCTION: Hepatic encephalopathy (HE) is the most common potentially modifiable reason for admission in patients with cirrhosis. Cognitive and physical components of frailty have pathophysiologic rationale as risk factors for HE. We aimed to assess the utility of a composite score (MoCA-CFS) developed using the Montreal Cognitive Assessment (MoCA) and the Clinical Frailty Scale (CFS) for predicting HE admissions within 6 months. METHODS: Consecutive adult patients with cirrhosis were followed for 6 months or until death/transplant. Patients with overt HE and dementia were excluded. Primary outcome was the prediction of HE-related admissions at 6 months. RESULTS: A total of 355 patients were included; mean age 55.9 ± 9.6; 62.5% male; Hepatitis C and alcohol etiology in 64%. Thirty-six percent of patients had cognitive impairment according to the MoCA (≤24) and 14% were frail on the CFS (>4). The MoCA-CFS independently predicted HE hospitalization within 6 months, a MoCA-CFS score of 1 and 2 respectively increasing the odds of hospitalization by 3.3 (95% CI:1.5-7.7) and 5.7 (95% CI:1.9-17.3). HRQoL decreased with increasing MoCA-CFS. Depression and older age were independent predictors of a low MoCA. CONCLUSIONS: Cognitive and physical frailty are common in patients with cirrhosis. In addition to being an independent predictor of HE admissions within 6 months, the MoCA-CFS composite score predicts impaired HRQoL and all-cause admissions within 6 months. These data support the predictive value of a "multidimensional" frailty tool for the prediction of adverse clinical outcomes and highlight the potential for a multi-faceted approach to therapy targeting cognitive impairment, physical frailty and depression.

Patient-perceived barriers to lifestyle interventions in cirrhosis.

BACKGROUND/AIMS: Sarcopenia, muscle weakness, and physical frailty are independent predictors of mortality in cirrhosis. These adverse prognostic factors are potentially modifiable with lifestyle interventions, including adequate nutritional intake and physical activity. Our aim was to identify patient-perceived barriers and enablers to these interventions. PATIENTS AND METHODS: Adult patients with cirrhosis were prospectively recruited from two tertiary care liver clinics. Patients were excluded if they had hepatocellular carcinoma beyond transplant criteria, other active malignancy, or advanced chronic disease. RESULTS: A total of 127 patients (mean age: 60 ± 9 years, 58% males, and 48% with Child-Pugh-B/C (CP-B/C) disease) were included. Two-thirds of the patients had cirrhosis related to alcohol or hepatitis C. CP-B/C patients were more likely to take oral nutritional supplements (56% vs 29%) and less likely to consume animal protein daily (66% vs 85%) when compared to CP-A patients. Early satiety, altered taste, and difficulty in buying/preparing meals were more common in CP-B/C patients and even present in 20-30% of CP-A patients. Most patients reported adequate funds to purchase food. As quantified by the International Physical Activity Questionnaire-Short Form, 47% reported low activity levels, with no significant differences between groups. CP-B/C patients were more fatigued with exercise, however, overall Exercise Benefits/Barriers Scale scores were similar across groups. CONCLUSIONS: Barriers to nutritional intake and physical activity are common in cirrhosis and should be evaluated and treated in all patients. Asking simple screening questions in clinic and referring at-risk patients to expert multidisciplinary providers is a reasonable strategy to address these barriers. Future research should evaluate techniques to overcome modifiable barriers and enhance enablers.

Three wavelengths parallel phase-shift interferometry for real-time focus tracking and vibration measurement.

Instantaneous high-resolution, wide-range focus tracking and a vibrometry system based on three-wavelength (3λ) parallel phase-shift polarization interferometry using three detectors per wavelength is presented. The system, implementing 3λ in-parallel three-phase-shift-interferometry channels for the first time, to the best of our knowledge, allows single-shot position tracking of motion profiles with extremely high velocities and vibration rates, long inter-step heights, and sub-nanometer scale accuracy. The system's simple design and algorithm presented here do not rely on active optical components, making its performance limited only by the detectors' bandwidths and allowing the setting up of a very high-performance low-cost vibrometry system.

Noninvasive tools and risk of clinically significant portal hypertension and varices in compensated cirrhosis: The "Anticipate" study.

In patients with compensated advanced chronic liver disease (cACLD), the presence of clinically significant portal hypertension (CSPH) and varices needing treatment (VNT) bears prognostic and therapeutic implications. Our aim was to develop noninvasive tests-based risk prediction models to provide a point-of-care risk assessment of cACLD patients. We analyzed 518 patients with cACLD from five centers in Europe/Canada with paired noninvasive tests (liver stiffness measurement [LSM] by transient elastography, platelet count, and spleen diameter with calculation of liver stiffness to spleen/platelet score [LSPS] score and platelet-spleen ratio [PSR]) and endoscopy/hepatic venous pressure gradient measurement. Risk of CSPH, varices, and VNT was modeled with logistic regression. All noninvasive tests reliably identified patients with high risk of CSPH, and LSPS had the highest discrimination. LSPS values above 2.65 were associated with risks of CSPH above 80%. None of the tests identified patients with very low risk of all-size varices, but both LSPS and a model combining TE and platelet count identified patients with very low risk (<5%) risk of VNT, suggesting that they could be used to triage patients requiring screening endoscopy. LSPS values of <1.33 were associated with a <5% risk of VNT, and 26% of patients had values below this threshold. LSM combined with platelet count predicted a risk <5% of VNT in 30% of the patients. Nomograms were developed to facilitate point-of-care risk assessment. CONCLUSION: A significant proportion of patients with a very high risk of CSPH, and a population with a very low risk of VNT can be identified with simple, noninvasive tests, suggesting that these can be used to individualize medical care. (Hepatology 2016;64:2173-2184).

Insufficient Protein Intake Is Associated With Increased Mortality in 630 Patients With Cirrhosis Awaiting Liver Transplantation.

BACKGROUND: For patients awaiting liver transplantation, we aimed to determine the prevalence and predictors of insufficient protein intake as well as to determine whether very low protein intake was an independent predictor of malnutrition and mortality. MATERIALS AND METHODS: Adults with cirrhosis who were activated on our local liver transplant waiting list between January 2000 and October 2009 were included. Estimated protein intake was derived from dietary records. Patients with incomplete dietary records were excluded. Multivariable logistic regression and competing risk analysis were used. RESULTS: Of 742 potential patients, 112 were excluded due to insufficient data, leaving 630 patients for evaluation. Mean protein intake was 1.0 ± 0.36 g/kg/d and only 24% of patients met the expert consensus recommended threshold of > 1.2 g/kg of protein per day. Very low protein intake (< 0.8 g/kg/d) was associated with worse liver disease severity (as measured by Child-Pugh or MELD). Protein intake below 0.8 g/kg/d was an independent predictor both of malnutrition as measured by the subjective global assessment (adjusted odds ratio [95% confidence interval (CI)]: 2.0 [1.3-3.0]) and of transplant waiting list mortality (adjusted hazard ratio [95% CI]: 1.8 [1.2-2.7]). CONCLUSION: In this large cohort of liver transplant waitlisted patients, very low protein intake was prevalent and independently associated with malnutrition and mortality. Unlike many other prognostic factors, protein intake is potentially modifiable. Prospective studies are warranted to evaluate the effect of targeted protein repletion on clinically relevant outcomes such as muscle mass, muscle function, immune function, and mortality.

Ultrahigh polarimetric image contrast enhancement for skin cancer diagnosis using InN plasmonic nanoparticles in the terahertz range.

Mueller matrix imaging sensitivity, to delicate water content changes in tissue associated with early stages of skin cancer, is demonstrated by numerical modeling to be enhanced by localized surface plasmon resonance (LSPR) effects at the terahertz (THz) range when InN nanoparticles (NPs) coated with Parylene-C are introduced into the skin. A skin tissue model tailored for THz wavelengths is established for a Monte Carlo simulation of polarized light propagation and scattering, and a comparative study based on simulated Mueller matrices is presented considering different NPs' parameters and insertion into the skin methods. The insertion of NPs presenting LSPR in the THz is demonstrated to enable the application of polarization-based sample characterization techniques adopted from the scattering dominated visible wavelengths domain for the, otherwise, relatively low scattering THz domain, where such approach is irrelevant without the NPs. Through these Mueller polarimetry techniques, the detection of water content variations in the tissue is made possible and with high sensitivity. This study yields a limit of detection down to 0.0018% for relative changes in the water content based on linear degree of polarization--an improvement of an order of magnitude relative to the limit of detection without NPs calculated in a previous ellipsometric study.

Validation of the five-variable Model for End-stage Liver Disease (5vMELD) for prediction of mortality on the liver transplant waiting list.

BACKGROUND: Modifications to the Model for End-Stage Liver Disease (MELD) have been proposed to improve prioritization of liver transplant (LT) candidates. Using a U.S. database, we derived a revised MELD including sodium and albumin [5-variable MELD (5vMELD)] that improved prediction of waiting list mortality. Our objectives were to confirm the association between hypoalbuminaemia and mortality and to externally validate 5vMELD in Canadian LT candidates. METHODS: Among adults registered on the LT waiting list at the University of Alberta (01/2000-10/2009), Cox regression determined the association between albumin and 1-year waiting list mortality. The discrimination of MELD, MELDNa and 5vMELD for predicting 1-year mortality were compared using c-statistics. RESULTS: Among 677 patients, 17% died and 51% underwent LT within 1 year of listing. Median serum albumin was 3.1 g/dl (IQR 2.6-3.6) and 70% of patients were hypoalbuminaemic (albumin <3.5 g/dl). One-year mortality in patients with normal serum albumin and hypoalbuminaemia were 14% and 29% respectively (P = 0.004). For patients with serum albumin between 2.0 and 4.0 g/dl, an approximately linear, inverse relationship was observed between albumin and 1-year mortality [adjusted hazard ratio (HR) 1.45; 95% CI 1.03-2.03; P = 0.03]. For this outcome, the c-statistic of 5vMELD (0.778) was superior to those of MELD (0.754) and MELDNa (0.765) (both P ≤ 0.05). CONCLUSIONS: Hypoalbuminaemia is an independent predictor of mortality on the LT waiting list. Compared with MELD and MELDNa, 5vMELD improves prediction of mortality suggesting that modification of these scores to include serum albumin should be considered as a means of prioritizing LT candidates.

Severe muscle depletion in patients on the liver transplant wait list: its prevalence and independent prognostic value.

As detected by cross-sectional imaging, severe muscle depletion, which is termed sarcopenia, holds promise for prognostication in patients with cirrhosis. Our aims were to describe the prevalence and predictors of sarcopenia in patients with cirrhosis listed for liver transplantation (LT) and to determine its independent prognostic significance for the prediction of waiting-list mortality. Adults listed for LT who underwent abdominal computed tomography/magnetic resonance imaging within 6 weeks of activation were retrospectively identified. The exclusions were hepatocellular carcinoma, acute liver failure, prior LT, and listing for multivisceral transplantation or living related LT. Sixty percent of the 142 eligible patients were male, the median age was 53 years, and the median Model for End-Stage Liver Disease (MELD) score at listing was 15. Forty-one percent were sarcopenic; sarcopenia was more prevalent in males versus females (54% versus 21%, P < 0.001) and increased with the Child-Pugh class (10% for class A, 34% for class B, and 54% for class C, P = 0.007). Male sex, the dry-weight body mass index (BMI), and Child-Pugh class C cirrhosis (but not the MELD score) were independent predictors of sarcopenia. Sarcopenia was an independent predictor of mortality (hazard ratio = 2.36, 95% confidence interval = 1.23-4.53) after adjustments for age and MELD scores. In conclusion, sarcopenia is associated with increased waiting-list mortality and is poorly predicted by subjective nutritional assessment tools such as BMI and subjective global assessment. If this is validated in larger studies, the objective assessment of sarcopenia holds promise for prognostication in this patient population.

Modeling of reflectometric and ellipsometric spectra from the skin in the terahertz and submillimeter waves region.

The human skin is modeled as a stack of homogeneous layers in the terahertz and submillimeter waves regions with some anisotropy due to the helical sweat glands and other elongated entities. A dielectric model for the skin is presented, valid for a wider frequency range (up to the terahertz region) taking into account the dispersive nature of the effective conductivity. Polarized reflectivity and generalized ellipsometric parameters are calculated versus angle and wavelength. Recent studies have claimed that the helical sweat ducts act as an array of low-Q helical antennae and are dominant in shaping the spectral response in the sub-terahertz region. We found that water absorption, dispersion and multiple interference effects play the major role in shaping the spectrum without the need for the assumption of the sweat ducts acting as low-Q helical antennae. High sensitivities to the water content are found particularly in the ellipsometric parameters at large incidence angles. Hence a new methodology is proposed to detect skin cancer using variable angle ellipsometry or polarized reflectometry. The parameter found with the highest sensitivity to water content is cos Δ(pp) with Δ(pp) being the phase of the on-diagonal reflection matrix ratio between p-to-p polarization.

Does human skin truly behave as an array of helical antennae in the millimeter and terahertz wave ranges?

The sweat ducts of the human perspiration system are helically shaped tubes, filled with a conductive aqueous solution. Recent studies have claimed that these ducts act as an array of low-Q helical antennae and are dominant in shaping the spectral response in the subterahertz region. Using local homogenization theory for the skin embedded with sweat ducts, we found that multiple interference effects from the skin layers play the major role in determining the skin electromagnetic characteristics in the millimeter and terahertz regions without the need for the assumption of the sweat ducts acting as low-Q helical antennae.

Osseointegration of titanium prostheses on the stapes footplate.

The success of middle ear reconstructive surgery depends on stable coupling between the prosthesis and residual ossicles. To establish a stable fixed point on the stapes footplate for subsequent prosthesis reconstruction, a titanium footplate anchor was coated with osteoinductive substances to induce a controlled osseointegration on the footplate. Various studies have shown that collagen-based matrices with and without bone growth and differentiation factors can induce and enhance bone formation and consequently increase implant stability. The ears of 23 one-year-old Merino sheep (n = 46) were divided into five groups and implanted with a specially designed footplate anchor. The surface of each implant was modified by applying a collagenous matrix (collagen I or II) either with immobilized bone morphogenic protein (BMP-4) or transforming growth factor-ss, respectively, to stimulate osteoblastic activation and differentiation on the stapes footplate with subsequent osseointegration. Polychrome labeling was used to assess new bone formation and remodeling during the study. After study termination on day 84, synchrotron radiation-based computed microtomography and histomorphometry were used to identify bone implant contact. Eight implants showed radiographical and/or histological evidence of integration by newly formed bone. An osseointegration could histologically be proven in two of these eight specimens, and additional ectopic bone formations were seen in another 21 specimens. In all animals, bone turnover on the footplate was proven by polychrome labeling. This study proves the general ability to induce a controlled osseointegration of titanium implants biologically activated with artificial extracellular matrices on their surfaces on the stapes footplate in a mammalian organism.

Osseointegration of prostheses on the stapes footplate: evaluation of the biomechanical feasibility by using a finite element model.

Restoration of hearing is one of the main issues of tympanoplasty. Depending on the extent of destruction, the ossicular chain is partially or totally replaced by prostheses. In the unfavorable event of complete ossicular chain destruction with only the stapes footplate remaining in the oval niche, implanting of a columella prosthesis represents the gold standard. Besides ventilation problems, the main causes of unsatisfactory hearing results are dislocation of the prosthesis and poor coupling to the footplate. Therefore, stable fixation of prostheses is desirable but has not been realized to date. In line with our experimental intention to realize a bony prosthesis fixation on the footplate, we designed a finite element model for the simulation of the interacting forces once an osseointegration was achieved. These preliminary results predict the mechanical feasibility of this endeavor and the necessary general preconditions, which have to be carefully considered. A specially designed titanium prosthesis anchor needs a minimal bony fixation of 104 microm accretion height on the footplate to withstand all emerging forces. Therefore, providing a sort of artificial stapedial suprastructure in the form of a firm, preferably bony, integration of a prosthesis anchor on the footplate seems to be realistic and worthwhile from a mechanical and medical point of view.