Trends in Hospitalizations for Clostridioides difficile Infection in End-Stage Liver Disease, 2005-2014.

BACKGROUND: Data on the current estimates of the disease burden of Clostridioides difficile (C. difficile) infection in the setting of end-stage liver disease (ESLD) are emerging. AIMS: We examined the recent trends and predictors of hospitalizations and in-hospital mortality from C. difficile infection among hospitalizations with ESLD in the USA. METHODS: We performed a retrospective analysis using the National Inpatient Sample, 2005-2014. We defined ESLD and C. difficile infection using the International Classification of Diseases, Ninth Revision, Clinical Modification. Multivariable logistic regression was used to determine the risk factors that impacted hospitalization and mortality. RESULTS: The prevalence of coding for C. difficile infection in decompensated cirrhosis increased from 1.3% in 2005 to 2.7% in 2014, with an annual rate of 7.8%. In hospitalizations with hepatocellular carcinoma, C. difficile infection increased steadily from 1.0 to 1.7% with an annual incremental rate of 6.4%. Among hospitalizations with ESLD, each passing 2-year period, increasing age, female, higher Charlson index, accompanying infection, hepatorenal syndrome, and ascites were associated with C. difficile infection. Although C. difficile infection was an independent predictor of in-hospital mortality during hospitalization with decompensated cirrhosis (odds ratio 1.53, 95% confidence interval 1.44-1.63), the proportion of in-hospital mortality during hospitalization with C. difficile infection and decompensated cirrhosis decreased from 15.4% in 2005 to 11.1% in 2014, with an annual rate of - 3.1% (95% CI - 5.7% to - 0.3%). CONCLUSIONS: While the prevalence of C. difficile infection in hospitalized patients with ESLD increased approximately twofold, the in-hospital mortality decreased significantly during the past decade.

Niche regulation of limbal epithelial stem cells: HC-HA/PTX3 as surrogate matrix niche.

Homeostasis of the corneal epithelium is ultimately maintained by stem cells that reside in a specialized microenvironment within the corneal limbus termed palisades of Vogt. This limbal niche nourishes, protects, and regulates quiescence, self-renewal, and fate decision of limbal epithelial stem/progenitor cells (LEPCs) toward corneal epithelial differentiation. This review focuses on our current understanding of the mechanism by which limbal (stromal) niche cells (LNCs) regulate the aforementioned functions of LEPCs. Based on our discovery and characterization of a unique extracellular matrix termed HC-HA/PTX3 (Heavy chain (HC1)-hyaluronan (HA)/pentraxin 3 (PTX3) complex, "-" denotes covalent linkage; "/" denotes non-covalent binding) in the birth tissue, i.e., amniotic membrane and umbilical cord, we put forth a new paradigm that HC-HA/PTX3 serves as a surrogate matrix niche by maintaining the in vivo nuclear Pax6+ neural crest progenitor phenotype to support quiescence and self-renewal but prevent corneal fate decision of LEPCs. This new paradigm helps explain how limbal stem cell deficiency (LSCD) develops in aniridia due to Pax6-haplotype deficiency and further explains why transplantation of HC-HA/PTX3-containing amniotic membrane prevents LSCD in acute chemical burns and Stevens Johnson syndrome, augments the success of autologous LEPCs transplantation in patients suffering from partial or total LSCD, and assists ex vivo expansion (engineering) of a graft containing LEPCs. We thus envisage that this new paradigm based on regenerative matrix HC-HA/PTX3 as a surrogate niche can set a new standard for regenerative medicine in and beyond ophthalmology.

Diet quality and its association with nonalcoholic fatty liver disease and all-cause and cause-specific mortality.

BACKGROUND & AIMS: Healthy diet has been recommended for nonalcoholic fatty liver disease (NAFLD), although it is not clear whether improving diet quality can prevent mortality. We aim to assess the impact of quality of diet on NAFLD and mortality in subjects with and without NAFLD. METHODS: We performed cohort study using the Third National Health and Nutrition Examination Survey from 1988 to 1994 and linked mortality data through 2015. We used the Healthy Eating Index (HEI) scores to define diet quality, with higher HEI scores (Q4) indicating better adherence to dietary recommendations. NAFLD was defined as ultrasonographic hepatic steatosis. RESULTS: Multivariate analysis showed that subjects with higher diet quality were inversely associated with NAFLD in a dose-dependent manner. During the median follow-up of 23 years, having a higher diet quality was associated with reduction in risk of all-cause mortality in the age, sex, Race/ethnicity-adjusted hazard ratio (HR) (Q4, HR: 0.60, 95% CI: 0.52-0.68) and the multivariate model (Q4, HR: 0.81, 95% CI: 0.71-0.92). Higher diet quality was associated with a lower risk for all-cause mortality in subjects without NAFLD; however, this protective association with diet quality was not noted in those with NAFLD. Furthermore, a high diet quality was associated with a lower risk for cancer-related mortality in the total population and among those without NAFLD. This association was not noted in those with NAFLD. CONCLUSIONS: High diet quality was inversely associated with NAFLD and was positively associated with a lower risk for cancer-related and all-cause mortality in those without NAFLD.

Differential Gene Expression between Limbal Niche Progenitors and Bone Marrow Derived Mesenchymal Stem Cells.

Purpose: To compare the difference in gene expression between human limbal niche cells (LNC) and bone marrow derived mesenchymal stem cells (BMMSC). Methods: LNC were isolated by collagenase and expanded in modified embryonic stem cell medium (MESCM) on a Matrigel coated plastic plate. Cell diameters were measured with Image J software. Relative gene expression levels between LNC and BMMSC were compared using Affymetrix Human Primer View Gene Expression Array. A subset of differentially expressed genes was verified by RT-qPCR. The protein level of LAMA1 and COL4A1 was confirmed by Western blot and immunostaining. Results: The average diameter of LNC was 10.2±2.4 µm, which was significantly smaller than that of BMMSC (14 ±3.4 µm) (p<0.0001). Expression of 20,432 genes was examined by Gene Expression Array, among which expression of 349 genes in LNC was 10-fold or higher than that of BMMSC and expression of 8 genes in LNC was 100-fold or higher than that of BMMSC, while expression of 3 genes in BMMSC was 100-fold higher than that of LNC. GO analysis and pathway analysis showed that the differentially expressed genes were mainly enriched in the extracellular matrix receptor interaction pathway and Wnt signaling pathway. In addition, RT-qPCR results demonstrated that the expression of CD73, CD90, CD105, PDGFRß, Vimentin, SCF, KIT (CD117), COL14A1, LAMA2, THBS2, FZD1, BMP2 and CXCL12 genes in LNC were at least 2 folds higher than BMMSC. The protein level of LAMA1 was higher but the protein level of COL4A1 was lower in LNC than that in BMMSC. Conclusion: LNC exhibit differential gene expression from BMMSC in the extracellular matrix (ECM) receptor interaction pathway and Wnt signaling pathway, suggesting that LNC have their unique signaling pathways to support limbal stem cell niches.

Efficacy and Safety of 1% Atropine on Retardation of Moderate Myopia Progression in Chinese School Children.

Background: To evaluate the long-term efficacy and safety of topical 1% atropine for retarding moderate myopia. Methods: A randomized, controlled study evaluating atropine and placebo in 660 Chinese children. Patients received drops q1month for 24 months, then q2month for 12 months, followed by no drops for 12 months. Spherical equivalent, axial length, intraocular pressure and atropine-related side effects were examined at 6, 12, 24, 36 and 48 months for all children. Results: Spherical equivalent, myopic progression, axial length augmentation, and progression rate were significantly reduced in the atropine group than those in the placebo group (all P<0.05), indicating that 1% atropine effectively retarded myopia. Moreover, myopic rebound and adverse effects of 1% atropine were eliminated by gradual withdrawal and elimination of 1% atropine. Furthermore, pupil size, near visual acuity, and amplitude of accommodation returned to pretreatment levels after withdrawal of atropine. Conclusion: Topical 1% atropine periodically and alternatively in phase I with gradual reduction in phase II and final withdrawal in phase III may effectively improve atropine efficacy, retard moderate myopia, reduce atropine side effects, minimize myopic rebound, and increase compliance of children simultaneously.

COX-2 Signaling in the Tumor Microenvironment.

Tumorigenesis is a multistep, complicated process, and many studies have been completed over the last few decades to elucidate this process. Increasingly, many studies have shifted focus toward the critical role of the tumor microenvironment (TME), which consists of cellular players, cell-cell communications, and extracellular matrix (ECM). In the TME, cyclooxygenase-2 (COX-2) has been found to be a key molecule mediating the microenvironment changes. COX-2 is an inducible form of the enzyme that converts arachidonic acid into the signal transduction molecules (thromboxanes and prostaglandins). COX-2 is frequently expressed in many types of cancers and has been closely linked to its occurrence, progression, and prognosis. For example, COX-2 has been shown to (1) regulate tumor cell growth, (2) promote tissue invasion and metastasis, (3) inhibit apoptosis, (4) suppress antitumor immunity, and (5) promote sustainable angiogenesis. In this chapter, we summarize recent advances of studies that have evaluated COX-2 signaling in TME.

Trabecular meshwork cells are a valuable resource for cellular therapy of glaucoma.

Trabecular meshwork (TM) contains a subset of adult stem cells or progenitors that can be differentiated into corneal endothelial cells, adipocytes and chondrocytes, but not osteocytes or keratocytes. Accordingly, these progenitors can be utilized as a cell-based therapy to prevent blindness caused by glaucoma, corneal endothelial dysfunction and other diseases in general. In this review, we review in vitro expansion techniques for TM progenitors, discuss their phenotypic properties, and highlight their potential clinical applications in various ophthalmic diseases.

Low-Normal Thyroid Function Is Associated With Advanced Fibrosis Among Adults in the United States.

The pathogenetic pathways leading to increasing prevalence of advanced fibrosis in the setting of nonalcoholic fatty liver disease (NAFLD) and resulting in higher rates of liver-related and cardiovascular morbidity and mortality in the United States are multifactorial.1 The negative health impact of "low-normal" thyroid function, which is defined as a higher level of thyroid-stimulating hormone (TSH) within the euthyroid reference range, may be comparable with overt and subclinical hypothyroidism.2-4 We reported a strong association between biopsy-proven advanced fibrosis in NAFLD with increasing TSH levels in a dose-dependent manner even within the euthyroid reference range.5 To generalize our findings across all ethnicities, we examined the association of both low-normal thyroid function and subclinical hypothyroidism with advanced fibrosis in the US general population.

Advances in culture, expansion and mechanistic studies of corneal endothelial cells: a systematic review.

Human corneal endothelial cells are notorious for their restricted proliferative ability in vivo and in vitro. Hence, injury or dysfunction of these cells may easily result in blindness. Currently, the only treatment is to transplant a donor cornea that contains a healthy corneal endothelium. However there is a severe global shortage of donor corneas and there remains an unmet clinical need to engineer human corneal grafts with healthy corneal endothelium. In this review, we present current advances in the culture, expansion, and molecular understandings of corneal endothelial cells in vitro in order to help establish methods of engineering human corneal endothelial grafts.

Elevated urinary bisphenol A levels are associated with non-alcoholic fatty liver disease among adults in the United States.

BACKGROUND AND AIMS: The relationship between bisphenol A (BPA) and non-alcoholic fatty liver disease (NAFLD) is undefined. We studied the impact of BPA on NAFLD. METHODS: We performed a cross-sectional analysis of data from the National Health and Nutrition Examination Survey (NHANES) 2005-2014 among adults in the United States (US). NAFLD was diagnosed using the hepatic steatosis index (HSI) and the US fatty liver index (USFLI) in the absence of other causes of chronic liver diseases. The first sample using HSI consisted of 7605 adults. The second sample using USFLI consisted of 3631 participants with availability of fasting data. RESULTS: Of the first 7605 participants (mean age 47 years, 48.4% male), the prevalence of NAFLD and abnormally elevated alanine aminotransferase (ALT) levels was correlated with urinary BPA levels (P < 0.05). Compared to the reference group with lowest quartile of urinary BPA levels, those with the third and fourth quartiles were 81% and 53% more likely to develop NAFLD defined by HSI. In a multivariate model, the ORs for NAFLD in the third and fourth quartiles were 1.69 (95% CI 1.39-2.04) and 1.44 (95% CI 1.19-1.76) respectively (P for trend <0.001). In the second sample using USFLI, high BPA levels (fourth quartile) remained an independent predictor of NAFLD (OR 1.44, 95% CI 1.05-1.98, P for trend = 0.012). CONCLUSIONS: High levels of urinary BPA were associated with NAFLD in a nationally representative sample of adults in the US. The pathophysiology remains unclear and warrants further investigation.

Trends in hospitalizations for chronic liver disease-related liver failure in the United States, 2005-2014.

BACKGROUND & AIMS: Current estimates of the population-based disease burden of liver failure or end-stage liver disease (ESLD) are lacking. We investigated recent trends in hospitalizations and in-hospital mortality among patients with ESLD in the United States (US). METHODS: A retrospective analysis was performed utilizing the National Inpatient Sample from 2005 to 2014. We defined ESLD as either decompensated cirrhosis or hepatocellular carcinoma (HCC), criteria obtained from the International Classification of Diseases, Ninth Revision. Nationwide rates of hospitalization and in-hospital mortality were analysed from 2005 to 2014. RESULTS: Hospitalization rates for decompensated cirrhosis during this period increased from 105.3/100 000 persons to 159.9/100 000 persons. In terms of HCC, hospitalization rates increased from 13.6/100 000 to 22.1/100 000. In patients with non-alcoholic fatty liver disease (NAFLD)-related decompensated cirrhosis, the hospitalization rate increased from 13.4/100 000 to 32.1/100 000 with an annual incremental increase of 10.6%, a magnitude twofold higher than other aetiologies. The proportion of NAFLD among hospitalizations with ESLD steadily increased from 12.7% to 20.1% for decompensated cirrhosis while the proportion of chronic hepatitis C (HCV) and alcoholic liver disease (ALD) declined (from 29.3% to 27.6% for HCV; from 39.0% to 37.4% for ALD). Although the overall in-hospital mortality rates for ESLD declined during the study, mortality rates for NAFLD-related decompensated cirrhosis showed no significant change. CONCLUSIONS: Among aetiologies of chronic liver disease, NAFLD demonstrated the fastest growing rate of hospitalizations in non-HCC patients with ESLD in the US. Our study highlights the need for a focus on NAFLD-related hospitalizations and its impact on resource utilization.

Injectable Amniotic Membrane/Umbilical Cord Particulate for Knee Osteoarthritis: A Prospective, Single-Center Pilot Study.

OBJECTIVE: To evaluate the short-term safety and effectiveness of amniotic membrane/umbilical cord particulate (AMUC) in managing pain in patients with various severities of knee osteoarthritis (OA). DESIGN: Single-center, prospective, investigator-initiated pilot study. SETTING: Private practice. SUBJECTS: A total of 20 knee OA patients aged ≥18 years were enrolled with pain >40 mm, as determined by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-A. METHODS: Patients received an ultrasound-guided, intra-articular injection of 50 mg of AMUC particulate reconstituted in 2 mL of preservative-free saline. All patients were then monitored at six weeks, 12 weeks, and 24 weeks postinjection. Patients who did not show >30% reduction in pain received a second injection of AMUC at six weeks. WOMAC, Patient Global Assessment, medication usage, and magnetic resonance imaging (MRI) were assessed. RESULTS: Knee OA pain significantly decreased from 74.3 ± 17.2 at baseline to 45.0 ± 25.4 at six weeks (P < 0.01), 35.4 ± 26.6 at 12 weeks (P < 0.001), and 37.4 ± 26.7 at 24 weeks (P < 0.001). This pain reduction was associated with a significant improvement in physical function (WOMAC-C) at all time points (P < 0.05) and stiffness (WOMAC-B) at 12 weeks (P = 0.01). Eleven patients received a second injection, which was significantly correlated with body mass index >30 kg/m2 (P = 0.025). MRI evaluation of the overall population revealed an improvement in the severity of bone marrow lesions in seven patients. No adverse events were observed. CONCLUSIONS: AMUC particulate injection relieved pain and improved physical function in patients with symptomatic knee OA.

Engineering of Human Corneal Endothelial Cells In Vitro.

Human corneal endothelial cells are responsible for controlling corneal transparency, however they are notorious for their limited proliferative capability. Thus, damage to these cells may cause irreversible blindness. Currently, the only way to cure blindness caused by corneal endothelial dysfunction is via corneal transplantation of a cadaver donor cornea with healthy corneal endothelium. Due to severe shortage of donor corneas worldwide, it has become paramount to develop human corneal endothelial grafts in vitro that can subsequently be transplanted in humans. Recently, we have reported effective expansion of human corneal endothelial cells by reprogramming the cells into progenitor status through use of p120-Kaiso siRNA knockdown. This new reprogramming approach circumvents the need of using induced pluripotent stem cells or embryonic stem cells. Successful promotion of this technology will encourage scientists to re-think how "contact inhibition" can safely be perturbed to our benefit, i.e., effective engineering of an in vivo-like tissue while successful maintaining the normal phenotype. In this review, we present current advances in reprogramming corneal endothelial cells in vitro, detail the methods to successful engineer human corneal endothelial grafts, and discuss their future clinical applications to cure corneal blindness.

Cellular Substrates for Cell-Based Tissue Engineering of Human Corneal Endothelial Cells.

Corneal endothelial tissue engineering aims to find solutions for blindness due to endothelial dysfunction. A suitable combination of endothelial cells, substrates and environmental cues should be deployed for engineering functional endothelial tissues. This manuscript reviews up-to-date topics of corneal endothelial tissue engineering with special emphasis on biomaterial substrates and their properties, efficacy, and mechanisms of supporting functional endothelial cells in vitro.

Retardation of Myopia Progression by Multifocal Soft Contact Lenses.

Myopia is an important public health problem due to its prevalence and significant public health cost. Elevating levels of myopia increase the risk of vision impairment, and therefore, high myopia has become one of the main causes of untreatable vision loss throughout the world due to its irreversible complications. At present, many options for slowing progression of myopia have already been proposed and evaluated such as progressive addition of executive bifocal spectacle lenses, peripheral defocusing lenses, overnight orthokeratology, pharmacological agents such as atropine eye drops, and multifocal soft contact lenses (MFSCLs). Use of MFSCLs has especially increased in recent years due to the growing demand to slow myopia progression during patient's adolescent growth period to avoid pathological myopia in adulthood. Compared with the other traditional methods of controlling myopia, MFSCLs allow myopic patients to better maintain their clear visual quality and slow myopia progression. In this manuscript, we aim to review the basics of myopia, recent advances in contact lenses to control myopia with emphasis on MFSCLs, define the elements for proper MFSCL fittings (such as pupil size, aberrations, accommodation and centering), discuss the potential rebound effect after discontinuation of contact lenses, and future directions for improvements of contact lenses for the control of myopia.

Human Trabecular Meshwork Progenitors.

Trabecular meshwork (TM) cells are a group of progenitors that have the ability to become adipocytes, chondrocytes and endothelial cells. Therefore, those adult corneal progenitors may be used as an effective therapy for trabecular meshwork diseases such as glaucoma, corneal endothelial dysfunctions such as blindness due to corneal endothelial dysfunction, and similar diseases. In order to promote the understanding of human trabecular meshwork progenitors, this article reviews human trabecular meshwork progenitor therapy and discusses its potential applications for curing human eye blindness.

Efficacy of Ahmed Glaucoma Valve Implantation on Neovascular Glaucoma.

To evaluate the efficacy of Ahmed glaucoma valve (AGV) implantation in treating neovascular glaucoma (NVG) and analyze the factors influencing the surgical success rate, a retrospective investigation of 59 NVG patients (66 eyes) who underwent AGV implantation was conducted at Jiangsu Province Hospital, China, from January 2014 to June 2018. Intraocular pressure (IOP), visual acuity, surgical success rates, medications, and complications were monitored at post-operative 1 day, 1 week, 1, 3, 6 and 12 months. Surgical success criteria were defined as 6 mm Hg < IOP < 21 mmHg with or without additional medications. Results showed average IOP was statistically significant between pre-operative visit and each follow-up visit (all P<0.05). At 12 months, the success rate was 66.7%. Multiple stepwise regression analysis suggested that age, panretinal photocoagulation (PRP), complications and hyphema were significant factors influencing the surgical success rate (all P<0.05). Thus, we conclude that AGV implantation is effective and safe for treatment of NVG. Surgical success is dependent on age, PRP, complications, and hyphema.

Efficacy of Anterior Stromal Puncture Surgery with Corneal Bandage Lens for Bullous Keratopathy.

Objective: To investigate the safety and efficacy of the combination therapy of anterior stromal puncture (ASP) with bandage contact lens for bullous keratopathy (BK). Methods: Twelve cases (12 eyes) with vision acuity no better than light perception were treated with ASP surgery and bandage contact lens. 200 points punctures were made through the corneal epithelium and Bowman's layer vertically, using fine needles. A soft bandage contact lens was applied immediately and removed 2 weeks later. The severity of irrigating symptoms including pain, photophobia and tearing was graded and calculated before treatment and 1, 2, 4, 12 weeks after the surgery, slit-lamp microscope examination was used to quantify the time for corneal epithelial blisters disappearing, optical coherence tomography (OCT) was used to monitor the central corneal thickness. Results: No cornea infection was observed during the following up period. The average grade scores of the irrigating symptoms was 8.3 ± 2.1 before surgery, while it was reduced to 4.8 ±1.9 two weeks after the surgery (p=0.0003). Slit-lamp microscope examination showed that corneal edema relieved obviously after the operation, the average time for epithelial blisters disappearing was 15.6 ± 4.0 days. The average central corneal thickness of the eyes was 999.3 ±278.0 µm before the treatment, while it was 805.1 ± 145.0 µm four weeks after the treatment, with a statistically significant difference (p=0.043). Conclusions: ASP with bandage contact lens is an effective and safe treatment for patients with BK and low vision that not suitable for corneal transplantation.

Limbal niche cells are a potent resource of adult mesenchymal progenitors.

Limbal niche cells located in the limbal Palisades of Vogt are mesenchymal stem cells that reside next to limbal basal epithelial cells. Limbal niche cells are progenitors that express embryonic stem cell markers such as Nanog, Nestin, Oct4, Rex1, Sox2 and SSEA4, mesenchymal cell markers such as CD73, CD90 and CD105, and angiogenesis markers such as Flk-1, CD31, CD34, VWF, PDGFRß and α-SMA, but negative for CD45. In addition, the stemness of limbal niche cells can be maintained during their cell culture in a three-dimension environment. Furthermore, expanded limbal niche cells have the capability to undergo adipogenesis, chondrogenesis, osteogenesis and endogenesis in vitro, indicating that they are in fact a valuable resource of adult progenitors. Furthermore studies on how the limbal niche cells regulate the aforementioned stemness and corneal fate decision are warranted, as those investigations will shed new light on how mesenchymal progenitors reverse limbal stem cell deficiency and lead to new methods for limbal niche cell treatment.

A New Isolation Method of Human Lacrimal Canaliculus Epithelial Stem Cells by Maintaining Close Association with Their Niche Cells.

Purpose: To investigate whether lacrimal canaliculus epithelial stem cells (LCESC) could be isolated and expanded in vitro. Methods: The lacrimal canaliculus epithelium of 6 patients with limbal stem cell deficiency (LSCD) caused by alkali burn or Stevens Johnson Syndrome were examined by lacrimal endoscope. Cadaveric eyelids were fixed and prepared for cross section and stained with HE and antibodies against PCK, Vim, p63α, SCF and c-Kit. Canaliculus tissue was separated under an operating microscope using a lacrimal probe as an indicator and digested with collagenase A. The clusters of epithelial cells with closely associated stroma were further digested with Trypsin/EDTA to obtain single cells for culture on Matrigel-coated plastic plates in MESCM media. The expression of SCF, c-Kit and p63α was determined by immunostaining. The colony-forming efficiency on 3T3 feeder layers was also measured by calculating the percentage of the clone number divided by the total number cells seeded. Results: The epithelial layers of five out of six inferior lacrimal canaliculi and all the six superior lacrimal canaliculi were visually normal in appearance. Five to fifteen layers of the epithelium in the human lacrimal canaliculi were present with a small, tightly compacted basal layer of cells expressing PCK, p63α, SCF and c-Kit. LCESC were isolated by collagenase A and obtained clonal growth in MESCM. The colony-forming efficiency of LCESC holoclones on a 3T3 feeder layer was 3.2%, compared to 1.9% for those of limbal stem cells (LSC). Conclusions: Herein, we first report that LCESCs can be isolated and have stem cell characteristics, similar to those of LSCs. Such a discovery raises a promising substrate resource of stem cells for LSC reconstruction in LSCD patients.