3D organoid cultivation improves the maturation and functional differentiation of cholangiocytes from human pluripotent stem cells.

Idiopathic cholangiopathies are diseases that affect cholangiocytes, and they have unknown etiologies. Currently, orthotopic liver transplantation is the only treatment available for end-stage liver disease. Limited access to the bile duct makes it difficult to model cholangiocyte diseases. In this study, by mimicking the embryonic development of cholangiocytes and using a robust, feeder- and serum-free protocol, we first demonstrate the generation of unique functional 3D organoids consisting of small and large cholangiocytes derived from human pluripotent stem cells (PSCs), as opposed to traditional 2D culture systems. At day 28 of differentiation, the human PSC-derived cholangiocytes expressed markers of mature cholangiocytes, such as CK7, CK19, and cystic fibrosis transmembrane conductance regulator (CFTR). Compared with the 2D culture system-generated cholangiocytes, the 3D cholangiocyte organoids (COs) showed higher expression of the region-specific markers of intrahepatic cholangiocytes YAP1 and JAG1 and extrahepatic cholangiocytes AQP1 and MUC1. Furthermore, the COs had small-large tube-like structures and functional assays revealed that they exhibited characteristics of mature cholangiocytes, such as multidrug resistance protein 1 transporter function and CFTR channel activity. In addition to the extracellular matrix supports, the epidermal growth factor receptor (EGFR)-mediated signaling regulation might be involved in this cholangiocyte maturation and differentiation. These results indicated the successful generation of intrahepatic and extrahepatic cholangiocytes by using our 3D organoid protocol. The results highlight the advantages of our 3D culture system over the 2D culture system in promoting the functional differentiation and maturation of cholangiocytes. In summary, in advance of the previous works, our study provides a possible concept of small-large cholangiocyte transdifferentiation of human PSCs under cost-effective 3D culture conditions. The study findings have implications for the development of effective cell-based therapy using COs for patients with cholangiopathies.

The hiPSC-derived corneal endothelial progenitor-like cell recovers the rabbit model of corneal endothelial dystrophy.

INTRODUCTION: Corneal endothelial dysfunction results in cornea opacity, damaging sightedness, and affecting quality of life. A corneal transplant is the current effective intervention. Due to the scarcity of donated cornea, such an unmet medical need requires a novel therapeutic modality. OBJECTIVES: Customizing patients' corneal endothelial progenitor cells with proliferative activity and lineage restriction properties shall offer sufficient therapeutic cells for corneal endothelial dystrophy. METHODS: The customized induced human corneal endothelial progenitor-like cell (iHCEPLC) was obtained through cell fate conversions starting from PBMC (peripheral blood mononuclear cell), hiPSC (human induced pluripotent stem cell), and hNCC (human neural crest cell), while it finally reached the iHCEPLC state via a series of induction. Several molecular diagnoses were applied to depict its progenitor state, including RNAseq, FlowCytometer, immunostainings, and rtPCR. Significantly, it can be induced to gain differentiation maturity through contact inhibition. In addition, a BAK-mediated rabbit model of corneal endothelial dystrophy was established in the present study to test the therapeutic effectiveness of the iHCEPLC. RESULTS: After inducing cell fate conversion, the specific HCEC markers were detected by rtPCR and immunostaining in iHCEPLC. Further, RNAseq was applied to distinguish its progenitor-like cell fate from primary human corneal endothelial cells (HECE). FlowCytometry profiled the heterogeneity subpopulation, consistently displaying a subtle difference from primary HCEC. A terminal differentiation can be induced in iHCEPLC, addressing its progenitor-like fate. iHCEPLC can restore the BAK-based rabbit model of corneal endothelial dystrophy. Immunohistochemistry verified that such acuity restoration of the BAK-treated cornea is due to the introduced iHCEPLC, and such therapeutic effectiveness is observed in the long term. CONCLUSION: Here, we demonstrated that customized iHCEPLC has long-term therapeutic efficacy. As a progenitor cell, our iHCEPLC has a restricted cell lineage nature and can proliferate in vitro, supporting sufficient therapeutic candidate cells. Due to the immune-privileged nature of the cornea, our iHCEPLC proves the principle of therapeutical feasibility in both autogenic and allogeneic modalities.

Corrigendum: Potential of cellular therapy for ALS: current strategies and future prospects.

[This corrects the article DOI: 10.3389/fcell.2022.851613.].

The Association between Elevated Hematocrit and Retinal Artery Occlusion in Adult Patients.

Retinal artery occlusion (RAO) is most commonly caused by embolism. Evidence showed that hematocrit (Hct) levels are often associated with embolic events. In this study, we aim to investigate the relationship between Hct levels and RAO. This retrospective study enrolled RAO patients between January 2011 and March 2020, who were 1:4 matched by age, gender, index date, and relevant comorbidities with the non-RAO group. Patient characteristics and laboratory data were collected. Univariate conditional logistic regression was applied by estimating crude matched odds ratios to determine the relevant factors for the occurrence of RAO. Furthermore, a narrative review of the relevant study was conducted to explore the association between Hct levels and embolism. Between January 2011 to March 2020, 82 RAO patients and 328 non-RAO patients matched with age, gender, index date, comorbidities of hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, stroke, and atrial fibrillation were enrolled after excluding ineligible individuals. Conditional logistic regression analysis showed that Hct level ≥ 40% was associated with developing RAO. A forest plot showed a trend of a non-linear dose-response association between Hct levels and ischemic vascular events in male patients. Hct levels ≥ 40% in patients older than 65 years with at least six comorbidities could be associated with RAO. We suggest that older patients who have multiple comorbidities, combined with elevated Hct levels, should be informed of the possible occurrence of RAO.

Potential of Cellular Therapy for ALS: Current Strategies and Future Prospects.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive upper and lower motor neuron (MN) degeneration with unclear pathology. The worldwide prevalence of ALS is approximately 4.42 per 100,000 populations, and death occurs within 3-5 years after diagnosis. However, no effective therapeutic modality for ALS is currently available. In recent years, cellular therapy has shown considerable therapeutic potential because it exerts immunomodulatory effects and protects the MN circuit. However, the safety and efficacy of cellular therapy in ALS are still under debate. In this review, we summarize the current progress in cellular therapy for ALS. The underlying mechanism, current clinical trials, and the pros and cons of cellular therapy using different types of cell are discussed. In addition, clinical studies of mesenchymal stem cells (MSCs) in ALS are highlighted. The summarized findings of this review can facilitate the future clinical application of precision medicine using cellular therapy in ALS.

Increased risk of glaucoma amongst new-onset gout patients aged 20-39 years: A nationwide population-based cohort study in Taiwan.

OBJECTIVES: To provide epidemiologic evidence of whether gout increases the risk of new-onset glaucoma. METHODS: We conducted a 13-year nationwide, population-based, retrospective cohort study to examine the association between the history of gout and risk of glaucoma by using the Longitudinal Health Insurance Database (LHID) of Taiwan. The gout cohort included 52 943 patients with newly diagnosed gout who were recruited between 2000 and 2012. Each patient was propensity score matching with 1:1 person without gout from the LHID. To determine glaucoma occurrence, the study population was followed up until the end of 2013. Cumulative incidence, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated after adjusting for age, sex, comorbidities, and ever ophthalmic visit. A Cox proportional hazard model was used to analyse the association between gout and incidence of glaucoma amongst patients with different potential risks. RESULTS: The adjusted HR for newly diagnosed glaucoma in the gout cohort was 1.00 (95% CI = 0.93-1.07, P = .931), compared with the non-gout cohort. Stratified subgroup analysis revealed that the HRs of glaucoma were 1.36 (95% CI = 1.09-1.70, P = .007), 0.99 (95% CI = 0.87-1.12, P = .871), and 0.95 (95% CI = 0.87-1.03, P = .235) in patients with gout aged 20-39, 40-54, and ≥55 years, respectively (P for interaction = .011). CONCLUSION: This nationwide population-based cohort study revealed that gout patients in the age group 20-39 years had a higher risk of glaucoma than non-gout controls.

Risk factors of strabismus surgery among pediatric cerebral palsy population with strabismus in Taiwan: A population-based cohort study.

BACKGROUND: To identify the risk factors of strabismus surgery among Taiwanese children with severe cerebral palsy (CP) and strabismus. METHODS: This retrospective nationwide population-based cohort study examined a cohort of newly diagnosed pediatric CP patients (age ≤ 10 y) between 1997 and 2013 with strabismus. The primary endpoint was strabismus surgery. A stepwise logistic regression was applied to determine the demographic factors, ophthalmic conditions, and comorbidities associated with strabismus surgery. RESULTS: Out of 808 patients, 115 had received strabismus surgery. The significant factors correlated to strabismus surgery in pediatric patients with severe CP and strabismus were CP diagnosis age < 4 years, residency in a suburban/rural area, low birth weight, and strabismic amblyopia. CONCLUSION: In CP children with strabismus who have risk factors of younger CP diagnosis age (age < 4 y), residency in a suburban/rural area, a low birthweight, and the presence of strabismic amblyopia, strabismus surgery should be considered.

Wireless Charging Deployment in Sensor Networks.

Charging schemes utilizing mobile wireless chargers can be applied to prolong the lifespan of a wireless sensor network. In considering charging schemes with mobile chargers, most current studies focus on charging each sensor from a single position, then optimizing the moving paths of the chargers. However, in reality, a wireless charger may charge the same sensor from several positions in its path. In this paper we consider this fact and seek to minimize both the number of charging locations and the total required charging time. Two charging plans are developed. The first plan considers the charging time required by each sensor and greedily selects the charging service positions. The second one is a two-phase plan, where the number of charging positions is first minimized, then minimum charging times are assigned to every position according to the charging requirements of the nearby sensors. This paper also corrects a problem neglected by some studies in minimizing the number of charging service positions and further provides a corresponding solution. Empirical studies show that compared with other minimal clique partition (MCP)-based methods, the proposed charging plan may save up to 60% in terms of both the number of charging positions and the total required charging time.

Characteristics of diabetic macular edema on optical coherence tomography may change over time or after treatment.

PURPOSE: To investigate optical coherence tomography (OCT) characteristics in diabetic macular edema (DME) over time and after treatment. PATIENTS AND METHODS: OCT morphological features in DME eyes treated with ranibizumab with at least 1 year of follow-up were retrospectively analyzed. RESULTS: Thirty-five eyes were included. From baseline to Month 12, mean visual gain was 7.2±13.6 letters and mean central retinal thickness reduction was 61.9±121.8 µm. Fovea-involving ellipsoid zone (EZ) disruption was significantly associated with final vision of <70 letters. Subretinal fluid at baseline was present only in eyes naïve to previous intravitreal pharmacotherapy and was related to better visual gain and fewer injections. Treatment-naïve eyes had shorter DME duration and less EZ damage. CONCLUSION: DME characteristics on OCT may change over time or after treatment. Subretinal fluid may be associated with earlier change and less EZ damage in DME.

Correlation between baseline retinal microstructures in spectral-domain optic coherence tomography and need for early intervention in central serous chorioretinopathy.

PURPOSE: To investigate the association between baseline retinal microstructures observed with spectral-domain optical coherence tomography (OCT) and the need for early intervention in central serous chorioretinopathy (CSC). METHODS: Cases of acute CSC from July 2011 to December 2014 were retrospectively reviewed. OCT images were further classified using six parameters: foveal serous retinal detachment; pigment epithelial detachment; fibrinous exudates in the subretinal space; retinal pigment epithelium bumps; thickened outer retinal layer and hyper-reflective dots in the intraretinal and/or subretinal layer. Correlation among these parameters and the need for intervention was analysed. Receiver operating characteristic (ROC) curves were performed to identify the optimal number of parameters for prediction. RESULTS: A total of 47 eyes from 47 patients were included. Among these, 25 eyes required treatment. The presence of subretinal hyper-reflective dots was the only OCT factor having significant association with the need for intervention. An ROC curve analysis revealed that the optimal cut-off value (Youden index) was achieved when combining subretinal hyper-reflective dots with aged ≥50 years and female sex for analysis (area under the curve, 0.735; Youden index: 0.425). CONCLUSION: The presence of subretinal/intraretinal hyper-reflective dots observed with OCT, female and aged ≥50 years might help predict the need for early intervention in acute CSC.

Successful Management in a Case of Traumatic Retinal Detachment due to Open Globe Injury Using Microincisional Vitrectomy.

BACKGROUND: Retinal detachment (RD) following ocular trauma often results in guarded visual prognosis and sometimes leads to loss of the eye. With the advent of microincisional vitrectomy surgery and the development of surgical techniques, the management of ocular trauma has been transformed. CASE PRESENTATION: A 34-year-old man sustained an open globe injury from fragmented glass at work. He received primary repair and another follow-up surgery 9 days later, including vitrectomy, silicone oil tamponade, and lensectomy for RD and traumatic cataract at another medical center. However, his retina was totally detached and completely curled up in a roll with choroid on display when he was seen by us 1 month later. He was managed with vigilant and patient peeling and unfolding of the retina using a 23-gauge forceps and silicone oil tamponade, and achieved anatomical success and preservation of his eye at 6-month follow-up. CONCLUSIONS: This report demonstrates that even in cases which appear to be hopeless at presentation, the surgeon's perseverance and surgical technique can salvage an eye that may otherwise be phthisical. It also encourages retinal surgeons to use microincisional vitrectomy to manage severe traumatic RD.

A pilot study on efficacy treatment of acne vulgaris using a new method: results of a randomized double-blind trial with Acne Dressing.

For many years the positive effect of hydrocolloid dressings on skin-related conditions attracted the attention of the medical scientific community. The use of Acne Dressing, a tape of hydrocolloid dressing, for the treatment of acne has not been reported previously. The aim of this study was to evaluate the clinical efficacy and beneficial effect of Acne Dressing on the marker for sebum output evaluations. We also determined the cosmetic outcome of this application during the treatment of acne and whether the material could prevent hand touching and UVB light from reaching the skin surface. The objective of this study was to assess improvement in acne vulgaris and tolerability during one week of short contact treatment with Acne Dressing compared to skin tapes. Efficacy data specific to treatment of acne vulgaris with Acne Dressing (3M Health Care) from a double-blind, randomized, skin types-controlled study is reported. A total of 20 patients with mild-to-moderate acne vulgaris applied the skin tapes or Acne Dressing every two days for up to one week. Twenty patients were enrolled in this study: ten patients received Acne Dressing and ten patients received skin tapes. Both groups showed decreases from baseline to the end of treatment in the mean of the overall severity scale (decrease of 1.37 from 1.8 to 0.43 with Acne Dressing and 0.28 from 1.08 to 0.8 with skin tapes). A statistically significant greater reduction was observed over a period of three to seven days in the overall severity of acne and inflammation in the Acne Dressing group compared with the mono-therapy (skin tapes) group. Similarly, Acne Dressing resulted in a significantly greater improvement in the redness, oiliness, dark pigmentation, and sebum casual level at days 3, 5, and 7. The ratio of transmission of UVB light with Acne Dressing was 7.4%, and 38% with skin tapes, which shows less UVB light reaching the skin surface with the Acne Dressing. No significant adverse events were identified in either group. The pilot study shows the benefit of treatment with Acne Dressing in improving mild-to-moderate inflammatory acne vulgaris. A future study will investigate a large set of patients in longer followup periods.

Neutrophilic panniculitis with myelodysplastic syndromes presenting as pustulosis: case report and review of the literature.

Neutrophilic panniculitis associated with myelodysplastic syndromes is rare. We report a 59-year-old patient who initially was diagnosed with myelodysplastic syndrome (MDS) and developed a sudden onset of widespread pustulosis and erythematous indurated papules. Examination of skin biopsies of a papule lesion showed dense neutrophilic infiltration limited to the subcutaneous tissue. The pustules and papules disappeared completely after treatment with systemic corticosteroids. To our knowledge, only one patient was identified by MEDLINE search of the English-language literature.