Phase I clinical trial of intracerebroventricular transplantation of allogeneic neural stem cells in people with progressive multiple sclerosis.

We report the analysis of 1 year of data from the first cohort of 15 patients enrolled in an open-label, first-in-human, dose-escalation phase I study (ClinicalTrials.gov: NCT03282760, EudraCT2015-004855-37) to determine the feasibility, safety, and tolerability of the transplantation of allogeneic human neural stem/progenitor cells (hNSCs) for the treatment of secondary progressive multiple sclerosis. Participants were treated with hNSCs delivered via intracerebroventricular injection in combination with an immunosuppressive regimen. No treatment-related deaths nor serious adverse events (AEs) were observed. All participants displayed stability of clinical and laboratory outcomes, as well as lesion load and brain activity (MRI), compared with the study entry. Longitudinal metabolomics and lipidomics of biological fluids identified time- and dose-dependent responses with increased levels of acyl-carnitines and fatty acids in the cerebrospinal fluid (CSF). The absence of AEs and the stability of functional and structural outcomes are reassuring and represent a milestone for the safe translation of stem cells into regenerative medicines.

High Rates of Hidden HCV Infections among Hospitalized Patients Aged 55-85.

BACKGROUND AND AIMS: The WHO has solicited all countries to eliminate HCV by 2030. The Italian government started routine screening for HCV infection in January 2021, initially targeting subjects born between 1969 and 1989. With the aim of achieving micro-elimination, we designed a hospital-wide project focusing on inpatients born from 1935 to 1985 and conducted it in our institution. METHOD: All inpatients aged 35 to 85, admitted from 10 February 2020 to 9 February 2021 for many different diseases and conditions underwent HCV antibody (HCVAb) testing by third-generation ELISA. When positive, reflex HCV RNA testing and genotyping were performed. Clinical history, fibrosis diagnosis, laboratory data and concomitant medications were available for all. RESULTS: The HCV screening rate of inpatients was 100%. In total, 11,748 participants were enrolled, of whom 53.50% were male. The HCVAb positivity rate was 3.03%. The HCVAb rate increased with age and was higher for patients born between 1935 and 1944 (4.81%). The rate of HCV RNA positivity was 0.97%. The vast majority (80.70%) of HCV RNA-positive participants were 55 or older; in about 40% of cases, HCV RNA-positive patients were unaware of their infection. Although 16 patients died after HCV chronic infection diagnosis (two due COVID-19) or HCV treatment prescription (one due to COVID-19), 74.56% of patient HCV diagnoses were linked to HCV treatment, despite their co-morbidities. All patients older than 65 who died had an active HCV infection. CONCLUSION: The present study revealed a rate of active HCV infections among inpatients lower than what has been reported in the past in the general population; this appears to be a result of the widespread use of pangenotypic direct-acting antiviral agents (DAAs). The overall rate of active infection was lower than the rate observed in the 1935-1954 cohort. The high rate of inpatients unaware of HCV infections and the high number of deaths among subjects with an active HCV infection born from 1935 to 1954, suggest that, at least in southern Italy, targeted screening of this birth cohort may be required to reduce the number of undiagnosed cases and hidden infections.

Chromophore-Assisted Retinal Break Detection to Manage Challenging Situations in Retinal Detachment Redo Surgery.

INTRODUCTION: The purpose of this case series is to demonstrate that subretinal blue dye injection, with and without 180-degree endolaser retinopexy, can be considered a useful tool in finding occult rhegmatogenous retinal breaks in eyes with recurrent retinal detachment. Case Presentation. Three patients with recurrent retinal detachment were treated between January and March 2018. In all cases, the intraoperative internal search did not demonstrate any obvious break or hole. MembraneBlue-Dual (Trypan Blue 0.15% + Brilliant Blue G 0.025% + 4% PEG) was then injected into the subretinal space using a 41-gauge cannula. The eye was rotated such that the dye was pushed through a tiny break which was causing the retinal detachment. 180-degree laser retinopexy was performed on a single eye. After silicon oil removal and absorption of the gas tamponade, retinas remained attached at three-months follow-up. CONCLUSIONS: Chromophore-assisted occult retinal break detection can be considered a useful but not risk-free surgical technique in managing some unexpected and challenging intraoperative situations.

Von Hippel-Lindau disease: when neurosurgery meets nephrology, ophthalmology and genetics.

INTRODUCTION: Von Hippel-Lindau (VHL) disease is a dominantly inherited condition associated with tumors in multiple organs, whose treatment requires heightened multidisciplinary teamwork. Therefore, a document summarizing all the pertinent knowledge is needed to enhance coordination of care. EVIDENCE ACQUISITION: A systematic review of the literature from the Medline, Embase and Cochrane Central databases was performed. From 1970 to 2017, all articles meeting specific inclusion criteria were included by at least one specialist physician for each field. EVIDENCE SYNTHESIS: We included 95 articles, mostly dealing with genetics or management of VHL associated tumors in one organ system. There were no papers discussing the manifestations of VHL altogether, which was the aim of our paper. CONCLUSIONS: VHL requires a multidisciplinary management to provide the highest quality of care. Coordination and communication between patients and caregivers is enhanced when knowledge is shared. Gathering together specialists in different domains around the production and reading of a comprehensive document such as the one hereby may contribute to this purpose.

Mutational screening of VSX1, SPARC, SOD1, LOX, and TIMP3 in keratoconus.

PURPOSE: To evaluate the involvement of Visual System Homeobox 1 (VSX1), Secreted Protein Acidic and Rich in Cysteine (SPARC), Superoxide Dismutase 1 (SOD1), Lysyl Oxidase (LOX), and Tissue Inhibitor of Metalloproteinase 3 (TIMP3) in sporadic and familial keratoconus. METHODS: Mutational analysis of the five genes was performed by sequencing and fragment analysis in a large cohort of 302 Italian patients, with a diagnosis of keratoconus based on clinical examination and corneal topography. The variants identified in VSX1 and SPARC were also assessed in the available relatives of the probands. RESULTS: A novel mutation p.G239R and previously reported mutations were found in VSX1. Novel and already reported variants were identified in SPARC and SOD1, whose pathogenic significance has not been established. No pathogenic variants have been identified in LOX and TIMP3. CONCLUSIONS: Molecular analysis of the five genes in a cohort of 225 sporadic and 77 familial keratoconus cases confirms the possible pathogenic role of VSX1 though in a small number of patients; a possible involvement of LOX and TIMP3 could be excluded; and the role played by SOD1 and SPARC in determining the disease as not been definitively clarified. Further studies are required to identify other important genetic factors involved in the pathogenesis and progression of the disease that in the authors' opinion, and according with several authors, should be considered as a complex disease.

Refractive outcome of keratoconus treated by combined femtosecond laser and big-bubble deep anterior lamellar keratoplasty.

PURPOSE: To report 1-year follow-up in 11 of 13 eyes with keratoconus treated by deep anterior lamellar keratoplasty with a combined femtosecond laser lamellar resection followed by a big-bubble dissection. METHODS: Thirteen eyes with keratoconus were treated. Recipient and donor were prepared with the 60-kHz IntraLase femtosecond laser (Abbott Medical Optics). In the recipient, the femtosecond laser, after performing a lamellar cut 100 µm above the thinnest corneal point (measured by Pentacam [Oculus Optikgeräte GmbH]), was used to make a mushroom-shaped resection (anterior diameter, 9 mm; posterior diameter, 8 mm) from the same depth. In the donor, the mushroom lamellar thickness was calculated according to an original model based on the recipient preoperative corneal thickness. Upon removal of the recipient lamella, air was injected into the residual stroma to achieve a big bubble. The keratectomy was continued up to Descemet membrane. The donor was fit into place and sutured using interrupted sutures, which were removed by 8 months postoperative. Corrected distance visual acuity (CDVA) and refractive astigmatism were calculated by manifest refraction, whereas topographic astigmatism and corneal thickness were measured by Pentacam. RESULTS: A big bubble was successfully achieved in 11 eyes. Twelve months after surgery, mean CDVA was 0.52±1.2 (decimal), and refractive sphere and cylinder were -1.50±1.70 diopters (D) and 2.00±2.60 D, respectively. Three (27%) of 11 eyes at 1 year had a manifest refraction spherical equivalent within 1.00 D of emmetropia. Topographic astigmatism was 2.90±1.60 D. The thinnest corneal point was 519±27 µm. CONCLUSIONS: This combination of a femtosecond laser lamellar dissection with a big-bubble technique can improve the standardization of deep anterior lamellar keratoplasty for keratoconus.

Standardized big-bubble technique in deep anterior lamellar keratoplasty assisted by the femtosecond laser.

We describe a variant of the big-bubble technique in deep anterior lamellar keratoplasty (DALK) assisted by the IntraLase femtosecond laser, which we call IntraBubble. The use of the 60 kHz IntraLase femtosecond laser allows dissection of the pre-Descemet-plane lamella to a predefined corneal depth and creation of a channel in the posterior stroma 50 µm above the endothelium into which a smooth cannula for air injection can be introduced. We lengthened the channel created by the laser using a pointed dissector. Eleven consecutive patients with keratoconus were treated, and all procedures were completed as DALK. The big bubble was achieved in 8 eyes (73%). In 3 cases (27%), intraoperative microperforations occurred and the procedures were completed with hand dissection without complications. This new application of femtosecond laser technology could lead to standardization of the big-bubble technique in DALK.

Anterior lamellar keratoplasty assisted by IntraLase™ femtosecond laser in a pediatric patient.

A 14-year-old boy affected by keratoconus underwent an anterior lamellar keratoplasty assisted by IntraLase femtosecond laser (Abbott Medical Optics, Abbott Park, IL). Results after 2 years of follow-up indicate the procedure may be safe and effective in pediatric patients.

Arcuate keratotomy for high postoperative keratoplasty astigmatism performed with the intralase femtosecond laser.

PURPOSE: To evaluate the refractive and keratometric effect of arcuate keratotomy performed using the IntraLase femtosecond laser (Abbott Medical Optics) in patients with high postoperative keratoplasty astigmatism. METHODS: Nine eyes of nine patients (mean age 45 +/- 7.5 years; mean spherical equivalent refraction -2.50 +/- 3.60 diopters [D]) who had undergone a penetrating keratoplasty were considered. The subjective refraction was measured, and corneal thickness and keratometric parameters were calculated by the Pentacam (Oculus Optikgeräte). All uncomplicated surgeries were performed with the IntraLase femtosecond laser. Paired 70 degrees arc length incisions were performed at 80% depth of the corneal thickness. The mean optical zone was 5.9 mm. The side cut was 90 degrees. All incisions were performed in the graft itself. Mean change in best spectacle-corrected visual acuity (BSCVA), refractive and keratometric astigmatism, and spherical equivalent refraction was evaluated. Follow-up was 3 months. Refractive and keratometric data were analyzed using vector analysis as described by Alpins. A paired Student t test was used to compare preoperative and 3-month postoperative data. A P value <.05 was considered significant. RESULTS: Mean preoperative BSCVA was 20/30, increasing to 20/25 postoperatively (P > .05). The mean refractive astigmatism decreased by 6.00 D (P < .05), whereas the mean keratometric value decreased by 4.60 D (P < .05). The mean spherical equivalent refraction did not change significantly. The surgical vectors in the refractive and keratometric analysis were calculated, showing good predictability. CONCLUSIONS: Arcuate keratotomy performed with the IntraLase femtosecond laser could be an effective, safe, and relatively predictable treatment of high postoperative keratoplasty astigmatism.

A new transepithelial phototherapeutic keratectomy mode using the NIDEK CXIII excimer laser.

PURPOSE: To evaluate epithelial healing, postoperative pain, and best spectacle-corrected visual acuity (BSCVA) after transepithelial photorefractive keratectomy (PRK) performed with a new phototherapeutic keratectomy (PTK) mode using the NIDEK CXIII excimer laser. METHODS: Fifteen eyes from 10 patients with myopia underwent transepithelial PRK using a multistage program to perform PTK followed by PRK. The PTK incorporated Flex Scan, which accounts for the loss of radial ablation efficiency on the peripheral cornea. The epithelium was removed with the excimer laser by monitoring the disappearance of blue fluorescence during the ablation. Epithelial healing was evaluated by taking slit-lamp photographs every 24 hours until complete reepithelialization. Postoperative pain was measured according to the Faces Pain Rating Scale. All outcomes are reported for 3 months postoperatively. Haze was graded by two ophthalmologists, each masked to the other's result. RESULTS: Mean reepithelialization took 3.50+/-0.85 days, mean pain score was 3.00+/-1.20, and BSCVA was 20/20 for 9 eyes, 20/30 for 3 eyes, and 20/40 for 3 eyes. All patients had haze below grade 2. CONCLUSIONS: The outcomes of the preliminary study show that the incorporation of the Flex Scan algorithm in the PTK mode is as safe and effective as conventional PTK algorithms. The primary advantage of this new PTK mode may be more consistent epithelial removal. Additional studies are needed to determine long-term outcomes.

Linkage analysis in keratoconus: replication of locus 5q21.2 and identification of other suggestive Loci.

PURPOSE: Keratoconus (KC) is the most common indication for corneal transplantation in the Western world, with etiologic mechanisms still poorly understood. The disease prevalence in the general population is approximately 1:2000, and familial aggregation, together with increased familial risk, suggests important genetic influences on its pathogenesis. To date, several loci for familial keratoconus have been described, without the identification of any responsible gene in the respective mapped intervals. The aim of this study was to identify causative/susceptibility genes for keratoconus. METHODS: A total of 133 individuals (77 affected and 59 unaffected) of 25 families from southern Italy were genotyped using microsatellite markers and included in a genome-wide scan. Nonparametric and parametric analysis using an affected-only strategy were calculated by using genetic algorithm software. RESULTS: The chromosomal regions 5q32-q33, 5q21.2, 14q11.2, 15q2.32 exhibited the strongest evidence of linkage by nonparametric analysis (NPL = 3.22, 2.73, 2.62, and 2.32, respectively). The regions 5q32-q33 and 14q11.2 were also supported by multipoint parametric analysis, for which heterogeneity LOD (HLOD) scores of 2.45 (alpha = 0.54) and 2.09 (alpha = 0.46), respectively, were obtained under an affected-only dominant model. CONCLUSIONS: This study represents the first KC linkage replication study on the chromosomal region 5q21.2 and reports evidence of suggestive linkage in several regions for which suggestive or significant linkage has been previously detected in different populations.

Comparison of corneal aberration changes after laser in situ keratomileusis performed with mechanical microkeratome and IntraLase femtosecond laser: 1-year follow-up.

PURPOSE: To compare corneal aberration changes 1 year after myopic laser in situ keratomileusis (LASIK) performed with a mechanical microkeratome and IntraLase femtosecond laser. METHODS: Twenty four eyes of 15 patients underwent LASIK with the Hansatome microkeratome, and 23 eyes of 13 patients underwent LASIK with the IntraLase femtosecond laser. A standard ablation was performed with the Bausch & Lomb Technolas 217 excimer laser. Topography data were used to calculate corneal aberrations with a 3.0 mm and 5.00 mm pupil, before and 12 months after surgery. The increasing factor (IF), defined as the ratio between the postoperative and preoperative mean value of the optical aberration, was calculated. The method of Mulhern et al was used to evaluate the centration of ablation. The comalike aberration was correlated with the decentration of ablation. The Student t test was used for the statistical anaylsis. RESULTS: The postoperative mean decentration of ablation was <0.5 mm. The comalike aberration appeared to be positively correlated with the decentration of ablation in both groups with a 5.0-mm pupil (P < 0.05). With a 3.00-mm pupil, the comalike aberration changed in the Hansatome group, whereas with a 5.00-mm pupil, all aberrations statistically significantly changed in both groups (P < 0.05). The IF similarly increased in 2 groups for spherical-like aberration, whereas IF greatly increased for total and comalike aberrations in the Hansatome group. CONCLUSIONS: Wavefront corneal aberrations change significantly 1 year after myopic LASIK performed with the Hansatome microkeratome as well as with IntraLase femtosecond lasers. Both of the procedures induce higher-order aberrations in the anterior corneal surface, but the amount of comalike aberration increases more with the Hansatome mechanical microkeratome.