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von Hippel-Lindau (VHL) disease is an autosomal dominant inherited multi systemic cancer syndrome that is classically associated with neoplasms in multiple organs, and caused by mutations in the VHL gene on chromosome 3p25-p26. Retinal hemangioblastoma (RH) is the most frequent and the earliest clinical sign of the disease, which is seen in 40.0-60.0% of patients. In recent years, studies of patients with VHL tried to put forward the relationship between genotype and phenotype. In this study, two VHL cases in the same family with clinical findings and genetic analysis results are presented. As a consequence of the genetic studies, a heterozygous missense mutation c.202 T>C, p.S68P (Ser68Pro) in exon 1 of the VHL gene that is mapped to chromosome 3p25.3, was found in the patients’ DNA sample. The germline mutation of [c.202T>C, p.S68P (Ser68Pro)] that was detected in both cases, has been reported in only two cases in the literature. However, in these reported cases, any systemic involvement except RH, were not reported. Although our cases had the same mutation, we detected renal involve-ment in both cases, and also central nervous system (CNS) involvement in one case, in addition to RH.

Simulating large systems often leaves the programmer with only one option: parallel distributed simulations where parts of the system are allocated and simulated on different processing elements (PEs). A large [...], In a parallel discrete-event simulation (PDES) scheme, tasks are distributed among processing elements (PEs) whose progress is controlled by a synchronization scheme. For lattice systems with short-range interactions, the progress of the conservative PDES scheme is governed by the Kardar-Parisi-Zhang equation from the theory of nonequilibrium surface growth. Although the simulated (virtual) times of the PEs progress at a nonzero rate, their standard deviation (spread) diverges with the number of PEs, hindering efficient data collection. We show that weak random interactions among the PEs can make this spread nondivergent. The PEs then progress at a nonzero, near-uniform rate without requiring global synchronizations.

Aim: To investigate the corneal central and limbal thickness in cornea scar patients using high-resolution anterior segment optical coherence tomography (AS-OCT) and to determine the changes in the limbal region due to the corneal scar. Also, to evaluate tear film parameters in scar patients., Methods: Thirty patients with central corneal scar and 30 control subjects. The control subjects were healthy individuals who came to our clinic for routine ophthalmological examination. They were enrolled in this matched case-control study. Central epithelial thickness (ET), stromal thickness (ST), limbal epithelial thickness (LET), and limbal stromal thickness (LST) were analyzed using high-resolution AS-OCT. For evaluation of the ocular surface, the following techniques were used: tear break-up time (BUT) employing standard sterile strips of fluorescein sodium, Schirmer test-I (SCH), and the Ocular Surface Disease Index (OSDI) Questionnaire., Results: The mean central ET of the patient group was 51.5 ± 12.4 µm, while the mean central ET of the control group was 59.2 ± 9.0 µm. There was a statistically significant difference between patients and controls (p = 0.008). The mean LST of the patients was 747.9 ± 115.7 µm, and the mean LST of the controls was 726.3 ± 79.7 µm. There was a statistically significant difference between patients and controls according to BUT (p = 0.009) and SCH (p = 0.04). However, there was no significant difference between OSDI results of patients and controls (p = 0.08)., Conclusion: Corneal monitoring with high-resolution AS-OCT is a simple, noninvasive, useful technique for corneal scar patients. Cornea scars cause decreased ET. This result could be associated with lower tear film parameters in scar patients. The scar length is associated with higher intraocular pressure (IOP) values. Decreased LET and increased LST were detected in scar patients., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Objective (Aim): To observe the ocular structural changes in active and inactive uveitis patients. Methods: This retrospective study involved 30 patients (32 eyes) with anterior and intermediate uveitis cases and 54 eyes of 54 cases in a control group, who were admitted to the Ophthalmology Department at Trakya University. In the study group, 14 patients were females, 16 patients were males and in the control group 26 volunteers were females, and 28 volunteers were male of the 54 volunteers. Anterior chamber depth, axial length, intraocular pressure, lens thickness, central corneal thickness, steep and flat values in keratometry, corrected visual acuity in both eyes, anterior chamber cells, and vitreous cells were measured and compared between three groups (two uveitis groups - active and inactive - and control group). Results: In the comparison of the median values of axial length, central corneal thickness, and steep and flat values of keratometry, the values of the patients with active uveitis were higher than the ones in the control group in each parameter, but no significant difference was observed. The anterior chamber depth parameter value was higher, the lens thickness value was lower in patients with active uveitis than the values in the control group and the differences were statistically significant (p<0,05). No significant structural differences in the values of the active and inactive group patients (p>0,05) were observed. Conclusions: Only lens thickness and anterior chamber depth parameters were statistically significant in patients with active uveitis, compared with the inactive uveitis group. Anterior chamber depth measurement values were higher and lens thickness measurement values were lower in patients with active uveitis when compared with the control group. Abbreviations: AAU = Acute anterior uveitis, CAU = Chronic Anterior Uveitis, AC = Anterior Chamber, IOP = Intraocular Pressure, IVCM = in vivo Confocal Microscopy, AS-OCT = Anterior Segment Optical Coherence Tomography, UBM = Ultrasound Biomicroscopy, LFP = Laser Flare Photometry, KP = Keratic Precipitates, OCT = Optical Coherence Tomography, AL = Axial Length, ACD = Anterior Chamber Depth, LT = Lens Thickness, CCT = Central Corneal Thickness, Ks = Steep Value of Keratometry, Kf = Flat Value of Keratometry, AUP = Active Uveitis Patients, IUP = Inactive Uveitis Patients, SUN = Standardization of Uveitis Nomenclature., (#x00A9; The Authors.Romanian Society of Ophthalmology.)

Objective: To evaluate whether lumbar subcutaneous fat tissue thickness (LSFTT) on midsagittal magnetic resonance imaging (MRI) is associated with lumbar spinal stenosis (LSS)., Study Design: Observational cross-sectional study., Place and Duration of Study: Department of Radiology and Neurosurgery, Istanbul Medeniyet University School of Medicine, Istanbul, Turkey between January 2018 and December 2020., Methodology: The study group included 79 patients, who had undergone surgery for lumbar spinal stenosis. The control group included MRI scans of 80 individuals without lumbar spinal stenosis. Association between LSFTT and LSS was analysed through a comparison of both the groups., Results: The agreement between the two observers was found to be very good agreement with a two-way mixed intra-class correlation coefficient of 0.986 or higher (p <0.001). There was statistically significant differences between the LSS and non-LSS groups for both L5-S1 and L4-5 level measurements, p=0.001, and p=0.004, respectively. L5-S1 level measurements in the LSS group showed 29% increase in average with respect to the non-LSS group; and in L4-L5 level measurements, the increase was 40% in median. Females exhibited significantly higher values in both levels, (p <0.001 and p <0.001, respectively)., Conclusions: Lumbar subcutaneous fat tissue thickness is significantly associated with lumbar spinal stenosis. Measuring LSFTT on mid-sagittal MRI is an easily applicable, reproducible alternative method for predicting LSS. Key Word: Lumbar, Spinal canal, Stenosis, Subcutaneous fat tissue, Magnetic resonance imaging.

Comparisons of the utility and accuracy of methods for measuring social interactions relevant to disease transmission are rare. To increase the evidence base supporting specific methods to measure social interaction, we compared data from self-reported contact surveys and wearable proximity sensors from a cohort of schoolchildren in the Pittsburgh metropolitan area. Although the number and type of contacts recorded by each participant differed between the two methods, we found good correspondence between the two methods in aggregate measures of age-specific interactions. Fewer, but longer, contacts were reported in surveys, relative to the generally short proximal interactions captured by wearable sensors. When adjusted for expectations of proportionate mixing, though, the two methods produced highly similar, assortative age-mixing matrices. These aggregate mixing matrices, when used in simulation, resulted in similar estimates of risk of infection by age. While proximity sensors and survey methods may not be interchangeable for capturing individual contacts, they can generate highly correlated data on age-specific mixing patterns relevant to the dynamics of respiratory virus transmission.

Purpose: Proliferative vitreoretinopathy (PVR) occurs in approximately 5-10% of patients after retinal detachment surgery. Neferine is a bis-benzylisoquinoline alkaloid found in the green seed embryos ( Nelumbo nucifera ) of the lotus flower and has various properties, such as being antithrombotic, antioxidant, neuroprotective, anticancerous, and anti-inflammatory. Although the effects of neferine on the proliferation and migration of cancer cells have been partially shown, their possible role and the mechanism of action on PVR remain unclear. Materials and methods: To mimic a PVR model in vitro , retinal pigment epithelial (RPE) cells were exposed to epidermal growth factor (EGF) and treated with various concentrations of neferine. Cell viability was determined by MTT test. Cell-cycle phase distribution and cell migration were examined by image-based cytometry and wound healing test, respectively. Messenger RNA (mRNA) and protein expression were determined by RT-qPCR and Western blotting, respectively. Results: Stimulation of the cells with EGF significantly increased the rate of proliferation, whilst treatment with low concentrations of neferine-reduced proliferation to a level equal to that seen in untreated cells. Neferine significantly downregulated EGF-increased cell viability, and survivin mRNA expression was depressed to the basal level. In addition, neferine treatment contributed to cell proliferation loss by upregulating p21 and p27 expression leading to cycle arrest at the G1 phase. The treatment significantly inhibited cell migration by upregulating the expression of epithelial markers, such as E-cadherin and occludin, and decreased MMP2, MMP9, α-SMA, and vimentin. Neferine treatment markedly reduced phosphotidyl inositol 3-kinase (PI3K), AKT, p-p38 mitogen-activated protein kinase (MAPK), and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) protein expression. Conclusion: It can be considered that neferine may be a potential candidate molecule in the treatment of PVR by inhibiting cell proliferation and the migration of EGF-induced RPE cells through the modulation of various transcriptional activities.

Background: In the United States, there is well-documented regional variation in prescription drug spending. However, the specific role of physician adoption of brand name drugs on the variation in patient-level prescription drug spending is still being investigated across a multitude of drug classes. Our study aims to add to the literature by determining the association between physician adoption of a first-in-class anti-diabetic (AD) drug, sitagliptin, and AD drug spending in the Medicare and Medicaid populations in Pennsylvania., Methods: We obtained physician-level data from QuintilesIMS Xponent™ database for Pennsylvania and constructed county-level measures of time to adoption and share of physicians adopting sitagliptin in its first year post-introduction. We additionally measured total AD drug spending for all Medicare fee-for-service and Part D enrollees (N = 125,264) and all Medicaid (N = 50,836) enrollees with type II diabetes in Pennsylvania for 2011. Finite mixture model regression, adjusting for patient socio-demographic/clinical characteristics, was used to examine the association between physician adoption of sitagliptin and AD drug spending., Results: Physician adoption of sitagliptin varied from 44 to 99% across the state's 67 counties. Average per capita AD spending was $1340 (SD $1764) in Medicare and $1291 (SD $1881) in Medicaid. A 10% increase in the share of physicians adopting sitagliptin in a county was associated with a 3.5% (95% CI: 2.0-4.9) and 5.3% (95% CI: 0.3-10.3) increase in drug spending for the Medicare and Medicaid populations, respectively., Conclusions: In a medication market with many choices, county-level adoption of sitagliptin was positively associated with AD spending in Medicare and Medicaid, two programs with different approaches to formulary management.

Purpose: To examine changes in retinal ganglion cell complex (GCC) and peripapillary retinal nerve fiber layer (RNFL) thicknesses by optical coherence tomography (OCT) in contralateral and ipsilatateral eyes of carotid artery stenosis (CAS) patients before and after carotid endarterectomy (CEA)., Methods: Forty-two consecutive patients diagnosed with CAS (70-99% stenosis rate) who underwent CEA were included in this prospective cross-sectional study. The indication for CEA was based on the Asymptomatic Carotid Atherosclerosis Study. Doppler ultrasonography and computed tomography angiography were performed to calculate CAS. All the subjects underwent an ophthalmological examination, including best corrected visual acuity (BCVA), intraocular pressure (IOP) measurements, biomicroscopy, fundoscopy, and OCT before and after the surgery., Results: The mean preoperative intraocular pressure was 15.2 ± 2.1 mmHg in the ipsilateral eye and 15.8 ± 2.7 in the contralateral eye. The mean postoperative intraocular pressure in the ipsilateral and contralateral eye was 18.6 ± 3.0 and 19.3 ± 3.8, respectively. The intraocular pressure was significantly higher in postoperative eyes (p = 0.0001). There was a statistically significant decrease in peripapillary RNFL thickness in superior quadrants postoperatively in ipsilateral eyes. The retinal GCC layer thickness was not significantly different before and after CEA in ipsilateral and contralateral eyes., Conclusions: Carotid endarterectomy results in thinning of the superior peripapillary RNFL thickness. To the best of our knowledge, this is the first study to examine peripapillary RNFL and GCC thicknesses before and after CEA.

Purpose: The aim of this study was to evaluate the ossicular chain erosions (OCE) in chronic otitis media patients with cholesteatoma (COM-C) or without cholesteatoma (COM)., Materials and Methods: The OCE and preoperative hearing levels of a total of 915 patients were evaluated retrospectively. Patients were divided into three groups. Of the 915 patients, 615 (67.2%) had COM, 234 (25.6%) had COM-C, and 66 (7.2%) had chronic otitis media with granulation tissue (COM-G)., Results: OCE was found in 291 (31.8%) of 915 patients. OCE was found in 192 (82%) of 234 patients with COM-C, 21 (31.8%) of 66 patients with COM-G, and 78 (12.7%) of 615 patients with COM., Conclusion: The most commonly seen OCE was incus erosion, followed by stapes and malleus erosions. The results of this study show that there are more OCE in the COM-C group than in the COM-G and COM groups. To our knowledge, this study has the widest patient population in the literature focused on the OCE relation with COM, COM-C, and COM-G and its effect on the preoperative hearing level.

Aim: To compare safety and efficacy of intravitreal dexamethasone (IVD) implant with topical nepafenac (TN) 0.1% in previously untreated Irvine-Gass syndrome (IGS) in clinical practice., Methods: This was a retrospective study of 62 eyes with IGS after phacoemulsification with posterior chamber intraocular lens (IOL) implantation. None of the patients used treatment before IVD or TN. Best-corrected visual acuity (BCVA) with Early Treatment Diabetic Retinopathy Study chart (ETDRS), slit-lamp, intraocular pressure (IOP) measurement, fundus examination, spectral-domain optical coherence tomography (OCT) and fundus florescein angiography were performed to all subjects at baseline, 1, 3 and 6mo., Results: The mean BCVA of the IVD group was 49.3±6.8, and the mean BCVA of the TN group was 32.9±7.3 ETDRS letters in post-treatment month 6. The mean central macular thickness (CRT) of IVD group was 266.6±53.5 µm and the mean CRT of TN group was 364.9±56.3 µm in post-treatment month 6. Baseline BCVA has correlation with final BCVA in TN group however there was no correlation between baseline BCVA and final BCVA in IVD group., Conclusion: IVD is found to be better than TN in controlling pseudophakic macular edema and improving visual acuity. IVD group also has significantly lower CRT however IOP is not significantly different between two groups in post-treatment month 6.

Purpose: The aim of this study is to investigate the effect of uveitis in corneal endothelial cell number and morphology by non-contact specular microscopy., Methods: Our cross-sectional study was performed on 56 eyes of uveitis patients and 53 eyes of healthy subjects. Non-contact specular microscopy was performed to all subjects. The cell density (CD), coefficient of variation, cell minimum area (Min) and cell maximum area (Max), the average of cell size (AVG), percent of hexagonality (HEX%), central corneal thickness (CCT), intraocular pressure (IOP) during uveitis and during remission were measured and compared between two groups., Results: The mean endothelial cell analysis of the patients was 2540 ± 619 cells/mm 2 , and the mean endothelial cell analysis of the control group was 2834 ± 413 cells/mm 2 . The difference was statistically significant between the groups (p = 0.01). There was a statistically significant difference between two groups in terms of Max, Min, AVG, and HEX values. However, there was no difference in terms of CCT between two groups. There was a significant negative correlation between CD and IOP during uveitis attack. There was a significant negative correlation between the anterior chamber cell value and CD., Conclusion: Our results suggested that uveitis affected endothelial cell density, cell size and shape but not the corneal thickness without being influenced by the duration and number of attacks. Increased IOP during uveitis and anterior chamber cell value had an important role on CD in patients with uveitis.

Although physicians learn about new medical technologies from their peers, the magnitude and source of peer influence is unknown. We estimate the effect of peer adoption of three first-in-class medications (dabigatran, sitigliptin, and aliskiren) on physicians' own adoption of those medications. We included 11,958 physicians in Pennsylvania prescribing anticoagulant, antidiabetic, and antihypertensive medications. We constructed 4 types of peer networks based on shared Medicare and Medicaid patients, medical group affiliation, hospital affiliation, and medical school/residency training. Instrumental variables analysis was used to estimate the causal effect of peer adoption (fraction of peers in each network adopting the new drug) on physician adoption (prescribing at least the median number prescriptions within 15 months of the new drug's introduction). We illustrate how physician network position can inform targeting of interventions to physicians by computing a social multiplier. Dabigatran was adopted by 25.2%, sitagliptin by 24.5% and aliskiren by 8.3% of physicians. A 10-percentage point increase in peer adoption in the patient-sharing network led to a 5.90% (SE = 1.50%, p<0.001) increase in physician adoption of dabigatran, 8.32% (SE = 1.51%, p<0.001) increase in sitagliptin, and 7.84% increase in aliskiren adoption (SE = 2.93%, p<0.001). Peer effects through shared hospital affiliation were positive but not significant, and medical group and training network effects were not reliably estimated. Physicians in the top decile of patient-sharing network peers were estimated to have nearly 2-fold stronger influence on their peers' adoption compared to physicians in the top decile of prescribing volume. Limitations include lack of detailed clinical information and pharmaceutical promotion, variables which may influence physician adoption but which are unlikely to bias our peer effect estimates. Peer adoption, especially by those with whom physicians share patients, strongly influenced physician adoption of new drugs. Our study shows the potential for using information on physician peer networks to improve technology diffusion., Competing Interests: The author RZ has a commercial affiliation The Permanente Medical Group, Inc that does not alter adherence to PLOS ONE policies on data sharing.

Purpose: Age-related macular degeneration (AMD) is the most common cause of visual loss. The dry AMD is characterized by retinal pigment epithelium (RPE) death and changes in AMD lead to severe loss of vision. Coumarin-derived esculetin has a number of therapeutic and pharmacological effects such as anti-inflammatory and antioxidant with various mechanisms. The purpose of this study was to investigate the effects of esculetin treatment on lipopolysaccharide (LPS)-induced inflammation, oxidative stress, and cell survival., Material and Methods: Human RPE cells (ARPE-19) were incubated for 24-72 h with 5 μg/ml LPS to induce inflammation and oxidative stress. Esculetin (5 μM) was used to protect the cells from LPS-induced damage. The cell viability was evaluated by quantitative 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide test. Interleukin 6 (IL-6), IL-12, and vascular endothelial growth factor (VEGF) levels were determined by enzyme-linked immunosorbent assay (ELISA). IL-1β, tumor necrosis factor receptor (TNFR), TNF-related apoptosis-inducing ligand (TRAIL), catalase, glutathione peroxidase (GPx), superoxide dismutase 1 (CuZnSOD) and SOD2 (MnSOD) mRNA expressions were analyzed by RT-quantitative polymerase chain reaction. Apoptosis was monitored by cell-based cytometer. NF-kappa B (NF-κB) p65/RelA levels were determined by ELISA, and NF-κB protein expression and extracellular signal-regulated kinase (ERK1/2) phosphorylation were evaluated by Western blot analysis., Results: Esculetin treatment significantly suppressed LPS-induced cell death mediated by apoptosis and necrosis in a concentration-dependent manner. While LPS caused significant inflammation with cytokine increase in cells, esculetin reduced the expression of LPS-induced cytokines, VEGF, TNFR, and TRAIL. Furthermore, exposure to LPS increased the expression of GPx and mitochondrial MnSOD, leading to oxidative stress in the cells. Esculetin treatment attenuated phosphorylation of ERK1/2 and NF-κB expression mediated by LPS., Conclusions: These results suggest that esculetin may be an alternative treatment option for endotoxin-induced inflammation and oxidative stress, which therefore may inhibit the development of LPS-mediated AMD.