DETECTION OF TREATMENT-NAIVE CHOROIDAL NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION BY SWEPT SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To compare the detection rate of choroidal neovascularization (CNV) in treatment-naive neovascular age-related macular degeneration by swept source optical coherence tomography angiography (SS-OCTA, Topcon's DRI Triton) working at 1,050 nm wavelength versus fluorescence angiography. METHODS: Cross-sectional analysis of 156 eyes (107 neovascular age-related macular degeneration and 49 dry AMD) in 98 patients, previously diagnosed by multimodal imaging using fluorescein (FA) and indocyanine green angiography (Heidelberg's Spectralis) in a tertiary retina center, evaluated by SS-OCTA 4.5 mm × 4.5 mm and 6 mm × 6 mm macular cubes. Main outcome measures were sensitivity and specificity of SS-OCTA in AMD. Potential factors influencing CNV detection rate were analyzed. RESULTS: Swept source optical coherence tomography angiography detected CNV in 81 of 107 eyes, resulting in a sensitivity of 75.7%. In 49 eyes with dry AMD, no CNV could be identified (specificity 100%). A statistical significance was calculated for nondetection of treatment-naive CNV by SS-OCTA in pigment epithelial detachment over 400 µm (P = 0.0238). CONCLUSION: Topcon's SS-OCTA was not able to detect all CNV lesions. Large pigment epithelial detachments were associated with signal loss. Fluorescence angiography still remains the gold standard, but the tested SS-OCTA device can be considered as a feasible additional diagnostic tool in AMD.

Primary liver transplantation and liver retransplantation: comparison of health-related quality of life and mental status - a cross-sectional study.

BACKGROUND: Liver Retransplantation (Re-LT) procedures are associated with an increased risk of morbidity and mortality. Up to date, there is no knowledge on the health-related quality of life and the mental status of these patients. METHODS: Health-Related Quality of Life (HRQoL) was assessed by using the Short Form 36 (SF-36) Health Survey and Mental Status was assessed by using the Hospital Anxiety and Depression Scale (HADS). The patients were examined in different assessments: During regular check-up examinations in the LT outpatient department in 2011 (Survey 1) and in a postal survey in 2013 (Survey 2). Their medical data was collected by using an established database. RESULTS: We received eligible surveys of 383 patients (55.6%) with a history of LT, of which 15 (3.9%) had undergone Re-LT (Re-LT group). These patients were compared to a group of 60 patients who had undergone only one LT. With regard to their HRQoL, the Re-LT group had significantly lower scores on the scales of physical function (PF, p = 0.026), their role-physical (RP, p = 0.008), their vitality (VIT, p = 0.040), and their role-emotional (RE, p = 0.005). The scores for anxiety and depression did not differ significantly between the groups. In a multiple regression analysis, chronic kidney disease was found to be an independent risk factor for decreased scores of PF (p = 0.023). CONCLUSIONS: Patients who have to undergo Re-LT procedures are faceing impairments in physical aspects of a HRQoL. Together with clinical results from other studies, the findings of the present examination underline the need for an optimized organ distribution strategy since not all patients listed for Re-LT appear to benefit from it.

Health-related quality of life and affective status in liver transplant recipients and patients on the waiting list with low MELD scores.

BACKGROUND: This study seeks to examine the impact of orthotopic liver transplantation (OLT) on Health-Related Quality of Life (HRQoL) and mental health in patients with different MELD scores. METHODS: Patients who has undergone orthotopic liver transplant (OLT) or were on the waiting list for OLT were submitted to HRQoL and depression/anxiety assessment by questionnaire: Short-Form 36 (SF-36), Questions on Life Satisfaction (FLZ-M), Patient Health Questionnaire-4 (PHQ-4). Data were analysed following division of patients into three groups: pretransplant patients with a MELD score <10, ≥10, and OLT recipients. RESULTS: The surveys were sent to 940 consecutive patients within one week in June 2013. Of these 940 patients, 869 (92.4%) met the inclusion criteria. In total, 291 (33.5%) eligible questionnaires (OLT group: 235, MELD <10: 25; MELD _10: 31) were suitable for analysis. General health (GH), vitality (VIT), and mental health (MH) were lower in both pretransplant groups compared to the OLT group (all p < 0.05). Anxiety and depression were higher in the MELD <10 group than in the OLT group (anxiety: p < 0.05; depression: p < 0.01). DISCUSSION: Patients with low MELD scores seem to benefit from OLT with regards to HRQoL and mental health.

Impact of different immunosuppressive regimens on the health-related quality of life following orthotopic liver transplantation.

BACKGROUND: The influence of immunosuppression on the recipients' quality of life (QoL) is of major importance after OLT and has not yet been evaluated. METHODS: The impact of different immunosuppression regimens after OLT was evaluated in 275 patients using the Short Form 36 (SF-36) survey. The following immunosuppressive strategies were compared: (a) CNI, (b) mTOR inhibitors, and (c) mTOR combined with CNI. All regimens were prescribed alone (mono) or in combination (+) with prednisolone and/or mycophenolate mofetil (MMF). RESULTS: Highest scores were evident in patients in the mTOR+ group. There were significantly higher values for general health perceptions (GH, p = 0.049), vitality (VIT, p = 0.020), and physical component summary (PCS, p = 0.041) when compared to CNImono and for GH (p = 0.042) and VIT (p = 0.043), when compared to mTORmono. Early conversion to mTOR inhibitors (two months after OLT), with a statistically significant improvement for the dimension role-emotional (RE, p = 0.027). DISCUSSION: mTOR inhibitor-based regimens appear to have beneficial effects on QoL after OLT, especially after an early conversion.

THOC5: a novel gene involved in HDL-cholesterol metabolism.

Although numerous genes are known to regulate serum lipid traits, identified variants explain only a small proportion of the expected heritability. We intended to identify further genetic variants associated with lipid phenotypes in a self-contained population of Sorbs in Germany. We performed a genome-wide association study (GWAS) on LDL-cholesterol, HDL-cholesterol (HDL-C), and triglyceride (TG) levels in 839 Sorbs. All single-nucleotide polymorphisms with a P value <0.01 were subjected to a meta-analysis, including an independent Swedish cohort (Diabetes Genetics Initiative; n = ∼3,100). Novel association signals with the strongest effects were subjected to replication studies in an additional German cohort (Berlin, n = 2,031). In the initial GWAS in the Sorbs, we identified 14 loci associated with lipid phenotypes reaching P values <10⁻5 and confirmed significant effects for 18 previously reported loci. The combined meta-analysis of the three study cohorts (n(HDL) = 6041; n(LDL) = 5,995; n(TG) = 6,087) revealed a novel association for a variant in THOC5 (rs8135828) with serum HDL-C levels (P = 1.78 × 10⁻7; Z-score = -5.221). Consistently, the variant was also associated with circulating APOA1 levels in Sorbs. The small interfering RNA-mediated mRNA silencing of THOC5 in HepG2 cells resulted in lower mRNA levels of APOA1, SCARB1, and ABCG8 (all P < 0.05). We propose THOC5 to be a novel gene involved in the regulation of serum HDL-C levels.

Swept Source-Optical Coherence Tomography Angiography for Management of Secondary Choroidal Neovascularization in Punctate Inner Choroidopathy.

The purpose was to demonstrate the diagnostic and therapeutic feasibility of swept source-optical coherence tomography angiography (SS-OCTA) by picturing neovascular changes secondary to a rare white dot syndrome following long-term intravitreal ranibizumab (IVR). A 28-year-old Caucasian myopic female presented with visual loss in her right eye only. The clinical examination and multimodal imaging including spectral domain (SD)-OCT, blue-peak autofluorescence, fluorescein, and indocyanine green angiography (HRA Spectralis, Heidelberg Engineering; Heidelberg, Germany) as well as SS-OCTA (DRI Triton, Topcon; Tokyo, Japan) led to the diagnosis of idiopathic punctate inner choroidopathy with secondary subfoveal choroidal neovascularization (CNV). In addition to oral corticosteroids, a pro re nata regimen with IVR was initiated and guided by repeated SD-OCT and SS-OCTA. Six IVR were administered based on functional SS-OCTA en face scans illustrating vessel transformation and downsizing of the CNV area while SD-OCT B-scans were inconclusive as indirect signs of activity were absent throughout the follow-up period. SS-OCTA provided new possibilities for monitoring vessel development. IVR was managed based on vessel density as displayed by SS-OCTA.

Fast Identification of Food Thickeners by Nontargeted NMR-Spectroscopy.

Food thickeners are carbohydrate additives that can only be determined by long-term, multistep analysis. Fast methods to directly determine thickeners in food matrixes are therefore welcome. In this study, a rapid procedure based on the direct 1H NMR analysis of food samples dissolved in deuterated water was developed. Individual thickeners were assigned due to specific marker signals gleaned from two-dimensional NMR analyses. The combination of one-dimensional 1H NMR and DOSY experiments enabled unequivocal assignments of thickeners even in complex matrixes. Using this approach, gum arabic, carrageenan, agar-agar, galactomannans, and pectin could be identified in pastille, glaze, and fruit spread. Because of low concentrations (<0.5%-1%, w/w), the same thickeners and others such as xanthan gum and alginate could not be determined directly by NMR in curry sauce, rice pudding, choco milk drink, and lemon peel flavor. Moreover, NMR analyses of the hydrolysate did not reveal the specific monomeric units of the thickeners under study, as shown for the hydrolysate of lemon peel flavor. Nevertheless, the NMR approach could provide welcome means in the future to directly determine intact thickeners in food.

Seven-Year Visual and Anatomical Outcomes of Intravitreal Vascular Endothelial Growth Factor Inhibition for Neovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate 7-year visual and anatomical outcomes of intravitreal injections (IVI) with antivascular endothelial growth factor (anti-VEGF) for neovascular age-related macular degeneration (nAMD) based on a personalized pro re nata (PRN) regimen. METHODS: Anonymized data of 124 consecutive eyes in 121 patients with treatment-naïve nAMD were initially collected in 2010. Of those, 45 received anti-VEGF IVI at least every 6months until 2017 in one single center in Austria and hence were retrospectively analyzed. All eyes had been initiated on a loading dose of 3 monthly IVI with different anti-VEGF agents followed by a PRN regimen in the first year. At year 2, monitoring as well as therapeutic intervention could be prolonged every 2weeks up to intervals of 3months without capping treatment. Primary outcome measure was the change of visual acuity (VA) assessed by Early Treatment Diabetic Retinopathy Study charts at 4 meters (ETDRS) in letters-counting every correctly read letter-and converted to Snellen. Secondary outcome measures were number of injections and change of central retinal thickness (CMT) from baseline. RESULTS: Mean baseline VA was 20/63 + 1 (0.63 ± 0.26 ETDRS) and declined to 20/100 + 2 (0.45 ± 0.33) with an overall loss of 9 letters ETDRS after 7years (p = 0.001). An average of 3.5 ± 1.9 IVI was given per year and eye. Mean CMT at baseline was 322 ± 95 µm, decreased by 52 µm, decreased by 52 µm, decreased by 52 µm, decreased by 52 µm to 270 ± 70 µm within the first year, and remained below baseline at year 7 (271 ± 106 µm; p = 0.001). An average of 3.5 ± 1.9 IVI was given per year and eye. Mean CMT at baseline was 322 ± 95 µm, decreased by 52 µm to 270 ± 70 µm within the first year, and remained below baseline at year 7 (271 ± 106 µm; p < 0.001). CONCLUSIONS: Our data confirm an absolute vision loss in eyes compromised by nAMD after 7 years of continuous VEGF inhibition. The visual decline was significantly related to baseline VA as well as the number of injections. We suggest following patients thoroughly independent of the initial VA and a greater incentive for the physician to treat.

Relationship between Neovascular Density in Swept Source-Optical Coherence Tomography Angiography and Signs of Activity in Exudative Age-Related Macular Degeneration.

PURPOSE: To assess the relationship between signs of activity in exudative neovascular age-related macular degeneration (nAMD) following anti-vascular endothelial growth factor (anti-VEGF) treatment and morphology of choroidal neovascularization (CNV) based on neovascular density as imaged using swept source-optical coherence tomography angiography (SS-OCTA) in a qualitative manner. METHODS: A single-cohort retrospective data analysis from one tertiary eye care center. Seventy-seven eyes of 72 patients were included and their charts reviewed which had been started on intravitreal injections with anti-VEGF for nAMD at least one year prior to enrollment. Clinically active disease was evaluated by slit-lamp fundus examination and spectral domain-OCT B-scans. Morphological appearance in SS-OCTA was characterized based on 5 different criteria and subsequently divided into 3 groups: predominantly hyperdense, minimally hyperdense, and hypodense lesions. RESULTS: Fifty-eight eyes (75%) were considered clinically active and 19 eyes (25%) clinically inactive. CNV was depicted in 71 eyes (92%) by SS-OCTA and separated accordingly into predominantly hyperdense (32%), minimally hyperdense (34%), and hypodense lesions (34%). A borderline significant difference in the probability of neovascular activity for predominantly hyperdense lesions compared to hypodense lesions was detected (p=0.05). CONCLUSIONS: Hyperdense choroidal neovascularization based on qualitative assessment of flow density showed a significant relation to active disease. Inactivity could not be matched adequately. This study demonstrated the potential usefulness of SS-OCTA for guidance of treatment in age-related macular degeneration.

Transcriptome profiling data reveals ubiquitin-specific peptidase 9 knockdown effects.

Ubiquitin specific peptidase 9 (USP9) is a deubiquitinase encoded by a sex-linked gene with a Y-chromosomal form (USP9Y) and an X-chromosomal form (USP9X) that escapes X-inactivation. Since USP9 is a key regulatory gene with sex-linked expression in the human brain, the gene may be of interest for researchers studying molecular gender differences and ubiquitin signaling in the brain. To assess the downstream effects of knocking down USP9X and USP9Y on a transcriptome-wide scale, we have conducted microarray profiling experiments using the human DU145 prostate cancer cell culture model, after confirming the robust expression of both USP9X and USP9Y in this model. By designing shRNA constructs for the specific knockdown of USP9X and the joint knockdown of USP9X and USP9Y, we have compared gene expression changes in both knockdowns to control conditions to infer potential shared and X- or Y-form specific alterations. Here, we provide details of the corresponding microarray profiling data, which has been deposited in the Gene Expression Omnibus database (GEO series accession number GSE79376). A biological interpretation of the data in the context of a potential involvement of USP9 in Alzheimer's disease has previously been presented in Köglsberger et al. (2016). To facilitate the re-use and re-analysis of the data for other applications, e.g. the study of ubiquitin signaling and protein turnover control, and the regulation of molecular gender differences in the human brain and brain-related disorders, we provide a more in-depth discussion of the data properties, specifications and possible use cases.

Automated high-throughput high-content autophagy and mitophagy analysis platform.

Autophagic processes play a central role in cellular homeostasis. In pathological conditions, the flow of autophagy can be affected at multiple and distinct steps of the pathway. Current analyses tools do not deliver the required detail for dissecting pathway intermediates. The development of new tools to analyze autophagic processes qualitatively and quantitatively in a more straightforward manner is required. Defining all autophagy pathway intermediates in a high-throughput manner is technologically challenging and has not been addressed yet. Here, we overcome those requirements and limitations by the developed of stable autophagy and mitophagy reporter-iPSC and the establishment of a novel high-throughput phenotyping platform utilizing automated high-content image analysis to assess autophagy and mitophagy pathway intermediates.

Gender-Specific Expression of Ubiquitin-Specific Peptidase 9 Modulates Tau Expression and Phosphorylation: Possible Implications for Tauopathies.

Public transcriptomic studies have shown that several genes display pronounced gender differences in their expression in the human brain, which may influence the manifestations and risk for neuronal disorders. Here, we apply a transcriptome-wide analysis to discover genes with gender-specific expression and significant alterations in public postmortem brain tissue from Alzheimer's disease (AD) patients compared to controls. We identify the sex-linked ubiquitin-specific peptidase 9 (USP9) as an outstanding candidate gene with highly significant expression differences between the genders and male-specific underexpression in AD. Since previous studies have shown that USP9 can modulate the phosphorylation of the AD-associated protein MAPT, we investigate functional associations between USP9 and MAPT in further detail. After observing a high positive correlation between the expression of USP9 and MAPT in the public transcriptomics data, we show that USP9 knockdown results in significantly decreased MAPT expression in a DU145 cell culture model and a concentration-dependent decrease for the MAPT orthologs mapta and maptb in a zebrafish model. From the analysis of microarray and qRT-PCR experiments for the knockdown in DU145 cells and prior knowledge from the literature, we derive a data-congruent model for a USP9-dependent regulatory mechanism modulating MAPT expression via BACH1 and SMAD4. Overall, the analyses suggest USP9 may contribute to molecular gender differences observed in tauopathies and provide a new target for intervention strategies to modulate MAPT expression.

Fatigue After Liver Transplant and Combined Liver and Kidney Transplant.

OBJECTIVES: To date, fatigue is still poorly understood in recipients of orthotopic liver transplant and simultaneous/sequential liver and kidney transplant procedures. The present study examined the appearance of fatigue in patients who received orthotopic liver and sequential liver and kidney transplant procedures compared with the general population and the influence of various clinical and socioeconomic factors on fatigue levels. MATERIALS AND METHODS: The Multidimensional Fatigue Inventory survey was sent to all patients with a history of orthotopic liver and simultaneous/sequential liver and kidney transplant. The results were compared to data from a reference population. RESULTS: Our survey included 276 eligible patients: 256 recipients (92.7%) of orthotopic liver transplant and 20 recipients (7.3%) of simultaneous/sequential liver and kidney transplant. Significantly lower fatigue scores were found in the general population compared with both transplant groups (P < .001). There were also no significant differences between the transplant groups. Among the clinical and socioeconomic factors, history of hepatocellular carcinoma, chronic kidney disease, age, family status, and education had a significant impact on fatigue levels. CONCLUSIONS: This is the first study to compare fatigue in recipients of orthotopic liver and simultaneous/sequential liver and kidney transplant. We found that fatigue is an important but still poorly understood outcome after transplant.

Pubertal Development in Pediatric Kidney Transplant Patients Receiving Mammalian Target of Rapamycin Inhibitors or Conventional Immunosuppression.

BACKGROUND: Data regarding the onset of puberty in children receiving mammalian target of rapamycin (mTOR) inhibitors are limited. METHODS: Kidney transplant patients aged <14 years were analyzed retrospectively to a maximum age of 18 years, with a minimal observation period of 1 year. Immunosuppression comprised (1) standard CNI-based regimen or (2) low-exposure mTOR inhibitor with reduced-exposure CNI, initiated either de novo or in the maintenance phase. RESULTS: Of 108 children analyzed, 67 received an mTOR inhibitor (56 everolimus, 11 sirolimus) and 41 did not. The age at which girls reached Tanner stage P2 was similar with mTOR inhibitor therapy (median 11.6 years) or without (median 11.1 years) (P = 0.262), as was age at stage B2 (median 11.6 vs. 11.2 years; P = 0.753). In boys, both the age of attaining Tanner stage P2 (median 12.9 vs. 13.0 years; P = 0.796) and Tanner stage G2 (median 13.1 vs. 12.9 years; P = 0.344) were also similar with or without an mTOR inhibitor. Age at menarche in girls, and age at spermarche in boys, did not differ between the 2 groups. CONCLUSIONS: In this retrospective analysis, sexual maturation ages and reproductive hormone levels were comparable in adolescent kidney transplant patients receiving low-exposure mTOR inhibitors and reduced CNI therapy or conventional CNI-based immunosuppression.

Mental Status in Patients Before and After Liver Transplantation.

BACKGROUND: In contrast to the well-described beneficial organic effects of liver transplantation (OLT) in patients with end-stage liver disease, changes in the mental status of patients after OLT remain poorly understood. The current study seeks to evaluate the influence of OLT on anxiety, depression, and dispositional optimism in patients with end-stage liver disease. MATERIAL AND METHODS: Questionnaires were sent to patients on the OLT waiting list and patients after OLT. Depression/anxiety and dispositional optimism were assessed using the HADS and LOT-R questionnaires, respectively. These findings were compared to results from the general population. RESULTS: The number of returned questionnaires was 292 of 940 (31.1%; 57 patients on the liver transplant waiting list: waiting group, 235 liver transplant recipients: OLT group). Both depression and anxiety scores were significantly higher in the waiting group when compared to the OLT group (p<0.05) and the general population (anxiety: p<0.001, depression: p<0.05), respectively. The OLT group was characterized by significantly higher anxiety scores (p<0.001) compared to the general population. Depression and summation scores did not differ (p>0.05). Dispositional optimism was higher in the OLT group compared to the waiting group (p<0.05) and to the general population (p<0.01). The waiting group had equal values as the general population (p>0.05). CONCLUSIONS: Besides beneficial effects on liver function, OLT appears to be associated with significant improvements in depression and anxiety and a more optimistic view of life.