The efficacy of ferroptosis-inducing compounds IKE and RSL3 correlates with the expression of ferroptotic pathway regulators CD71 and SLC7A11 in biliary tract cancer cells.

INTRODUCTION: Biliary tract cancer (BTC) is a lethal disease with a bad overall survivability, partly arising from inadequate therapeutic alternatives, detection at a belated stage, and a resistance to common therapeutic approaches. Ferroptosis is a form of programmed cell death that depends on reactive oxygen species (ROS) and iron, causing excessive peroxidation of polyunsaturated fatty acids (PUFAs). Therefore, the objective of this investigation is, whether ferroptosis can be induced in BTC in vitro and whether this induction is dependent on specific molecular markers. METHODS: The study conducted resazurin assay and IC25/50 calculation to explore the possible cytotoxic outcomes of different classes of ferroptosis-inducing substances (FINs) on a comprehensive in vitro model of 11 BTC cell lines. Combinatory treatments with different cell death inhibitors were performed to evaluate the magnitude of ferroptosis induction. To ascertain whether ferroptotic cell death occurred, liperfluo and iron assay kits were employed to evaluate lipid ROS and intracellular iron abundance. Potential biomarkers of ferroptosis sensitivity were then assessed via western blot analysis, a rtPCR panel and functional assay kits. RESULTS: The study found that different FINs reduced cell viability in a cell line-dependent manner. In addition, we measured increased lipid ROS and intracellular Fe2+ levels upon exposure to FINs in BTC cells. Combining FINs with inhibitors of ferroptosis, necroptosis or apoptosis suggests the occurrence of ferroptotic events in BTC cell lines CCC-5, HuH-28 and KKU-055. Furthermore, we found that BTC cells display a heterogeneous profile regarding different molecular genes/markers of ferroptosis. Subsequent analysis revealed that sensitivity of BTC cells towards IKE and RSL3 positively correlated with CD71 and SLC7A11 protein expression. CONCLUSION: Our results demonstrate that induction of ferroptosis is a promising approach to inhibit BTC cell growth and that the sensitivity of BTC cells towards ferroptosis induction might be dependent on molecular markers such as CD71 and SLC7A11.

Ubiquitous Superconducting Diode Effect in Superconductor Thin Films.

The macroscopic coherence in superconductors supports dissipationless supercurrents that could play a central role in emerging quantum technologies. Accomplishing unequal supercurrents in the forward and backward directions would enable unprecedented functionalities. This nonreciprocity of critical supercurrents is called the superconducting (SC) diode effect. We demonstrate the strong SC diode effect in conventional SC thin films, such as niobium and vanadium, employing external magnetic fields as small as 1 Oe. Interfacing the SC layer with a ferromagnetic semiconductor EuS, we further accomplish the nonvolatile SC diode effect reaching a giant efficiency of 65%. By careful control experiments and theoretical modeling, we demonstrate that the critical supercurrent nonreciprocity in SC thin films could be easily accomplished with asymmetrical vortex edge and surface barriers and the universal Meissner screening current governing the critical currents. Our engineering of the SC diode effect in simple systems opens the door for novel technologies while revealing the ubiquity of the Meissner screening effect induced SC diode effect in superconducting films, and it should be eliminated with great care in the search for exotic superconducting states harboring finite-momentum Cooper pairing.

Change in Metabolomic Profile Associated with an Average Increase in Plain Water Intake of >+ 1 L/Day, Sustained Over 4 Weeks, in Healthy Young Men with Initial Total Water Intake Below 2 L/Day.

Background/Aims: Cells adapt to chronic extracellular hypotonicity by altering metabolism. Corresponding effects of sustained hypotonic exposure at the whole-person level remain to be confirmed and characterized in clinical and population-based studies. This analysis aimed to 1) describe changes in urine and serum metabolomic profiles associated with four weeks of sustained > +1 L/d drinking water in healthy, normal weight, young men, 2) identify metabolic pathways potentially impacted by chronic hypotonicity, and 3) explore if effects of chronic hypotonicity differ by type of specimen and/or acute hydration condition. Materials: Untargeted metabolomic assays were completed for specimen stored from Week 1 and Week 6 of the Adapt Study for four men (20-25 years) who changed hydration classification during that period. Each week, first-morning urine was collected after overnight food and water restriction, and urine (t+60 min) and serum (t+90 min) were collected after a 750 mL bolus of drinking water. Metaboanalyst 5.0 was used to compare metabolomic profiles. Results: In association with four weeks of > + 1 L/d drinking water, urine osmolality decreased below 800 mOsm/kg H2O and saliva osmolality decreased below 100 mOsm/kg H2O. Between Week 1 and Week 6, 325 of 562 metabolic features in serum changed by 2-fold or more relative to creatinine. Based on hypergeometric test p-value <0.05 or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway impact factor >0.2, the sustained > + 1 L/d of drinking water was associated with concurrent changes in carbohydrate, protein, lipid, and micronutrient metabolism, a metabolomic pattern of carbohydrate oxidation via the tricarboxylic acid (TCA) cycle, instead of glycolysis to lactate, and a reduction of chronic disease risk factors in Week 6. Similar metabolic pathways appeared potentially impacted in urine, but the directions of impact differed by specimen type. Conclusion: In healthy, normal weight, young men with initial total water intake below 2 L/d, sustained > + 1 L/d drinking water was associated with profound changes in serum and urine metabolomic profile, which suggested normalization of an aestivation-like metabolic pattern and a switch away from a Warburg-like pattern. Further research is warranted to pursue whole-body effects of chronic hypotonicity that reflect cell-level effects and potential beneficial effects of drinking water on chronic disease risk.

Improvement of Pain Symptoms in Musculoskeletal Diseases After Multimodal Spa Therapy in the Austrian Gastein Valley-A Study Based on Longitudinal Registry Data.

Objective: The study aim was to investigate the course of pain in rest and motion in seven different rheumatic diseases (RMD), prior and after multimodal spa therapy including low-dose radon treatment and at 3-, 6-; and 9-month follow up. Methods: Complete data from the radon indication registry including information on 561 subjects with RMD were analysed to explore the association of timepoint of measurement with pain in rest and motion. For this purpose, linear regression models adjusted for RMD-type, age, sex and body mass index (BMI) were applied. Results: The mean age of the sample was 55 years, the average body mass index was 26.8, and 275 subjects were women. Pain scores were significantly improved at all-time points compared to baseline. Pain courses were different for each RMD with the largest improvement seen in fibromyalgia. Conclusion: Timing spa facility visits according to RMD-specific pain courses may result in sustained pain reduction.

Ouabain at nanomolar concentrations is cytotoxic for biliary tract cancer cells.

Biliary tract cancer is a deadly disease with limited therapeutic options. Ouabain is a well-known inhibitor of the pumping function of Na+/K+-ATPase, though there is evidence that low concentrations of ouabain lead to a reduction of cell viability of cancer cells independent of its inhibition of the pumping function of the Na+/K+-ATPase. Regarding the impact of ouabain on biliary tract cancer, no data is currently available. Therefore, we aimed for a first-time investigation of ouabain as a potential anti-neoplastic biliary tract cancer agent using comprehensive human biliary tract cancer in vitro models. We found that ouabain has a strong cell line-dependent cytotoxic effect with IC50 levels in the (low) nanomolar-range and that this effect was not associated with the mRNA expression levels of the Na+/K+-ATPase α, ß and fxyd-subunits. Regarding the mode of cytotoxicity, we observed induction of apoptosis in biliary tract cancer cells upon treatment with ouabain. Interestingly, cytotoxic effects of ouabain at sub-saturating (< µM) levels were independent of cellular membrane depolarization and changes in intracellular sodium levels. Furthermore, using a 3D cell culture model, we found that ouabain disturbs spheroid growth and reduces the viability of biliary tract cancer cells within the tumor spheroids. In summary, our data suggest that ouabain possesses anti-biliary tract cancer potential at low µM-concentration in 2D and 3D in vitro biliary tract cancer models and encourage further detailed investigation.

Evaluation of Tazemetostat as a Therapeutically Relevant Substance in Biliary Tract Cancer.

Biliary tract cancer (BTC) is a gastrointestinal malignancy associated with a poor survival rate. Current therapies encompass palliative and chemotherapeutic treatment as well as radiation therapy, which results in a median survival of only one year due to standard therapeutic ineffectiveness or resistance. Tazemetostat is an FDA-approved inhibitor of enhancer of Zeste homolog 2 (EZH2), a methyltransferase involved in BTC tumorigenesis via trimethylation of histone 3 at lysine 27 (H3K27me3), an epigenetic mark associated with silencing of tumor suppressor genes. Up to now, there are no data available regarding tazemetostat as a possible treatment option against BTC. Therefore, the aim of our study is a first-time investigation of tazemetostat as a potential anti-BTC substance in vitro. In this study, we demonstrate that tazemetostat affects cell viability and the clonogenic growth of BTC cells in a cell line-dependent manner. Furthermore, we found a strong epigenetic effect at low concentrations of tazemetostat, which was independent of the cytotoxic effect. We also observed in one BTC cell line that tazemetostat increases the mRNA levels and protein expression of the tumor suppressor gene Fructose-1,6-bisphosphatase 1 (FBP1). Interestingly, the observed cytotoxic and epigenetic effects were independent of the mutation status of EZH2. To conclude, our study shows that tazemetostat is a potential anti-tumorigenic substance in BTC with a strong epigenetic effect.

Patient-Reported Quality of Care for Osteoarthritis in General Practice in South Tyrol, Italy: Protocol for Translation, Validation and Assessment of the OsteoArthritis Quality Indicator Questionnaire (OA-QI).

BACKGROUND: Evidence-based recommendations for the treatment of knee and hip osteoarthritis are similar internationally. Nevertheless, clinical practice varies across countries. Instruments for measuring quality have been developed to improve health care through targeted interventions. Studies on health service quality must consider the structural and cultural characteristics of countries, because each of their strengths and weaknesses differ. However, such instruments for health-related patient-reported outcomes for osteoarthritis have not yet been validated in German and Italian languages. OBJECTIVES: In order to be able to set targeted measures for the improvement of prevention and non-surgical treatment of osteoarthritis in South Tyrol, Italy, the quality of care must be recorded. Therefore, the aim of the project is to update, translate, and validate the OsteoArthritis Quality Indicator (OA-QI) questionnaire version 2, an established and validated questionnaire in Norwegian and English, for Germany and Italy. The second aim is to determine the quality of care for osteoarthritis of the hip and knee in a sample of patients who consult general practice in South Tyrol, and for comparison with patients who are admitted to rehabilitative spa-treatments for osteoarthritis in the state of Salzburg, Austria. DISCUSSION: The results of this study will enable the identification and closure of gaps in osteoarthritis care. Although it is expected that body weight and exercise will play special roles, other areas of nonsurgical care might also be involved.

Comparison of Stimulus Types for Retinotopic Cortical Mapping of Macular Disease.

Purpose: Retinotopic maps acquired using functional magnetic resonance imaging (fMRI) provide a valuable adjunct in the assessment of macular function at the level of the visual cortex. The present study quantitatively assessed the performance of different visual stimulation approaches for mapping visual field coverage. Methods: Twelve patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) were examined using high-resolution ultra-high field fMRI (Siemens Magnetom 7T) and microperimetry (MP; Nidek MP-3). The population receptive field (pRF)-based coverage maps obtained with two different stimulus techniques (moving bars, and rotating wedges and expanding rings) were compared with the results of MP. Correspondence between MP and pRF mapping was quantified by calculating the simple matching coefficient (SMC). Results: Stimulus choice is shown to bias the spatial distribution of pRF centers and eccentricity values with pRF sizes obtained from wedge/ring or bar stimulation showing systematic differences. Wedge/ring stimulation results show a higher number of pRF centers in foveal areas and strongly reduced pRF sizes compared to bar stimulation runs. A statistical comparison shows significantly higher pRF center numbers in the foveal 2.5 degrees region of the visual field for wedge/ring compared to bar stimuli. However, these differences do not significantly influence SMC values when compared to MP (bar <2.5 degrees: 0.88 ± 0.13; bar >2.5 degrees: 0.88 ± 0.11; wedge/ring <2.5 degrees: 0.89 ± 0.12 wedge/ring; >2.5 degrees: 0.86 ± 0.10) for the peripheral visual field. Conclusions: Both visual stimulation designs examined can be applied successfully in patients with GA. Although the two designs show systematic differences in the distribution of pRF center locations, this variability has minimal impact on the SMC when compared to the MP outcome.

Subcutaneous rituximab in patients with diffuse large B cell lymphoma and follicular lymphoma: Final results of the non-interventional study MabSCale.

BACKGROUND: Rituximab has become a standard treatment for non-Hodgkin lymphoma. Clinical studies have demonstrated the efficacy of rituximab in combination with standard chemotherapies in the treatment of follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) patients. This non-interventional study aimed to evaluate the effectiveness and safety of subcutaneous (SC) rituximab in routine clinical practice. METHODS: Adult patients with previously untreated CD20 positive DLBCL or FL who received rituximab SC and chemotherapy as first-line treatment were observed between 07/2014 and 07/2019 at 99 institutions in Germany. Primary endpoint was the (unconfirmed) complete remission (CR/CRu) rate. Primary outcome was analyzed inferentially; other variables were evaluated descriptively. RESULTS: Overall 583 patients (247 FL; 336 DLBCL) were evaluated. CR/CRu rates were 51.4% (95% CI: 45.2; 57.6) in the FL set and 48.5% (95% CI: 43.2; 53.8) in the DLBCL set. Regarding progression-free survival in the FL group, the probability of being event-free was 94.2% in the first year and 86.2% in the second year. An overall response was achieved in 85.8% (FL) and 85.4% patients (DLBCL). Patient satisfaction at the end of study with the time saving simplification of the SC vs. intravenous route was 98% for FL and 97% for DLBCL. 45.3% of FL and 47.0% of DLBCL patients experienced an adverse event of grade ≥3. Serious adverse events of grade ≥3 occurred in 27.9% FL and 32.4% DLBCL patients, with the highest incidences for leucopenia, anemia, nausea, and fatigue. No new safety signals were detected. CONCLUSIONS: The results confirmed the effectiveness and safety of rituximab SC in both the FL and the DLBCL group. Satisfaction of patients and nurses with SC administration was high.

Small Charging Energies and g-Factor Anisotropy in PbTe Quantum Dots.

PbTe is a semiconductor with promising properties for topological quantum computing applications. Here, we characterize electron quantum dots in PbTe nanowires selectively grown on InP. Charge stability diagrams at zero magnetic field reveal large even-odd spacing between Coulomb blockade peaks, charging energies below 140 µeV and Kondo peaks in odd Coulomb diamonds. We attribute the large even-odd spacing to the large dielectric constant and small effective electron mass of PbTe. By studying the Zeeman-induced level and Kondo splitting in finite magnetic fields, we extract the electron g-factor as a function of magnetic field direction. We find the g-factor tensor to be highly anisotropic with principal g-factors ranging from 0.9 to 22.4 and to depend on the electronic configuration of the devices. These results indicate strong Rashba spin-orbit interaction in our PbTe quantum dots.

Sustained improvements in EQ-5D utility scores and self-rated health status in patients with ankylosing spondylitis after spa treatment including low-dose radon - an analysis of prospective radon indication registry data.

BACKGROUND: Patients with ankylosing spondylitis (AS) have significantly lower quality of life (QoL) than the general population. Holistic interventions addressing QoL comprise spa- or balneotherapy including radon. These interventions have shown to be beneficial in reducing pain and improving QoL in AS-patients. We explored the association of spa-therapy including low-dose radon with QoL in AS-patients over an extended time period. METHODS: Registry data collected for the "Radon indication registry" in the Austrian Gastein valley comprising data on QoL (EuroQol EQ-5D) directly before the treatment (baseline), directly(t1), 3 (t2); 6(t3) and 9(t4) months after the treatment, age, sex and body mass index (BMI) were analysed. Linear regression models explored the association of measurement time with 1) EQ-5D-5L utilities and 2) EuroQol visual analogue scale (VAS) score. Alterations of 0.05 (utilities) and 5.00 (VAS) were considered clinically relevant. RESULTS: Two-hundred-ninety-one AS-patients were included in the analyses. Forty-four percent (n = 128) were women, the mean age was 52 (SD 10) and the average BMI was 26 (SD 4). Utilities (t1: 0.09 [0.07;0.11]; t2: 0.08 [0.06; 0.10]; t3: 0.06 [0.05;0.09]; t4: 0.04 [0.02;0.06]) and VAS (t1: 11.68 [9.38; 13.97]; t2: 12.20 [9.78; 14.61]; t3: 9.70 [7.24; 12.17]; t4: 6.11 [3.57; 8.65]) were significantly higher at all timepoints compared to baseline. Improvements were clinically relevant at all timepoints in case of the VAS and until 6 months after treatment for the utilities. CONCLUSION: AS-patients who received spa therapy including radon show significantly and clinically relevant improvements in Qol until 6-9 months after treatment.

Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation.

Ferroptosis, an iron and reactive oxygen species (ROS)-dependent non-apoptotic type of regulated cell death, is characterized by a massive iron overload and peroxidation of polyunsaturated fatty acids (PUFAs), which finally results in cell death. Recent studies suggest that ferroptosis can influence carcinogenesis negatively and therefore may be used as a novel anti-cancer strategy. Hepatocellular carcinoma (HCC) is a deadly malignancy with poor chances of survival and is the second leading cause of cancer deaths worldwide. Diagnosis at an already late stage and general resistance to current therapies may be responsible for the dismal outcome. As the liver acts as a key factor in iron metabolism, ferroptosis is shown to play an important role in HCC carcinogenesis and, more importantly, may hold the potential to eradicate HCC. In this review, we summarize the current knowledge we have of the role of ferroptosis in HCC and the application of ferroptosis as a therapy option and provide an overview of the potential translation of ferroptosis in the clinical practice of HCC.

Characterization of Choriocapillaris and Choroidal Abnormalities in Alport Syndrome.

Purpose: To analyze the characteristics of the choriocapillaris and the choroid in patients with Alport syndrome (AS) and investigate their clinical and demographic associations. Methods: Multicenter, cross-sectional study. Forty-two eyes with AS were consecutively enrolled. A cohort of 33 healthy eyes was included as controls. Demographics and medical history were collected for each participant. Each eye underwent 3 × 3 swept-source optical coherence tomography angiography (PLEX Elite 9000 2.0; Carl Zeiss Meditec, Dublin, CA, USA) and spectral-domain OCT (Spectralis HRA2; Heidelberg Engineering, Heidelberg, Germany). Choriocapillaris flow deficit (FD) number, mean FD size, total FD area, FD density, subfoveal choroidal thickness (CT), total CT, and choroidal vascularity index (CVI) were compared between AS and control eyes. Factors associated with the FD density and the CVI in AS were explored with multivariable linear mixed models. Results: There was high intragroup variability in choriocapillaris and choroidal measurements in patients with AS. Choriocapillaris FD in patients with AS were more numerous compared to controls (P = 0.02). FD density in eyes with AS increased with older age (estimate = 0.31% for each year; 95% confidence interval [CI], 0.06-0.57; P = 0.02) and was higher in patients with a history of kidney transplant (estimate = 9.66% in case of positive history; 95% CI, 3.52-15.8; P = 0.006). The CVI was lower in eyes with dot maculopathy (estimate = -3.30% if present; 95% CI, -6.38 to -0.21; P = 0.04) and anterior lenticonus (estimate = -6.50% if present; 95% CI, -10.99 to -2.00; P = 0.006). Conclusions: Patients with AS with kidney involvement requiring transplant may present with more severe choriocapillaris impairment. Lower choroidal vascularity was found in the presence of other ocular structural abnormalities. Translational Relevance: An increased load of choriocapillaris flow deficits on optical coherence tomography angiography was found in patients with Alport syndrome who also had severe kidney disease requiring transplant.

Projected number of osteoarthritis patients in Austria for the next decades - quantifying the necessity of treatment and prevention strategies in Europe.

BACKGROUND: The present study aimed to predict the expected number of patients with osteoarthritis (OA) in Austria up to the year 2080. METHODS: Demographic data and population projections between 2019 and 2080 were obtained from European authorities. Information about recent age- and sex-stratified prevalence of patients with self-reported physician-diagnosed OA was obtained from the Austrian Health Interview Survey (n = 15,771). Projections were stratified by age and sex; sensitivity analyses were performed based on aging, main (most likely), and growth scenarios of the population. RESULTS: Based on the projection, the overall increase in the total number of patients with OA from 2019 to 2080 will be 38% for men and women. In 2019, the highest number of OA-patients nested in the groups of persons aged 70-79 (n = 238,749) and 60-69 (n = 237,729) years. In 2080, the 80+ age group is predicted to have the highest number of OA with 421,548 individuals (i.e. factor 3.45 and factor 2.48 increase in the male and female group, respectively, compared to 2019), followed by the group aged 70-79 with 314,617 individuals (factor 1.45 and factor 1.28 increase in the male and female group, respectively, compared to 2019). Similar trends were found in the ageing and growing scenarios. CONCLUSIONS: The projected increase in the occurrence of OA will likely lead to a substantial socioeconomic burden for the Austrian healthcare system in the near and far future. The current findings plead for the development of sustainable concepts for the treatment and prevention of OA by European authorities.

THE SPECTRUM OF INTERNAL LIMITING MEMBRANE DISEASE IN ALPORT SYNDROME: A Multimodal Imaging Study.

PURPOSE: To characterize the spectrum of internal limiting membrane (ILM) disease in Alport syndrome using multimodal imaging, including widefield (WF) and ultra-widefield (UWF) modalities, and to report their relative prevalence according to the genetic pattern of inheritance. METHODS: Cross-sectional clinical study of patients diagnosed with Alport syndrome. All patients underwent UWF color photography and autofluorescence, WF-optical coherence tomography angiography and spectral-domain optical coherence tomography. Demographics, past medical and ophthalmic history, and genetic mutation history were collected. RESULTS: Forty-two eyes of 21 patients (11 men; age 36.6 ± 12.9 years) were included. Macular spectral-domain optical coherence tomography revealed ILM granularity, more frequent in X-linked Alport syndrome and corresponding to dot maculopathy on color fundus. Mid-peripheral spectral-domain optical coherence tomography scans revealed multilamellated ILM in eight eyes (19%), presumably progressive, which corresponded to a cavitary pattern on en-face OCT. En-face OCT revealed multiple areas of retinal nerve fiber layer dehiscence in the macula, overlapping with vascular lacunae on optical coherence tomography angiography, and a coarse arrangement of retinal nerve fiber layer above and below the temporal raphe in 20 eyes (52%). CONCLUSION: Multimodal imaging allowed for the detection/characterization of retinal findings (ILM granularity, progressive ILM lamellation, retinal nerve fiber layer dehiscence, vascular lacunae, and coarse arrangement of retinal nerve fiber layer toward the disc) as multifaceted manifestations of ILM disease in Alport syndrome.

Macular Telangiectasia type 2: multimodal assessment of retinal function and microstructure.

PURPOSE: To assess the impact of neurodegenerative morphologic alterations due to macular telangiectasia type 2 (MacTel) on microperimetry (MP) and multifocal electroretinography (mfERG). METHODS: Thirty-five eyes of 18 patients with MacTel were examined using spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), mfERG and MP. Software was used to match SD-OCT B-scans with the corresponding retinal sensitivity map and multifocal electroretinograms (mfERGs), thus enabling direct structure/function correlation. RESULTS: Loss of the ellipsoid zone (EZ) had the strongest negative association with retinal sensitivity (16.77 dB versus 4.58 dB, adj. p < 0.001) of all parameters examined, and a limited negative effect on mfERGs (0.32 SD versus -1.97 SD adj. p = 0.121). Ellipsoid zone (EZ) irregularity was associated with reduced MP values but preserved mfERGs. There was a significant association between areas of inner retinal hyporeflectivity and loss of MP sensitivity (adj. p < 0.001) but the reduction in sensitivity was less than in locations with EZ loss. Areas of mfERG abnormality showed similar sensitivity loss with either inner retinal hyporeflectivity or EZ loss (adj. p = 0.063). In areas with EZ loss alone, preservation of the external limiting membrane (ELM) was associated with higher MP values than in areas with additional ELM loss; the integrity of the ELM alone was not associated with changes either in MP or mfERG. Increased FAF was observed in 51% of eyes, mixed/reduced FAF in 40%, and no abnormality was detected in 9% of eyes. CONCLUSION: The data suggest both MP and mfERG to be useful non-invasive modalities for detecting localised macular dysfunction in MacTel. The findings suggest a different sensitivity of the two modalities to inner and outer retinal changes in macular function and are therefore complementary.

Intrasession and Intersession Reproducibility of Artificial Scotoma pRF Mapping Results at Ultra-High Fields.

Functional magnetic resonance imaging (fMRI) combined with population receptive field (pRF) mapping allows for associating positions on the visual cortex to areas on the visual field. Apart from applications in healthy subjects, this method can also be used to examine dysfunctions in patients suffering from partial visual field losses. While such objective measurement of visual deficits (scotoma) is of great importance for, e.g., longitudinal studies addressing treatment effects, it requires a thorough assessment of accuracy and reproducibility of the results obtained. In this study, we quantified the reproducibility of pRF mapping results within and across sessions in case of central visual field loss in a group of 15 human subjects. We simulated scotoma by masking a central area of 2° radius from stimulation to establish ground-truth conditions. This study was performed on a 7T ultra-high field MRI scanner for increased sensitivity. We found excellent intrasession and intersession reproducibility for the pRF center position (Spearman correlation coefficients for x, y: >0.95; eccentricity: >0.87; polar angle: >0.98), but only modest reproducibility for pRF size (Spearman correlation coefficients around 0.4). We further examined the scotoma detection performance using an automated method based on a reference dataset acquired with full-field stimulation. For the 2° artificial scotoma, the group-averaged scotoma sizes were estimated at between 1.92° and 2.19° for different sessions. We conclude that pRF mapping of visual field losses yields robust, reproducible measures of retinal function and suggest the use of pRF mapping as an objective method for monitoring visual deficits during therapeutic interventions or disease progression.

Expanding the Phenotype of the FAM149B1-Related Ciliopathy and Identification of Three Neurogenetic Disorders in a Single Family.

Biallelic truncating FAM149B1 variants result in cilia dysfunction and have been reported in four infants with Joubert syndrome and orofaciodigital syndrome type VI, respectively. We report here on three adult siblings, 18 to 40 years of age, homozygous for the known FAM149B1 c.354_357delinsCACTC (p.Gln118Hisfs*20) variant. Detailed clinical examinations were performed including ocular and gait analyses, skeletal- and neuroimaging. All three patients presented with neurological and oculomotor symptoms since birth and mild skeletal dysplasia in infancy resulting in characteristic gait abnormalities. We document mild skeletal dysplasia, abnormal gait with increased hip rotation and increased external foot rotation, ataxia, variable polydactyly, ocular Duane syndrome, progressive ophthalmoplegia, nystagmus, situs inversus of the retinal vessels, olfactory bulb aplasia, and corpus callosal dysgenesis as novel features in FAM149B1-ciliopathy. We show that intellectual disability is mild to moderate and retinal, renal and liver function is normal in these affected adults. Our study thus expands the FAM149B1-related Joubert syndrome to a mainly neurological and skeletal ciliopathy phenotype with predominant oculomotor dysfunction but otherwise stable outcome in adults. Diagnosis of FAM149B1-related disorder was impeded by segregation of multiple neurogenetic disorders in the same family, highlighting the importance of extended clinical and genetic studies in families with complex phenotypes.

Semiconductor Epitaxy in Superconducting Templates.

Integration of high-quality semiconductor-superconductor devices into scalable and complementary metal-oxide-semiconductor compatible architectures remains an outstanding challenge, currently hindering their practical implementation. Here, we demonstrate growth of InAs nanowires monolithically integrated on Si inside lateral cavities containing superconducting TiN elements. This technique allows growth of hybrid devices characterized by sharp semiconductor-superconductor interfaces and with alignment along arbitrary crystallographic directions. Electrical characterization at low temperature reveals proximity induced superconductivity in InAs via a transparent interface.