Recent and rapid human population growth has led to an excess of rare genetic variants that are expected to contribute to an individual's genetic burden of disease risk. To date, much of the focus has been on rare protein-coding variants, for which potential impact can be estimated from the genetic code, but determining the impact of rare noncoding variants has been more challenging. To improve our understanding of such variants, we combined high-quality genome sequencing and RNA sequencing data from a 17-individual, three-generation family to contrast expression quantitative trait loci (eQTLs) and splicing quantitative trait loci (sQTLs) within this family to eQTLs and sQTLs within a population sample. Using this design, we found that eQTLs and sQTLs with large effects in the family were enriched with rare regulatory and splicing variants (minor allele frequency < 0.01). They were also more likely to influence essential genes and genes involved in complex disease. In addition, we tested the capacity of diverse noncoding annotation to predict the impact of rare noncoding variants. We found that distance to the transcription start site, evolutionary constraint, and epigenetic annotation were considerably more informative for predicting the impact of rare variants than for predicting the impact of common variants. These results highlight that rare noncoding variants are important contributors to individual gene-expression profiles and further demonstrate a significant capability for genomic annotation to predict the impact of rare noncoding variants.

Background: Osteochondral knee defects (OCD) are often symptomatic, causing pain and functional impairment even in young and active patients. Regenerative surgical options, aiming to stimulate natural cartilage healing, have been recently used as a first line treatment. In this study, a new hydrogel is investigated in its capacity to regenerate the ultra-structural quality of hyaline cartilage when combined with a classical microfracture technique. Material and methods: Forty-six patients, affected by grade III and IV knee chondropathies, were consecutively treated between 2013 and 2015 with microfractures followed by application of a modern hydrogel in the lesion site. All patients underwent clinical evaluation (WOMAC) pre-operatively, at 6,12 and at 24 months postoperatively: the results were compared with a subsequent, consecutive, matched, control group of 23 patients treated with microfractures alone. In a parallel and separate in-vitro histological study, adipose derived mesenchymal stem cells (ADMSCs) were encapsulated in the hydrogel scaffold, induced to differentiation into chondrocytes, and observed for a 3 weeks period. Results: The initial WOMAC score of 58.6 AE 11.0 in the study group was reduced by 88% at 6 months (7.1 AE 9.2) and 95% at 24 months (2.9 AE 5.9). The "in-vitro" study revealed a histological characterization typical of hyaline cartilage in study group. Separate biopsies performed at 12 months post-op in the study group also revealed type 2 collagen and hyaline-like cartilage in the regenerated tissue. Conclusion: Our study demonstrated high patient satisfaction rates after microfractures combined with a modern hydrogel scaffold; histologic evaluation supported the hypothesis of creating an enhanced chondrogenic environment. Microfracture "augmentation" using modern acellular biomaterials, like hydrogels, might improve the clinical outcomes of this classical bone marrow stimulating procedure.

Patients' HRQoL after prostate cancer treatment varies by treatment method. Notably, sexual function recovers most for RALP patients. UI remains worse at 24 months after surgery, compared to other methods of prostate cancer treatment.

The functional organization of diverse retinal ganglion cell (RGC) types, which shape the visual signals transmitted to the brain, has been examined in many species. The unique spatial, temporal, and chromatic properties of the numerically dominant RGC types in macaque monkey retina are presumed to most accurately model human vision. However, the functional similarity between RGCs in macaques and humans has only begun to be tested, and recent work suggests possible differences. Here, the properties of the numerically dominant human RGC types were examined using large-scale multi-electrode recordings with fine-grained visual stimulation in isolated retina, and compared to results from dozens of recordings from macaque retina using the same experimental methods and conditions. The properties of four major human RGC types -- ON-parasol, OFF-parasol, ON-midget, and OFF-midget -- closely paralleled those of the same macaque RGC types, including the spatial and temporal light sensitivity, precisely coordinated mosaic organization of receptive fields, ON-OFF asymmetries, spatial response nonlinearity, and sampling of photoreceptor inputs over space. Putative smooth monostratified cells and polyaxonal amacrine cells were also identified based on similarities to cell types previously identified in macaque retina. The results suggest that recently proposed differences between human and macaque RGCs probably reflect experimental differences, and that the macaque model provides an accurate picture of human RGC function.

Vision restoration with retinal implants is limited by indiscriminate simultaneous activation of many cells and cell types, which is incompatible with reproducing the neural code of the retina. Recent work has shown that macaque retinal ganglion cells (RGCs), which transmit visual information to the brain, can be directly electrically activated with single-cell, single-spike, cell-type precision – however, this possibility has never been tested in the human retina. Here, the electrical activation properties of identified RGC types in the human retina were examined using large-scale, multi-electrode recording and stimulation ex vivo and were compared directly to results from macaque. Precise activation was often possible without activating overlying axon bundles, at low stimulation current levels similar to those observed in macaque. The major RGC types could be identified and targeted based on their distinctive electrical signatures. The measured electrical activation properties of RGCs, combined with a dynamic stimulation algorithm, was sufficient to produce a nearly optimal evoked visual signal. These results reveal the possibility of high-fidelity vision restoration using bi-directional retinal implants.