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Longitudinal characterization of early brain growth in-utero has been limited by a number of challenges in fetal imaging, the rapid change in size, shape and volume of the developing brain, and the consequent lack of suitable algorithms for fetal brain image analysis. There is a need for an improved digital brain atlas of the spatiotemporal maturation of the fetal brain extending over the key developmental periods. We have developed an algorithm for construction of an unbiased four-dimensional atlas of the developing fetal brain by integrating symmetric diffeomorphic deformable registration in space with kernel regression in age. We applied this new algorithm to construct a spatiotemporal atlas from MRI of 81 normal fetuses scanned between 19 and 39 weeks of gestation and labeled the structures of the developing brain. We evaluated the use of this atlas and additional individual fetal brain MRI atlases for completely automatic multi-atlas segmentation of fetal brain MRI. The atlas is available online as a reference for anatomy and for registration and segmentation, to aid in connectivity analysis, and for groupwise and longitudinal analysis of early brain growth.

Hidradenitis suppurativa (HS) is a highly prevalent, morbid inflammatory skin disease with limited treatment options. The major cell types and inflammatory pathways in skin of patients with HS are poorly understood, and which patients will respond to TNF-α blockade is currently unknown. We discovered that clinically and histologically healthy appearing skin (i.e., nonlesional skin) is dysfunctional in patients with HS with a relative loss of immune regulatory pathways. HS skin lesions were characterized by quantitative and qualitative dysfunction of type 2 conventional dendritic cells, relatively reduced regulatory T cells, an influx of memory B cells, and a plasma cell/plasmablast infiltrate predominantly in end-stage fibrotic skin. At the molecular level, there was a relative bias toward the IL-1 pathway and type 1 T cell responses when compared with both healthy skin and psoriatic patient skin. Anti-TNF-α therapy markedly attenuated B cell activation with minimal effect on other inflammatory pathways. Finally, we identified an immune activation signature in skin before anti-TNF-α treatment that correlated with subsequent lack of response to this modality. Our results reveal the fundamental immunopathogenesis of HS and provide a molecular foundation for future studies focused on stratifying patients based on likelihood of clinical response to TNF-α blockade.

Hidradenitis suppurativa (HS) is a chronic skin condition affecting approximately 1% of the US population. HS skin lesions are highly inflammatory and characterized by a large immune infiltrate. While B cells and plasma cells comprise a major component of this immune milieu, the biology and the contribution of these cells in HS pathogenesis are unclear. We aimed to investigate the dynamics and microenvironmental interactions of B cells within cutaneous HS lesions. Combining histological analysis, single-cell RNA sequencing, and spatial transcriptomics profiling of HS lesions, we defined the tissue microenvironment relative to B cell activity within this disease. Our findings identified tertiary lymphoid structures (TLSs) within HS lesions and described organized interactions among T cells, B cells, antigen-presenting cells, and skin stroma. We found evidence that B cells within HS TLSs actively underwent maturation, including participation in germinal center reactions and class switch recombination. Moreover, skin stroma and accumulating T cells were primed to support the formation of TLSs and facilitate B cell recruitment during HS. Our data definitively demonstrated the presence of TLSs in lesional HS skin and point to ongoing cutaneous B cell maturation through class switch recombination and affinity maturation during disease progression in this inflamed nonlymphoid tissue.

Regulatory T cells (Tregs) are essential for maintaining immune tolerance in both lymphoid and non-lymphoid tissues. We discovered that layilin, a C-type lectin receptor, is predominantly expressed on Tregs in skin. Layilin was highly expressed on a subset of clonally expanded ‘effector’ Tregs in both healthy and psoriatic human skin. Layilin-expressing Tregs exhibited a transcriptional profile indicative of enhanced adhesion. Deletion of layilin in Tregs in mice in vivo resulted in significantly attenuated skin inflammation. Mechanistically, layilin enhanced in vitro human Treg adhesion via modulation of lymphocyte function-associated antigen-1, resulting in distinct cytoskeletal alterations consistent with enhanced focal adhesion and lamellipodia formation. Taken together, we define layilin as a critical regulator of Treg-suppressive capacity by modulating motility and adhesion in a non-lymphoid tissue.

Triceps tendon rupture in females is rare. In this case report, we present a young adult female patient with a distal triceps tendon rupture from bouldering treated with open surgical repair technique using a modified bone tunnel and suture anchor fixation technique. The diagnosis and technique for repair and postoperative rehabilitation are described. A review of the current literature of biomechanical and clinical outcomes of various repair techniques is also presented.

Multi-site MRI studies are often necessary for recruiting sufficiently sized samples when studying rare conditions. However, they require pooling data from multiple scanners into a single data set, and therefore it is critical to evaluate the variability of quantitative MRI measures within and across scanners used in multi-site studies. The aim of this study was to evaluate the reproducibility of structural and diffusion weighted (DW) MRI measurements acquired on seven scanners at five medical centers as part of the Tuberous Sclerosis Complex Autism Center of Excellence Research Network (TACERN) multisite study. The American College of Radiology (ACR) phantom was imaged monthly to measure reproducibility of signal intensity and uniformity within and across seven 3T scanners from General Electric, Philips, and Siemens vendors. One healthy adult male volunteer was imaged repeatedly on all seven scanners under the TACERN structural and DW protocol (5 b = 0 s/mm and 30 b = 1000 s/mm ) over a period of 5 years (age 22-27 years). Reproducibility of inter- and intra-scanner brain segmentation volumes and diffusion tensor imaging metrics fractional anisotropy (FA) and mean diffusivity (MD) within white matter regions was quantified with coefficient of variation. The American College of Radiology Phantom signal intensity and uniformity were similar across scanners and changed little over time, with a mean intra-scanner coefficient of variation of 3.6 and 1.8%, respectively. The mean inter- and intra-scanner coefficients of variation of brain structure volumes derived from T1-weighted (T1w) images of the human phantom were 3.3 and 1.1%, respectively. The mean inter- and intra-scanner coefficients of variation of FA in white matter regions were 4.5 and 2.5%, while the mean inter- and intra-scanner coefficients of variation of MD in white matter regions were 5.4 and 1.5%. Our results suggest that volumetric and diffusion tensor imaging (DTI) measurements are highly reproducible between and within scanners and provide typical variation amplitudes that can be used as references to interpret future findings in the TACERN network.

Suppose that virtue is intrinsically morally good, and that we have a pro tanto moral reason to act in ways which promote it. Further suppose that the failure of agents to receive what they deserve is intrinsically morally bad, and that we have a pro tanto moral reason not to act in ways which frustrate desert. When we are deciding whether to encourage others to make altruistic sacrifices, these two pro tanto moral reasons come into conflict. To encourage such sacrifices promotes virtue; it also causes virtuous agents to be worse off, preventing them from receiving their deserts. I argue that these effects on desert can reduce the moral desirability of promoting altruism so significantly as to make it morally wrong. This has implications for public policy, since certain practical questions turn on the extent to which we ought to rely on altruism as a means of solving social problems.

According to an influential family of views, agents are virtuous when and because they possess the correct attitudes towards the actual good and bad. But there are multiple ways of conceptualizing the actual good and bad, and attitudes towards some conceptualizations of the good and bad seem to be irrelevant to moral character. It is deceptively difficult to provide a theoretical rationale for distinguishing between those conceptualizations of the good and bad that seem to be relevant and those that do not: I argue that a previous attempt to provide such a rationale fails, as do a number of seemingly promising alternatives. This problem merits further attention not only because it shows that certain theoretical accounts of character are incomplete, but because it is likely to interfere with our ability to evaluate certain real-world agents, who care about the actual good conceptualized in certain ways but not in others. Since a generalized version of the problem of conceptualization also affects other “intrinsic” accounts of virtue and vice, I argue that we must either solve this problem or abandon such accounts.