624 - Vitiligo biomarker CXCL10 correlates with clinical response in the phase 2 randomized, double-blind, vehicle-controlled TRuE-V mechanism of action study

Abstract: Introduction/Background: Ruxolitinib cream is a topical formulation of the selective Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib and is the first and only repigmentation treatment approved by the US Food and Drug Administration and European Commission for nonsegmental vitiligo in patients ≥12 years old. Objectives: To evaluate treatment-associated changes in biomarkers among patients with vitiligo, correlate changes in key biomarkers with efficacy, and assess the safety and tolerability of ruxolitinib cream. Methods: The phase 2, randomized, double-blind, vehicle-controlled TRuE-V mechanism of action study (NCT04896385) was conducted in adult patients (≥18 years) with vitiligo ≤50% of total body surface area. Patients were randomized 2:1 to twice-daily 1.5% ruxolitinib cream or vehicle cream for 24 weeks, after which all patients could apply 1.5% ruxolitinib cream through Week 52. Changes from baseline in local and systemic immune biomarkers, including C-X-C motif chemokine ligand 10 (CXCL10), were evaluated at Weeks 4, 12, and 24. The relative expression of >3000 serum protein analytes was assessed using the Olink Explore platform, and a validated Meso Scale Discovery (MSD) assay was used to confirm absolute levels of serum CXCL10. Relative CXCL10 expression was determined by quantitative polymerase chain reaction (qPCR) from isolated biopsy samples. Punch biopsies (2.5 mm) were taken from lesional and nonlesional skin at baseline and lesional skin (even if the lesion had cleared) at Weeks 12, 24, and 40. Treatment efficacy was determined by the percentage change from baseline in facial and total Vitiligo Area Scoring Index (F-VASI and T-VASI, respectively). Safety was evaluated by the frequency and severity of adverse events. Results: The study enrolled 60 patients (ruxolitinib cream, n=41; vehicle, n=19). Patients’ mean (SD) age was 44.7 (12.8) years, 56.7% were male, and 53.3% had lighter skin (Fitzpatrick skin types I–III). At baseline, patients had a median (range) disease duration of 12.0 (0.1–52.9) years and mean (SD) F-VASI and T-VASI scores of 1.1 (0.6) and 12.1 (9.4), respectively. Olink Explore identified few differentially expressed proteins in patient sera (adjusted P<0.05 and log2 fold change >1.25), including CXCL10, SH2D1A, and granzyme B. As early as Week 12, serum CXCL10 levels (in MSD assay) were significantly reduced in ruxolitinib cream–treated patients compared with baseline. Skin CXCL10 levels were similar in lesional and nonlesional skin at baseline but were significantly lowered in lesional skin at Week 12 with ruxolitinib cream. In ruxolitinib cream–treated patients, significant mean [SD] percentage reductions from baseline were seen in F-VASI scores at Week 12 (–32.9 [33.6]) and in T-VASI scores at Week 24 (–21.2 [18.5]). Further, T-VASI scores significantly correlated with a change in serum CXCL10 levels between baseline and Week 24. Most systemic proteins did not correlate or only weakly correlated with F-VASI and T-VASI scores. Through Week 24, 46.3% of 41 patients who applied ruxolitinib cream reported treatment-emergent adverse events (none serious), the most common being COVID-19 (9.8%), application site acne (4.9%), and application site rash (4.9%). Conclusions: Taken together, these data are consistent with the role of the interferon-gamma:CXCL10 axis as a central mediator of vitiligo pathogenesis. Serum CXCL10 levels decreased significantly in patients who applied ruxolitinib cream, which correlated with improvement in T-VASI scores. Additionally, skin CXCL10 levels were significantly reduced after 12 weeks of ruxolitinib cream treatment

Penis size: Survey of female perceptions of sexual satisfaction

BACKGROUND: Does the size of the male penis, in terms of length or width, make a difference in female sexual satisfaction? METHOD: To study the effect of penis width vs. length on female sexual satisfaction, 50 sexually active female undergraduate students were asked which felt better, i. e., was penis width or length more important for their sexual satisfaction. RESULTS: None reported they did not know, or that width and length were equally satisfying. A large majority, 45 of 50, reported width was more important (p < .001). CONCLUSION: Implications are discussed, including the fact that the data seem to contradict Masters and Johnson about penis size having no physiological effect on female sexual satisfaction

Limits to Poisson's ratio in isotropic materials

A long-standing question is why Poisson's ratio v nearly always exceeds 0.2 for isotropic materials, whereas classical elasticity predicts v to be between -1 to 1/2. We show that the roots of quadratic relations from classical elasticity divide v into three possible ranges: -1 < v <= 0, 0 <= v <= 1/5, and 1/5 <= v < 1/2. Since elastic properties are unique there can be only one valid set of roots, which must be 1/5 <= v < 1/2 for consistency with the behavior of real materials. Materials with Poisson's ratio outside of this range are rare, and tend to be either very hard (e.g., diamond, beryllium) or porous (e.g., auxetic foams); such substances have more complex behavior than can be described by classical elasticity. Thus, classical elasticity is inapplicable whenever v < 1/5, and the use of the equations from classical elasticity for such materials is inappropriate.Comment: Physical Review B, in pres

''Sex changes'? Paradigm shifts in 'sex' and 'gender' following the gender recognition act?'

Gender transformations are normatively understood as somatic, based on surgical reassignment, where the sexed body is aligned with the gender identity of the individual through genital surgery - hence the common lexicon 'sex change surgery'. We suggest that the UK Gender Recognition Act 2004 challenges what constitutes a 'sex change' through the Act's definitions and also the conditions within which legal 'recognition' is permitted. The sex/gender distinction, (where sex normatively refers to the sexed body, and gender, to social identity) is demobilised both literally and legally. This paper discusses the history of medico-socio-legal definitions of sex have been developed through decision making processes when courts have been faced with people with gender variance and , in particular, the implications of the Gender Recognition Act for our contemporary legal understanding of sex. We ask, and attempt to answer, has 'sex' changed

Exponential Barycenters of the Canonical Cartan Connection and Invariant Means on Lie Groups

International audienceWhen performing statistics on elements of sets that possess a particular geometric structure, it is desirable to respect this structure. For instance in a Lie group, it would be judicious to have a notion of a mean which is stable by the group operations (composition and inversion). Such a property is ensured for Riemannian center of mass in Lie groups endowed with a bi-invariant Riemannian metric, like compact Lie groups (e.g. rotations). However, bi-invariant Riemannian metrics do not exist for most non compact and non-commutative Lie groups. This is the case in particular for rigid-body transformations in any dimension greater than one, which form the most simple Lie group involved in biomedical image registration. In this paper, we propose to replace the Riemannian metric by an affine connection structure on the group. We show that the canonical Cartan connections of a connected Lie group provides group geodesics which are completely consistent with the composition and inversion. With such a non-metric structure, the mean cannot be defined by minimizing the variance as in Riemannian Manifolds. However, the characterization of the mean as an exponential barycenter gives us an implicit definition of the mean using a general barycentric equation. Thanks to the properties of the canonical Cartan connection, this mean is naturally bi-invariant. We show the local existence and uniqueness of the invariant mean when the dispersion of the data is small enough. We also propose an iterative fixed point algorithm and demonstrate that the convergence to the invariant mean is at least linear. In the case of rigid-body transformations, we give a simple criterion for the global existence and uniqueness of the bi-invariant mean, which happens to be the same as for rotations. We also give closed forms for the bi-invariant mean in a number of simple but instructive cases, including 2D rigid transformations. For general linear transformations, we show that the bi-invariant mean is a generalization of the (scalar) geometric mean, since the determinant of the bi-invariant mean is the geometric mean of the determinants of the data. Finally, we extend the theory to higher order moments, in particular with the covariance which can be used to define a local bi-invariant Mahalanobis distance

The Semiotic Fractures of Vulnerable Bodies: Resistance to the Gendering of Legal Subjects

While the turn to vulnerability in law responds to a recurrent critique by feminist scholars on the disembodiment of legal personhood, this article suggests that the mobilization of vulnerability in the criminal courts does not necessarily offer female drug mules a direct path to justice. Through an analysis of sentencing appeals of female drug mules in England and Wales, this article presents a feminist critique of the dispositif of the person and its relation to vulnerability. Discourses on drug mules’ vulnerability mobilize the trope of the colonial victim in need of protection, which is often translated into legal mercy. But mercy is rather an expression of biopower which inscribes not only fragility onto the bodies of drug mules by figuring them as exemplar paradigms of colonial subjectivity, but also reinvigorates the dispositif of gender implicit in the legal person. In this set-up, it would appear as if law and politics totalize the registers of life, in this case the contours of vulnerable body. The article suggests we must revisit the image of the wounded body in order to carve out a space for resistance. Drawing on Elaine Scarry and Judith Butler, it suggests vulnerable bodies are marked by a semiotic openness, which renders them subject to appropriation but also able to signify the precarity produced by the law through their resistance to representation