Efficacy of topical progesterone versus topical clobetasol propionate in patients with vulvar Lichen sclerosus - A double-blind randomized phase II pilot study.

BACKGROUND Lichen sclerosus (LS) is a chronic inflammatory skin disease that mostly affects the anogenital region of women and lowers patients' quality of life. Current standard treatment of LS is topical steroids. OBJECTIVE To evaluate the efficacy of topical progesterone 8% ointment and compare to standard therapy with topical clobetasol propionate 0.05% in premenopausal women presenting with previously untreated early onset LS. STUDY DESIGN Randomized, double-blind, 2-arm, single center superiority trial in premenopausal women with histologically confirmed vulvar LS who were randomized in a 1:1 ratio to receive clobetasol propionate 0.05% ointment or progesterone 8% ointment. The primary outcome was the clinical severity LS score after 12 weeks, which consists of six clinical features assessed by the physician. Secondary outcomes were the symptom severity LS score, which consists of three symptoms rated by the patient, the Short Form SF-12 physical and mental health scores, and adverse events. Response to medication was assessed by biopsy at the end of the treatment to evaluate inflammatory parameters. RESULTS Overall, 105 women were screened, 102 underwent vulvar biopsy and 37 received a histologically confirmed diagnosis of LS and were randomized: 17 to progesterone and 20 to clobetasol propionate. At 12 weeks, the mean clinical LS scores improved from 4.6 (SD 2.0) to 4.5 (SD 1.7) in the progesterone arm, and from 4.6 (SD 2.8) to 2.9 (SD 2.2) in the clobetasol propionate arm (difference in favor of clobetasol 1.61; 95% CI 0.44 to 2.77, p = 0.009), and the mean symptom severity LS scores improved from 4.5 (SD 3.8) to 3.1 (SD 3.0) in the progesterone arm, and from 4.7 (SD 2.8) to 1.9 (SD 1.8) in the clobetasol propionate arm (difference in favor of clobetasol 1.32; 95% CI -0.25 to 2.89, p = 0.095). LS was in complete remission in 6 out of 10 patients (60%) with available biopsy in the progesterone arm, and in 13 out of 16 patients (81.3%) in the clobetasol propionate arm (odds ratio in favor of clobetasol 0.35; 95% CI 0.06 to 2.06, p = 0.234). No drug-related serious adverse event occurred during the trial. CONCLUSIONS Topical progesterone 8% ointment is inferior to standard therapy with topical clobetasol propionate 0.05% in previously untreated premenopausal women with vulvar LS after 12 weeks treatment

A Selection Fit Mechanism in BMP Receptor IA as a Possible Source for BMP Ligand-Receptor Promiscuity

Background: Members of the TGF-b superfamily are characterized by a highly promiscuous ligand-receptor interaction as is readily apparent from the numeral discrepancy of only seven type I and five type II receptors available for more than 40 ligands. Structural and functional studies have been used to address the question of how specific signals can be deduced from a limited number of receptor combinations and to unravel the molecular mechanisms underlying the protein-protein recognition that allow such limited specificity. Principal Findings: In this study we have investigated how an antigen binding antibody fragment (Fab) raised against the extracellular domain of the BMP receptor type IA (BMPR-IA) recognizes the receptor’s BMP-2 binding epitope and thereby neutralizes BMP-2 receptor activation. The crystal structure of the complex of the BMPR-IA ectodomain bound to the Fab AbD1556 revealed that the contact surface of BMPR-IA overlaps extensively with the contact surface for BMP-2 interaction. Although the structural epitopes of BMPR-IA to both binding partners coincides, the structures of BMPR-IA in the two complexes differ significantly. In contrast to the structural differences, alanine-scanning mutagenesis of BMPR-IA showed that the functional determinants for binding to the antibody and BMP-2 are almost identical. Conclusions: Comparing the structures of BMPR-IA bound to BMP-2 or bound to the Fab AbD1556 with the structure of unbound BMPR-IA shows that binding of BMPR-IA to its interaction partners follows a selection fit mechanism, possibly indicating that the ligand promiscuity of BMPR-IA is inherently encoded by structural adaptability. The functional and structural analysis of the BMPR-IA binding antibody AbD1556 mimicking the BMP-2 binding epitope may thus pave the way for the design of low-molecular weight synthetic receptor binders/inhibitors

Anthracycline-Induced Cardiotoxicity: Cardiac Monitoring by Continuous Wave-Doppler Ultrasound Cardiac Output Monitoring and Correlation to Echocardiography

Background: Anthracyclines are agents with a well-known cardiotoxicity. The study sought to evaluate the hemodynamic response to an anthracycline using real-time continuous-wave (CW)-Doppler ultrasound cardiac output monitoring (USCOM) and echocardiography in combination with serum biomarkers. Methods: 50 patients (26 male, 24 female, median age 59 years) suffering from various types of cancer received an anthracycline-based regimen. Patients' responses were measured at different time points (T0 prior to infusion, T1 6 h post infusion, T2 after 1 day, T3 after 7 days, and T4 after 3 months) with CW-Doppler ultrasound (T0-T4) and echocardiography (T1, T4) for hemodynamic parameters such as stroke volume (SV; SVUSCOM ml) and ejection fraction (EF; EFechocardiography%) and with NT-pro-BNP and hs-Troponin T (T0-T4). Results: During the 3-month observation period, the relative decrease in the EF determined by echocardiography was -2.1% (Delta T0-T4, T0 71 +/- 7.8%, T4 69.5 +/- 7%, p = 0.04), whereas the decrease in SV observed using CW-Doppler was -6.5% (Delta T0-T4, T0 54 +/- 19.2 ml, T4 50.5 +/- 20.6 ml, p = 0.14). The kinetics for serum biomarkers were inversely correlated. Conclusions: Combining real-time CW-Doppler USCOM and serum biomarkers is feasible for monitoring the immediate and chronic hemodynamic changes during an anthracycline-based regimen; the results obtained were comparable to those from echocardiography

Being More Realistic About Reasons: On Rationality and Reasons Perspectivism

This paper looks at whether it is possible to unify the requirements of rationality with the demands of normative reasons. It might seem impossible to do because one depends upon the agent’s perspective and the other upon features of the situation. Enter Reasons Perspectivism. Reasons perspectivists think they can show that rationality does consist in responding correctly to reasons by placing epistemic constraints on these reasons. They think that if normative reasons are subject to the right epistemic constraints, rational requirements will correspond to the demands generated by normative reasons. While this proposal is prima facie plausible, it cannot ultimately unify reasons and rationality. There is no epistemic constraint that can do what reasons perspectivists would need it to do. Some constraints are too strict. The rest are too slack. This points to a general problem with the reasons-first program. Once we recognize that the agent’s epistemic position helps determine what she should do, we have to reject the idea that the features of the agent’s situation can help determine what we should do. Either rationality crowds out reasons and their demands or the reasons will make unreasonable demands

Participatory Patterns in an International Air Quality Monitoring Initiative

The issue of sustainability is at the top of the political and societal agenda, being considered of extreme importance and urgency. Human individual action impacts the environment both locally (e.g., local air/water quality, noise disturbance) and globally (e.g., climate change, resource use). Urban environments represent a crucial example, with an increasing realization that the most effective way of producing a change is involving the citizens themselves in monitoring campaigns (a citizen science bottom-up approach). This is possible by developing novel technologies and IT infrastructures enabling large citizen participation. Here, in the wider framework of one of the first such projects, we show results from an international competition where citizens were involved in mobile air pollution monitoring using low cost sensing devices, combined with a web-based game to monitor perceived levels of pollution. Measures of shift in perceptions over the course of the campaign are provided, together with insights into participatory patterns emerging from this study. Interesting effects related to inertia and to direct involvement in measurement activities rather than indirect information exposure are also highlighted, indicating that direct involvement can enhance learning and environmental awareness. In the future, this could result in better adoption of policies towards decreasing pollution.Comment: 17 pages, 6 figures, 1 supplementary fil

Characterization of the radiation tolerance of cryogenic diodes for the High Luminosity LHC inner triplet circuit

Cryogenic bypass diodes are part of the baseline powering layout for the circuits of the new Nb3Sn based final focus magnets of the high luminosity Large Hadron Collider. They will protect the magnets against excessive transient voltages during a nonuniform quenching process. The diodes are located inside an extension to the magnet cryostat, operated in superfluid helium and exposed to ionizing radiation. Therefore, the radiation tolerance of different types of diodes has been tested at cryogenic temperatures in CERN’s CHARM irradiation test facility during its 2018 run. The forward bias characteristics, the turn-on voltage and the reverse blocking voltage of each diode were measured weekly at 4.2 K and 77 K, as a function of the accumulated radiation dose. The diodes were submitted to a total dose close to 12 kGy and a 1 MeV neutron equivalent fluence of 2.2×1014  cm−2. After the end of the irradiation program the annealing behavior of the diodes was tested by increasing the temperature slowly to 293 K. This paper describes the experimental setup, the measurement procedure and the analysis of the measurements performed during the irradiation program as well as the results of the annealing study

Observation of enhanced chiral asymmetries in the inner-shell photoionization of uniaxially oriented methyloxirane enantiomers

Most large molecules are chiral in their structure: they exist as two enantiomers, which are mirror images of each other. Whereas the rovibronic sublevels of two enantiomers are almost identical, it turns out that the photoelectric effect is sensitive to the absolute configuration of the ionized enantiomer - an effect termed Photoelectron Circular Dichroism (PECD). Our comprehensive study demonstrates that the origin of PECD can be found in the molecular frame electron emission pattern connecting PECD to other fundamental photophysical effects as the circular dichroism in angular distributions (CDAD). Accordingly, orienting a chiral molecule in space enhances the PECD by a factor of about 10

On the Energy Dependence of the Dipole-Proton Cross Section in Deep Inelastic Scattering

We study the dipole picture of high-energy virtual-photon-proton scattering. It is shown that different choices for the energy variable in the dipole cross section used in the literature are not related to each other by simple arguments equating the typical dipole size and the inverse photon virtuality, contrary to what is often stated. We argue that the good quality of fits to structure functions that use Bjorken-x as the energy variable - which is strictly speaking not justified in the dipole picture - can instead be understood as a consequence of the sign of scaling violations that occur for increasing Q^2 at fixed small x. We show that the dipole formula for massless quarks has the structure of a convolution. From this we obtain derivative relations between the structure function F_2 at large and small Q^2 and the dipole-proton cross section at small and large dipole size r, respectively.Comment: 27 page