Prompt Agalsidase Alfa Therapy Initiation is Associated with Improved Renal and Cardiovascular Outcomes in a Fabry Outcome Survey Analysis

BACKGROUND: The timing of enzyme replacement therapy initiation in patients with Fabry disease is hypothesized to be critical. In this study, we used Fabry Outcome Survey data to assess the impact of prompt versus delayed initiation of treatment with agalsidase alfa on cardiovascular and renal events in patients with Fabry disease. METHODS: Available genetic data at baseline were used to define patients with mutations associated with classical versus late-onset Fabry disease. Time to cardiovascular or renal events, from treatment initiation until 120 months, was compared for patients in prompt versus delayed groups. “Prompt” was defined as treatment initiation < 24 months from symptom onset (analysis A) or diagnosis (analysis B), and “delayed” was defined as ≥ 24 months from symptom onset (analysis A) or diagnosis (analysis B). Kaplan–Meier curves and Log rank tests compared event-free probabilities and time to first event. Multivariate Cox regression estimated hazard ratios (HRs). RESULTS: Analysis by time from symptom onset included 1374 patients (172 prompt, 1202 delayed). In a multivariate Cox regression analysis, prompt versus delayed treatment initiation significantly reduced the probability of cardiovascular (HR=0.62; P< 0.001) and renal (HR=0.57; P=0.001) events. History of cardiovascular or renal events was associated with increased risk of respective events. Analysis by time from diagnosis included 2051 patients (1006 prompt, 1045 delayed). In a multivariate Cox regression analysis, prompt treatment initiation significantly reduced the probability of cardiovascular events (HR=0.83; P=0.003) after adjusting for history of cardiovascular events, sex, and age at treatment initiation. Univariate analysis showed that the probability of renal events was significantly lower in the prompt group (P=0.018); this finding was attenuated in the multivariate Cox regression analysis. CONCLUSIONS: This analysis suggests that prompt treatment initiation with agalsidase alfa provided better renal and cardiovascular outcomes than delayed treatment in patients with Fabry disease

Career Goals and Student Perceptions of a Post-Professional Occupational Therapy Doctoral Experiential Component

Clinical doctoral education for occupational therapy includes the acquisition of advanced clinical reasoning skills, leadership capacity, and opportunities for professional development and career achievement. Post-professional students represent motivated individuals seeking to enhance their education, experiences, and explore professional growth opportunities. While not required, the final semester of a clinical doctoral program typically includes a doctoral experiential component (DEC), or culminating project. The purpose of this retrospective, mixed-methods study was to examine the DEC goals and experiences of post-professional occupational therapy doctoral (POTD) students. A total of 49 student DEC proposals, each including multiple personal goals, were categorized according to one or more POTD program goals. The most frequently selected long-term DEC goals by participants in this study were developing educative roles (n = 37, 27.30%), scholarly activities (n = 31, 22.96%), and advanced clinical skills (n = 31, 22.96). The DEC goals developed by the students were also categorized according to the experience as perceived by the students. Three primary areas of growth experienced by the students during their DEC were: (1) improved self-awareness and confidence through reflection, (2) a challenging, yet fulfilling, experience and (3) translation of new knowledge and skills to practice. The outcomes of this study may offer insight for administrators and prospective students of post-professional programs and align with the American Occupational Therapy Association’s Vision 2025 to produce effective and collaborative leaders capable of implementing evidence-based, client-centered, and cost-effective treatment to influence the complexities of healthcare

Nitrogen pair-induced temperature insensitivity of the band gap of GaNSb alloys

The temperature dependence of the band gap of GaN x Sb1−x films with x ≤ 1.3% has been studied in the 1.1–3.3 m (0.35–1.1 eV) range using infrared absorption spectroscopy between 4.2 and 300 K. As with other dilute nitride semiconductors, the temperature dependence of the band gap is reduced by alloying with nitrogen when compared to the host binary compound. However, for GaNSb, the smallest variation of the band gap with temperature is observed for samples with the lowest N content for which the band gap is almost totally insensitive to temperature changes. This contrasts with the more widely studied GaN x As1−x alloys in which the band gap variation with temperature decreases with increasing N content. The temperature-dependent absorption spectra are simulated within the so-called band anticrossing model of the interaction between the extended conduction band states of the GaSb and the localized states associated with the N atoms. The N next-nearest neighbor pair states are found to be responsible for the temperature insensitivity of the band gap of the GaNSb alloys as a result of their proximity to the conduction band edge giving them a more pronounced role than in GaNAs alloys

Effects of Baseline Left Ventricular Hypertrophy and Decreased Renal Function on Cardiovascular and Renal Outcomes in Patients with Fabry Disease Treated with Agalsidase Alfa: A Fabry Outcome Survey Study

PURPOSE: The initiation of enzyme-replacement therapy prior to the occurrence of substantial and irreversible organ damage in patients with Fabry disease is of critical importance. The Fabry Outcome Survey is an international disease registry of patients with a confirmed diagnosis of Fabry disease. In this study, data from the Fabry Outcome Survey were used for the assessment of the risks for cardiovascular and renal events in patients who received agalsidase alfa treatment. METHODS: Eligible patients were males and females aged ≥18 years with Fabry disease treated with agalsidase alfa. Cardiovascular events included myocardial infarction, left ventricular hypertrophy (LVH), heart failure, arrhythmia, conduction abnormality, and cardiac surgery. Renal events included dialysis, transplantation, and renal failure. Kaplan-Meier curves and log-rank tests were used for comparing event-free probabilities and time to first cardiovascular or renal event, from agalsidase alfa initiation to a maximum of 120 months, in patients with LVH versus normal left ventricular mass index (LVMI; ≤50 g/m2.7 in males and ≤48 g/m2.7 in females) at treatment initiation (baseline), and in patients with a low estimated glomerular filtration rate (eGFR; <90 mL/min/1.73 m2) versus normal eGFR at baseline. Multivariate Cox regression analysis was used for examining the association between key study variables and the risks for cardiovascular and renal events. FINDINGS: Among the 560 patients (269 males; 291 females) with available LVMI data, 306 (55%) had LVH and 254 (45%) had normal LVMI at baseline. The risk for a cardiovascular event was higher in the subgroup with LVH versus normal LVMI at baseline (hazard ratio [HR] = 1.57; 95% CI, 1.21-2.05; P < 0.001), but the risk for a renal event was similar between the 2 subgroups (HR = 1.90; 95% CI, 0.94-3.85; P = 0.074). Among the 1093 patients (551 males; 542 females) with available eGFR data, 433 (40%) had a low eGFR and 660 (60%) had a normal eGFR at baseline. The subgroup with a low eGFR at baseline had a significantly higher risk for a cardiovascular event (HR = 1.33; 95% CI, 1.04-1.70; P = 0.021) or a renal event (HR = 5.88; 95% CI, 2.73-12.68; P < 0.001) compared with patients with a normal eGFR at baseline. IMPLICATIONS: In the present study, the presence of LVH and/or reduced renal function at agalsidase alfa initiation was associated with a significantly higher risk for a cardiovascular or renal event, indicating that cardiovascular and renal pathologies in Fabry disease may be inter-related. Early initiation of agalsidase alfa treatment prior to the onset of severe organ damage may improve outcomes. ClinicalTrials.gov identifier: NCT03289065

The geodesic approximation for lump dynamics and coercivity of the Hessian for harmonic maps

The most fruitful approach to studying low energy soliton dynamics in field theories of Bogomol'nyi type is the geodesic approximation of Manton. In the case of vortices and monopoles, Stuart has obtained rigorous estimates of the errors in this approximation, and hence proved that it is valid in the low speed regime. His method employs energy estimates which rely on a key coercivity property of the Hessian of the energy functional of the theory under consideration. In this paper we prove an analogous coercivity property for the Hessian of the energy functional of a general sigma model with compact K\"ahler domain and target. We go on to prove a continuity property for our result, and show that, for the CP^1 model on S^2, the Hessian fails to be globally coercive in the degree 1 sector. We present numerical evidence which suggests that the Hessian is globally coercive in a certain equivariance class of the degree n sector for n>1. We also prove that, within the geodesic approximation, a single CP^1 lump moving on S^2 does not generically travel on a great circle.Comment: 29 pages, 1 figure; typos corrected, references added, expanded discussion of the main function spac

Collapse of an Instanton

We construct a two parameter family of collapsing solutions to the 4+1 Yang-Mills equations and derive the dynamical law of the collapse. Our arguments indicate that this family of solutions is stable. The latter fact is also supported by numerical simulations.Comment: 17 pages, 1 figur

Aortic remodelling in Fabry disease

Aims To evaluate thoracic aortic dilation in patients with Fabry disease (FD). Methods and results A cohort of 106 patients with FD (52 males; 54 females) from three European centres were studied. The diameter of the thoracic aorta was assessed at three levels (sinus of Valsalva, ascending aorta, and descending aorta) using echocardiograms and cardiovascular magnetic resonance imaging. Aortic dilation at the sinus of Valsalva was found in 32.7% of males and 5.6% of females; aneurysms were present in 9.6% of males and 1.9% of females. No aortic dilation was observed in the descending aorta. There was no correlation between aortic diameter at the sinus of Valsalva and cardiovascular risk factors. Conclusion Fabry disease should be considered as a cardiovascular disease that affects the heart and arterial vasculature, including the thoracic aorta. Thus, patients with FD should be closely monitored for the presence, and possible progression and complications of aortic dilation. Clinical Trial Registration: Protocol 101/01. Ethics committee, Faculty of Medicine, Lausann

Optical markers of magnetic phase transition in CrSBr

Here, we investigate the role of the interlayer magnetic ordering of CrSBr in the framework of $\textit{ab initio}$ calculations and by using optical spectroscopy techniques. These combined studies allow us to unambiguously determine the nature of the optical transitions. In particular, photoreflectance measurements, sensitive to the direct transitions, have been carried out for the first time. We have demonstrated that optically induced band-to-band transitions visible in optical measurement are remarkably well assigned to the band structure by the momentum matrix elements and energy differences for the magnetic ground state (A-AFM). In addition, our study reveals significant differences in electronic properties for two different interlayer magnetic phases. When the magnetic ordering of A-AFM to FM is changed, the crucial modification of the band structure reflected in the direct-to-indirect band gap transition and the significant splitting of the conduction bands along the $\Gamma-Z$ direction are obtained. In addition, Raman measurements demonstrate a splitting between the in-plane modes $B^2_{2g}$/$B^2_{3g}$, which is temperature dependent and can be assigned to different interlayer magnetic states, corroborated by the DFT+U study. Moreover, the $B^2_{2g}$ mode has not been experimentally observed before. Finally, our results point out the origin of interlayer magnetism, which can be attributed to electronic rather than structural properties. Our results reveal a new approach for tuning the optical and electronic properties of van der Waals magnets by controlling the interlayer magnetic ordering in adjacent layers.Comment: 33 pages, 15 figure