Search

Background: Switching between antibody classes might be a treatment option in migraine patients who have not responded to one class of a CGRP-(receptor) monoclonal antibody (mAb), but there are no efficacy data so far. In this real-world analysis, we assessed the treatment response to a CGRP-mAb in patients that have previously failed the CGRP-receptor-mAb erenumab. Methods: We analyzed retrospective headache diary data of 78 patients with migraine who switched between CGRP-mAbs classes at four German headache centers either due to lack of efficacy or intolerable side effects. Among these, we identified 25 patients who did not respond to erenumab after three treatment cycles (defined as <30% reduction of monthly headache days) and had complete headache documentation at least one month before and during both treatments. We assessed the ≥30% responder rate at month three after switching from erenumab to a CGRP-mAb (galcanezumab or fremanezumab) (primary endpoint). Secondary endpoints included ≥50% responder rate, monthly headache days, and monthly days with acute medication use. In an exploratory subgroup analysis patients were stratified for daily and non-daily headache. Results: The switch from erenumab to a CGRP-mAb led to a ≥30% response in one-third (32%) of the patients after three treatment cycles. A ≥50% response was achieved in 12% of the patients. Monthly headache days were reduced in month three compared to baseline (20.8 ± 7.1 to 17.8 ± 9.1; p = 0.009). Stratified analysis revealed that no patient with daily headache (n = 9) responded to the treatment switch, while a 30% response was achieved by 50% of patients with non-daily headache (n = 16). Conclusion: Our findings demonstrate that a relevant proportion of erenumab non-responders might benefit from a treatment switch to a CGRP-mAb. Switching seems to be a promising treatment option especially in migraine patients with non-daily headache. [ABSTRACT FROM AUTHOR]

Das Wirtschaftsstrafrecht sei beispielsweise dadurch gekennzeichnet, dass die Verfahrensbeteiligten prozessual häufig über das Verfahrensergebnis, den Verfahrensstoff und die Verfahrensregeln einzelfallbezogen verhandelten und somit u. U. von den formal bindenden Normen der Strafprozessordnung in der Weise abwichen, dass die Normen nicht angewendet würden oder die Rechtsfolgen nicht einträten. Professor I Singelnstein i kam unter dem Stichwort der "Gesellschaftlichen Praxis der Kriminalisierung" letztlich zu dem Schluss, dass es im Bereich der Fahrlässigkeit stärker als bei Vorsatztaten an dem aus gesellschaftlicher Perspektive eine Strafe rechtfertigenden Umstand fehle, dass neben die Abweichung von einer Norm die Abweichung der jeweiligen Täter vom durchschnittlichen Lebensstil der Gesamtbevölkerung trete. Professor I Singelnstein i ergänzte, dass auch er davon ausgehe, dass die Fahrlässigkeitsstrafbarkeit in der Praxis vor allem die Funktion hat, die Verursachung schwerer Folgen für die Gesellschaft sichtbar zu sanktionieren. Das bedeute, dass, wenn die Verantwortung in Bereichen, in denen Großschäden drohen, nicht wirklich gerecht dem Individuum zuzurechnen sei, die Scheinwaffe auf die Institutionen und die Möglichkeiten gerichtet werden müsste, die dort etwas ausrichten können. Insbesondere sollten nach dem Konzept der Veranstalterin und der Veranstalter der Hannoveraner Tagung die Fragen erörtert werden, was die Kriminalisierung fahrlässigen Verhaltens antreibe, wohin diese führe, wie die Argumente derer zu beurteilen seien, die die Fahrlässigkeit entkriminalisieren wollten und ob die Ausweitung der Fahrlässigkeitsstrafbarkeit nicht die Freiheit, Risiken einzugehen, gefährde. [Extracted from the article]

Background: Primary progressive multiple sclerosis (PPMS) is characterised by gradual worsening of disability from symptom onset. Knowledge about the natural course of PPMS remains limited. Methods: PPMS patients from the German NeuroTransData (NTD) MS registry with data from 56 outpatient practices were employed for retrospective cross-sectional and longitudinal analyses. The cross-sectional analysis included a contemporary PPMS cohort with a documented visit within the last 2 years before index date (1 Jan 2021). The longitudinal analysis included a disease modifying therapy (DMT)-naïve population and focused on the evolution of expanded disability status scale (EDSS) from the first available assessment at or after diagnosis within the NTD registry to index date. Outcome measures were estimated median time from first EDSS assessment to first 24-week confirmed EDSS ≥ 4 and ≥ 7. Besides EDSS change, the proportion of patients on disability pension were described over time. Results: The cross-sectional analysis included 481 PPMS patients (59.9% female, mean [standard deviation, SD] age 60.5 [11.5] years, mean [SD] EDSS 4.9 [2.1]). Estimated median time from first EDSS assessment after diagnosis to reach 24-week confirmed EDSS ≥ 4 for DMT-naïve patients was 6.9 years. Median time to EDSS ≥ 7 was 9.7 years for 25% of the population. Over a decade mean (SD) EDSS scores increased from 4.6 (2.1) to 5.7 (2.0); the proportion of patients on disability pension increased from 18.9% to 33.3%. Conclusions: This study provides first insights into the German NTD real-world cohort of PPMS patients. Findings confirm the steadily deteriorating course of PPMS accompanied by increasingly limited quality of life. [ABSTRACT FROM AUTHOR]

Regularization methods in linear regression models with manifest variables have been shown to be effective in selecting key predictors from a set of many variables, while improving predictions for novel observations. Regularization methods are particularly attractive for the analysis of complex multidimensional data when theory development is the primary goal; for example when researchers attempt to predict general or specific factors in bifactor models using many potentially relevant predictors. However, applications of regularization methods in such models are still scarce. In a simulation study, we examined the performance of different regularization methods in bifactor-(S-1) models, varying the number of predictors, the correlations with the outcome (effect size), the underlying structure of multicollinearity as well as the sample size, the type of penalty, and a single-step versus a two-step approach. We explore potential caveats in the use of regularization methods in bifactor-(S-1) models, provide practical recommendations, and discuss future directions. [ABSTRACT FROM AUTHOR]

We show that separable nonlinear least squares (SNLLS) estimation is applicable to all linear structural equation models (SEMs) that can be specified in RAM notation. SNLLS is an estimation technique that has successfully been applied to a wide range of models, for example neural networks and dynamic systems, often leading to improvements in convergence and computation time. It is applicable to models of a special form, where a subset of parameters enters the objective linearly. Recently, Kreiberg et al. (Struct Equ Model Multidiscip J 28(5):725–739, 2021. https://doi.org/10.1080/10705511.2020.1835484) have shown that this is also the case for factor analysis models. We generalize this result to all linear SEMs. To that end, we show that undirected effects (variances and covariances) and mean parameters enter the objective linearly, and therefore, in the least squares estimation of structural equation models, only the directed effects have to be obtained iteratively. For model classes without unknown directed effects, SNLLS can be used to analytically compute least squares estimates. To provide deeper insight into the nature of this result, we employ trek rules that link graphical representations of structural equation models to their covariance parametrization. We further give an efficient expression for the gradient, which is crucial to make a fast implementation possible. Results from our simulation indicate that SNLLS leads to improved convergence rates and a reduced number of iterations. [ABSTRACT FROM AUTHOR]

In many medical disciplines, red blood cells are discovered to be biomarkers since they "experience" various conditions in basically all organs of the body. Classical examples are diabetes and hypercholesterolemia. However, recently the red blood cell distribution width (RDW), is often referred to, as an unspecific parameter/marker (e.g., for cardiac events or in oncological studies). The measurement of RDW requires venous blood samples to perform the complete blood cell count (CBC). Here, we introduce Erysense, a lab-on-a-chip-based point-of-care device, to evaluate red blood cell flow properties. The capillary chip technology in combination with algorithms based on artificial neural networks allows the detection of very subtle changes in the red blood cell morphology. This flow-based method closely resembles in vivo conditions and blood sample volumes in the sub-microliter range are sufficient. We provide clinical examples for potential applications of Erysense as a diagnostic tool [here: neuroacanthocytosis syndromes (NAS)] and as cellular quality control for red blood cells [here: hemodiafiltration (HDF) and erythrocyte concentrate (EC) storage]. Due to the wide range of the applicable flow velocities (0.1–10 mm/s) different mechanical properties of the red blood cells can be addressed with Erysense providing the opportunity for differential diagnosis/judgments. Due to these versatile properties, we anticipate the value of Erysense for further diagnostic, prognostic, and theragnostic applications including but not limited to diabetes, iron deficiency, COVID-19, rheumatism, various red blood cell disorders and anemia, as well as inflammation-based diseases including sepsis. [ABSTRACT FROM AUTHOR]

Background: McLeod syndrome (MLS) is an X-linked multisystemic progressive disorder caused by loss of function mutations in the XK gene. The rare blood group phenotype of MLS patients with absent Kx antigen requires the support of specialized transfusion institutions because of the risk of transfusion complications. Acanthocytosis of red blood cells occurs in almost all patients. Nonhematological manifestations of MLS are very similar to those of VPS13A disease (chorea-acanthocytosis), an autosomal-recessive condition. Their shared phenotype apart from acanthocytosis includes movement disorders such as chorea and dystonia, epilepsy, peripheral neuropathy, and muscle involvement, typically with creatine kinase (CK) elevation, cardiomyopathy included. Summary: In this review, we describe the nonhematological manifestations of MLS in comparison with those of VPS13A disease. While there are many similarities, differences such as mode of inheritance, sex distribution, age at manifestation, severity of heart involvement, frequency of feeding dystonia or of involuntary head drops may help to distinguish these disorders in the clinic. Immunohematological demonstration of the McLeod-Kell phenotype or detection of pathogenic mutations of XK (or VPS13A, respectively) is the gold standard for distinction. "Neuroacanthocytosis" was often used as an overarching term, but is potentially misleading, as the term does not refer to a defined disease entity. Its use, if continued, must not prevent clinicians to seek a final diagnosis on the basis of molecular findings. The clinical similarity of MLS and VPS13A disease has long suggested some shared pathophysiology. Evidence for molecular interaction between XK, the McLeod protein, and chorein, the VPS13A gene product, has recently been put forward: XK forms a complex with chorein/VPS13A, a bulk lipid transporter located at various membrane contact sites. The exact role of XK in this complex needs to be further elucidated. Impairment of bulk lipid transport appears as the common denominator of both MLS and VPS13A disease. A variety of further conditions may in time be added to the "bulk lipid transport diseases," such as the recently recognized disorders caused by mutations in the VPS13B, VPS13C, and VPS13D genes. Key Messages: (1) Patients diagnosed with the rare red cell McLeod phenotype (McLeod syndrome, MLS) require interdisciplinary collaboration of transfusion medicine specialists, neurologists, and cardiologists for both their hematological and nonhematological disease manifestations. (2) The phenotypical similarity of MLS and VPS13A disease, often leading to either confusion or insufficient diagnostic depth (under the label of "neuroacanthocytosis"), is based on interaction of the respective proteins, XK and chorein, within the cellular machinery for bulk lipid transport. (3) Overall, the term "bulk lipid transport diseases" seems useful for further research on a group of conditions that may not only share pathophysiology, but may also share treatment approaches. [ABSTRACT FROM AUTHOR]