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Apple proliferation is among the most important diseases in European fruit production. Early and reliable detection enables farmers to respond appropriately and to prevent further spreading of the disease. Traditional phenotyping approaches by human observers consider multiple symptoms, but these are difficult to measure automatically in the field. Therefore, the potential of hyperspectral imaging in combination with data analysis by machine learning algorithms was investigated to detect the symptoms solely based on the spectral signature of collected leaf samples. In the growing seasons 2019 and 2020, a total of 1160 leaf samples were collected. Hyperspectral imaging with a dual camera setup in spectral bands from 400 nm to 2500 nm was accompanied with subsequent PCR analysis of the samples to provide reference data for the machine learning approaches. Data processing consists of preprocessing for segmentation of the leaf area, feature extraction, classification and subsequent analysis of relevance of spectral bands. The results show that imaging multiple leaves of a tree enhances detection results, that spectral indices are a robust means to detect the diseased trees, and that the potentials of the full spectral range can be exploited using machine learning approaches. Classification models like rRBF achieved an accuracy of 0.971 in a controlled environment with stratified data for a single variety. Combined models for multiple varieties from field test samples achieved classification accuracies of 0.731. Including spatial distribution of spectral data further improves the results to 0.751. Prediction of qPCR results by regression based on spectral data achieved RMSE of 14.491 phytoplasma per plant cell.

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that may cause life-threatening hemorrhages in patients with plasma cell dyscrasias (PCDs). Early diagnosis and treatment require a thorough understanding of its underlying pathophysiology. Two patients with IgG MGUS presented with dramatically decreased plasma von Willebrand factor (VWF) and a severe type-1 pattern on multimer analysis. A prompt response to intravenous immunoglobulins (IVIG), but not to VWF/FVIII, was consistent with accelerated immunologic clearance of plasma VWF. Another IgG MGUS patient showed a type-2 pattern and a less pronounced response to IVIG, suggesting that additional mechanism(s) contributed to AVWS evolution. In a patient with Waldenström’s macroglobulinemia and severe depletion of plasma VWF, multimer analysis indicated association of the IgM paraprotein with VWF before, but not after plasmapheresis, resulting in destruction of the agarose gel and a characteristically distorted band structure of VWF multimers. A type-2 pattern with highly abnormal VWF triplets and laboratory evidence of excessive fibrinolytic activity suggested that plasmin-mediated VWF degradation contributed to AVWS in a patient with multiple myeloma (MM) and AL amyloidosis. Finally, in a patient with IgG MM, maximally prolonged PFA-100® closure times and a specific defect in ristocetin-induced platelet agglutination, both of which resolved after remission induction, indicated interference of the paraprotein with VWF binding to platelet GPIb. Importantly, in none of the six patients, circulating autoantibodies to VWF were detected by a specific in-house ELISA. In summary, when evaluating PCD patients with severe bleeding symptoms, AVWS due to various pathogenic mechanisms should be considered.

In haemophilia, thrombin generation and fibrin deposition upon vascular injury critically depend on the tissue factor (TF)-driven coagulation pathway. TF expression by monocytes/macrophages and circulating microvesicles contributes to haemostasis, thrombosis and inflammation. Inflammation is a hallmark of blood-induced joint disease. The aim of this study is to correlate TF production by whole-blood monocytes with inflammatory markers and clinical parameters in patients with moderate-to-severe haemophilia A or B (n = 43) in comparison to healthy males (n = 23). Monocyte TF antigen and microvesicle-associated TF procoagulant activity (MV TF PCA) were measured immediately after blood draw (baseline) and following incubation of whole blood with buffer or lipopolysaccharide (LPS) using two-colour flow cytometry and chromogenic FXa generation assay, respectively. Patients with HIV or uncontrolled HBV/HCV infections were excluded. TF was hardly detectable and not different in baseline and buffer-treaded samples from both groups. Stimulation with LPS, however, induced monocyte TF production, with increased TF-specific mean fluorescence intensity (P = 0.08) and MV TF PCA (P < 0.05) in patients compared to controls. Patients also had elevated hs-CRP and IL-6 serum levels (P < 0.001), which correlated with LPS-induced TF parameters. Further exploratory analyses revealed that the presence of systemic (low-grade) inflammation and boosted LPS-induced monocyte TF production were mainly restricted to patients with clinically controlled HBV and/or HCV infection (n = 16), who were older and also had a significantly worse orthopaedic joint score than patients with no history of viral hepatitis (P < 0.01). Our study delineates a previously unrecognised link between systemic inflammation and inducible monocyte TF production in patients with haemophilia A or B.

Background: Systematically documented data on real-world use of emicizumab, a bispecific antibody factor (F)VIII mimetic, are still lacking in people with severe haemophilia A (PwSHA). Smart medication, a real-time, online platform, monitors treatment administration and outcomes for people with haemophilia A in Germany. Objective: To evaluate annualised bleeding rates (ABRs) and annualised joint bleeding rates (AJBRs), using data documented in the smart medication eDiary, for PwSHA receiving emicizumab. Design: Data for 97 PwSHA without FVIII inhibitors who started emicizumab treatment between 1 January 2018 and 31 March 2023, with >24 weeks of documentation after switching from FVIII replacement, were collected in the smart medication eDiary. Those with ⩾24 weeks of pre-emicizumab data were included for analysis 24 weeks before and after switching. Methods: The primary objective was to evaluate ABR and AJBR for treated bleeds. The proportion of bleed-free participants was calculated and administration frequency for FVIII and emicizumab were collected. The mean dosing frequencies for FVIII replacement and emicizumab were also evaluated. Results: The mean calculated ABR and AJBR were 0.64 and 0.39, respectively, after initiating emicizumab. For those with documentation before starting emicizumab (n = 58), ABR decreased by 79.6% and AJBR decreased by 90.8%. The proportion of bleed-free participants increased by 21.3%, and joint bleed-free participants increased by 18.2%. The median FVIII dosing frequency was every 3.5 days (n = 54; range: 1.0–20.8); median emicizumab dosing frequency was every 11.2 days (N = 97; range: 6.6–29.4). Conclusion: Real-world data collected using the smart medication eDiary provide insights into efficacy outcomes after switching from FVIII replacement to emicizumab prophylaxis. Bleeds, including joint bleeds, decreased after switching.

Background: Although hemophilia A mainly affects males, carriers (defined as females with hemophilia A, as well as symptomatic or asymptomatic hemophilia A carriers) are at risk of excessive bleeding, particularly during trauma or during surgical procedures. Clinical trials have focused on male patients with severe disease, and data for females are limited. Improved, evidence-based treatment guidelines for management of hemophilia A carriers are required. Objectives and design: The NuDIMENSION study is a phase IV, prospective, open-label, single-arm study that will evaluate the perioperative efficacy and safety of simoctocog alfa (Nuwiq®), a recombinant factor VIII (FVIII), in women/girls with hemophilia A undergoing major surgery. The study will be conducted at approximately 15 centers worldwide. Women/girls aged ⩾12 years, with mild or moderate hemophilia A (residual FVIII activity (FVIII:C) ⩾1% to <40%) and with no current/past FVIII inhibitors are eligible. All patients must be scheduled to undergo a major surgical procedure during which simoctocog alfa will be administered. Methods and analysis: The primary endpoint is overall perioperative hemostatic efficacy (“success” or “failure”) of simoctocog alfa. Hemostatic efficacy will be assessed at the end of surgery and at the end of the postoperative period (i.e., completion of wound healing), with overall adjudication by an Independent Data Monitoring Committee. Safety endpoints will include the incidences of thrombotic events and FVIII inhibitor development. The aim is to recruit 28 patients to achieve 26 evaluable surgeries. Ethics: Ethical approval will be received from institutional review boards/independent ethics committees, and the study will be conducted in compliance with the Declaration of Helsinki. Discussion: Data from NuDIMENSION will generate much-needed evidence on surgical management of women/girls with hemophilia A, which will help to enable the development of treatment guidelines specific for such patients. Trial Registration: CT EU 2022-502061-17-00; NCT05936580 Plain language summary Design of an international study (NuDIMENSION) to examine the use of a factor VIII therapy during surgery in female hemophilia A patients Hemophilia A is an inherited bleeding disorder caused by an abnormality in the F8 gene that leads to a reduction in clotting factor VIII (FVIII). Females who inherit the abnormal gene can pass on the gene to their children and are known as ‘carriers’. Some carriers have FVIII levels below 40% of normal levels and are classified as having hemophilia A. However, excessive bleeding can also occur in females with FVIII levels greater than 40% of normal. Excessive bleeding may only be evident after injury, during surgery or during childbirth, but can also cause heavy periods, for example. Replacement therapy with FVIII can be used to treat or prevent bleeds in people with hemophilia A. During surgery higher levels of FVIII may be needed to prevent excessive bleeding. However, information on the use of FVIII comes predominantly from trials in male patients with severe disease. Information on the treatment of carriers is limited, and treatment guidelines for surgical management of carriers are lacking. Simoctocog alfa (Nuwiq®), a FVIII therapy, is effective at preventing and treating bleeds, including during surgery, in males with severe hemophilia A. NuDIMENSION is a multicenter, international study that will evaluate simoctocog alfa in women and girls with hemophilia A who need major surgery. The study will include women/girls aged 12 years or older who have mild or moderate hemophilia A and who are planned to have a major surgery. The primary endpoint is overall hemostatic efficacy (“success” or “failure”), that is, how well bleeding is prevented/controlled. This will be assessed at the end of the surgery and at the end of the postoperative period. Up to 28 women and girls will take part in the study. Data from NuDIMENSION will provide important information to help decide how best to treat women/girls with hemophilia A who need surgery. Graphical abstract

Over recent decades, management of people with hemophilia (PwH) has been greatly improved by scientific advances that have resulted in a rich and varied therapeutic landscape. Nevertheless, treatment limitations continue to drive innovation, and emerging options have the potential to realize further improvement. We advocate four general principles to optimize benefits from innovation: individualizing the treatment approach, targeting ‘normal,’ making the most of available resources, and considering treatment affordability. Ultimately, all PwH—men and women, of all ages and severities, and worldwide—should have access to treatment that fully prevents bleeding, while allowing personal, social, family, and professional lives of choice. Clearly, we are not there yet, but developing goals/milestones based on the principles we describe may help to achieve this. Graphical abstract

The disease burden and bleeding risk of patients with mild hemophilia may be underestimated. Their health-related quality of life (QoL) may be negatively impacted by insufficient treatment and bleed-related joint damage connected to a potentially delayed diagnosis. This study aims to gain information on the care reality and QoL of patients aged ≥12 years with mild hemophilia in Germany. An anonymous cross-sectional patient survey using standardized questionnaires was conducted in a validated electronic patient-reported outcome system. Medical specialists, hemophilia centers, patient organizations, and support groups across Germany invited the patients. A total of 43 patients (35 patients with hemophilia A, 5 patients with hemophilia B, and 3 patients for whom the information was missing) with a median age of 33 years were analyzed. The median age at diagnosis was 6.0 years (interquartile range [IQR] 2.0-15.0), and the median factor activity was 14.0% (IQR 12.0-25.0). Nearly 85% of the patients received factor concentrates in the past, and the most common reasons for the treatment were surgery or joint bleeding (each 65.6%). Half of the patients who provided feedback experienced complications during bleeding episodes. Prophylactic treatment with factor concentrates was rare (10.3%). The patients had minor problems regarding their health status. Bleeding complications and joint bleeding, in particular, may be highly underestimated in patients with mild hemophilia, highlighting a medical need in this population. Patients with a potential benefit from prophylaxis need to be identified. Mild hemophilia has a negative impact on patients' QoL. Hemophilia centers satisfied the patients' needs. Further research is needed to address the current lack of awareness and improve adequate treatment in the future.

Autoimmune protein S (PS) deficiency is a highly thrombotic, potentially life‐threatening disorder. Its pathophysiological relevance in the context of primary antiphospholipid syndrome (APS) is unclear. Here, we report the case of a 76‐year‐old woman, who presented with a painful reticular skin erythema caused by microvascular thromboses. Disseminated intravascular coagulation (DIC) with consumptive coagulopathy was controlled only by continuous anticoagulation. While significantly elevated IgM antibodies to cardiolipin and β2‐glycoprotein‐I were consistent with primary APS, a function‐blocking PS autoantibody of the IgG isotype was detected. Robust microvesicle (MV)‐associated tissue factor (TF) procoagulant activity (PCA) was isolated from patient plasma. Moreover, patient IgG, but not IgM, induced expression of TF PCA and release of TF‐bearing MVs by peripheral blood mononuclear cells from healthy donors. In primary APS, induction of monocyte TF in combination with an acquired PS inhibitor may provoke a deleterious imbalance of procoagulant and anticoagulant pathways with evolution of thrombotic DIC.

Multisite phosphorylation networks are encountered in many intracellular processes like signal transduction, cell-cycle control, or nuclear signal integration. In this contribution, networks describing the phosphorylation and dephosphorylation of a protein at n sites in a sequential distributive mechanism are considered. Multistationarity (i.e., the existence of at least two positive steady state solutions of the associated polynomial dynamical system) has been analyzed and established in several contributions. It is, for example, known that there exist values for the rate constants where multistationarity occurs. However, nothing else is known about these rate constants. Here, we present a sign condition that is necessary and sufficient for multistationarity in n -site sequential, distributive phosphorylation. We express this sign condition in terms of linear systems, and show that solutions of these systems define rate constants where multistationarity is possible. We then present, for n ≥2, a collection of feasible linear systems, and hence give a new and independent proof that multistationarity is possible for n ≥2. Moreover, our results allow to explicitly obtain values for the rate constants where multistationarity is possible. Hence, we believe that, for the first time, a systematic exploration of the region in parameter space where multistationarity occurs has become possible. One consequence of our work is that, for any pair of steady states, the ratio of the steady state concentrations of kinase-substrate complexes equals that of phosphatase-substrate complexes.

Multisite protein phosphorylation plays a prominent role in intracellular processes like signal transduction, cell-cycle control and nuclear signal integration. Many proteins are phosphorylated in a sequential and distributive way at more than one phosphorylation site. Mathematical models of n -site sequential distributive phosphorylation are therefore studied frequently. In particular, in Wang and Sontag (J Math Biol 57:29–52, 2008 ), it is shown that models of n -site sequential distributive phosphorylation admit at most 2 n - 1 steady states. Wang and Sontag furthermore conjecture that for odd n , there are at most n and that, for even n , there are at most n + 1 steady states. This, however, is not true: building on earlier work in Holstein et al. (Bull Math Biol 75(11):2028–2058, 2013 ), we present a scalar determining equation for multistationarity which will lead to parameter values where a 3 -site system has 5 steady states and parameter values where a 4 -site system has 7 steady states. Our results therefore are counterexamples to the conjecture of Wang and Sontag. We furthermore study the inherent geometric properties of multistationarity in n -site sequential distributive phosphorylation: the complete vector of steady state ratios is determined by the steady state ratios of free enzymes and unphosphorylated protein and there exists a linear relationship between steady state ratios of phosphorylated protein.