Instantaneous control of interacting particle systems in the mean-field limit

Controlling large particle systems in collective dynamics by a few agents is a subject of high practical importance, e.g., in evacuation dynamics. In this paper we study an instantaneous control approach to steer an interacting particle system into a certain spatial region by repulsive forces from a few external agents, which might be interpreted as shepherd dogs leading sheep to their home. We introduce an appropriate mathematical model and the corresponding optimization problem. In particular, we are interested in the interaction of numerous particles, which can be approximated by a mean-field equation. Due to the high-dimensional phase space this will require a tailored optimization strategy. The arising control problems are solved using adjoint information to compute the descent directions. Numerical results on the microscopic and the macroscopic level indicate the convergence of optimal controls and optimal states in the mean-field limit,i.e., for an increasing number of particles.Comment: arXiv admin note: substantial text overlap with arXiv:1610.0132

Proteomics : A Tool to Study Platelet Function

Acknowledgments: Authors acknowledge Laxmikanth Kollipara for the critical review and Julia Lill for support with figures preparation. The Figure 2 was created in Biorender.Peer reviewedPublisher PD

Decline in the number of patients with meningitis in German hospitals during the COVID-19 pandemic

BACKGROUND AND OBJECTIVES: In 2020, a wide range of hygiene measures was implemented to mitigate infections caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In consequence, pulmonary infections due to other respiratory pathogens also decreased. Here, we evaluated the number of bacterial and viral meningitis and encephalitis cases during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: In a multicentre retrospective analysis of data from January 2016 until December 2020, numbers of patients diagnosed with bacterial meningitis and other types of CNS infections (such as viral meningitis and encephalitis) at 26 German hospitals were studied. Furthermore, the number of common meningitis-preceding ear-nose-throat infections (sinusitis, mastoiditis and otitis media) was evaluated. RESULTS: Compared to the previous years, the total number of patients diagnosed with pneumococcal meningitis was reduced (n = 64 patients/year in 2020 vs. n = 87 to 120 patients/year between 2016 and 2019, all p < 0.05). Additionally, the total number of patients diagnosed with otolaryngological infections was significantly lower (n = 1181 patients/year in 2020 vs. n = 1525 to 1754 patients/year between 2016 and 2019, all p < 0.001). We also observed a decline in viral meningitis and especially enterovirus meningitis (n = 25 patients/year in 2020 vs. n = 97 to 181 patients/year between 2016 and 2019, all p < 0.001). DISCUSSION: This multicentre retrospective analysis demonstrates a decline in the number of patients treated for viral and pneumococcal meningitis as well as otolaryngological infections in 2020 compared to previous years. Since the latter often precedes pneumococcal meningitis, this may point to the significance of the direct spread of pneumococci from an otolaryngological focus such as mastoiditis to the brain as one important pathophysiological route in the development of pneumococcal meningitis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00415-022-11034-w

Clinical features of neuromuscular disorders in patients with N-type voltage-gated calcium channel antibodies

Neuromuscular junction disorders affect the pre- or postsynaptic nerve to muscle transmission due to autoimmune antibodies. Members of the group like myasthenia gravis and Lambert-Eaton syndrome have pathophysiologically distinct characteristics. However, in practice, distinction may be difficult. We present a series of three patients with a myasthenic syndrome, dropped-head syndrome, bulbar and respiratory muscle weakness and positive testing for anti-N-type voltage-gated calcium channel antibodies. In two cases anti-acetylcholin receptor antibodies were elevated, anti-P/Q-type voltage-gated calcium channel antibodies were negative. All patients initially responded to pyridostigmine with a non-response in the course of the disease. While one patient recovered well after treatment with intravenous immunoglobulins, 3,4-diaminopyridine, steroids and later on immunosuppression with mycophenolate mofetil, a second died after restriction of treatment due to unfavorable cancer diagnosis, the third patient declined treatment. Although new antibodies causing neuromuscular disorders were discovered, clinical distinction has not yet been made. Our patients showed features of pre- and postsynaptic myasthenic syndrome as well as severe dropped-head syndrome and bulbar and axial muscle weakness, but only anti-N-type voltage-gated calcium channel antibodies were positive. When administered, one patient benefited from 3,4-diaminopyridine. We suggest that this overlap-syndrome should be considered especially in patients with assumed seronegative myasthenia gravis and lack of improvement under standard therapy

Total Plasma Exchange in Neuromuscular Junction Disorders&mdash;A Single-Center, Retrospective Analysis of the Efficacy, Safety and Potential Diagnostic Properties in Doubtful Diagnosis

Neuromuscular junction disorders (NJDs) are a heterogeneous group of diseases including myasthenia gravis (MG). In some cases, patients are present with myasthenic symptoms without evidence of autoimmune antibodies, making diagnosis challenging. Total plasma exchange (TPE) has proven efficacy in NJDs. The objective is to describe the safety and efficacy of TPE in NJD patients with questionable disease activity or uncertain diagnosis in order to assess the diagnostic potential of TPE. We report an observational, retrospective cohort study of clinical routine data. All the data were derived from the electronic medical records of the Department of Neurology at University Hospital Essen. We searched for patients with NJDs between 1 July 2018 and 30 June 2021. Of the 303 patients who presented to the department with NJDs, 20 were treated with TPE; 9 patients did not show a measurable benefit from TPE (45%), 6 of whom were diagnosed with seronegative MG. Of these, 3 (50%) had long-standing ocular symptoms. There were decreases in the mean arterial pressure, hemoglobin, hematocrit and fibrinogen during treatment, which were not considered clinically relevant. In (seronegative) myasthenic patients, TPE may help to verify an uncertain diagnosis or to reveal possible muscle damage, allowing unnecessary therapy to be avoided

Instantaneous control of interacting particle systems in the mean-field limit

\u3cp\u3eControlling large particle systems in collective dynamics by a few agents is a subject of high practical importance, e.g., in evacuation dynamics. In this paper we study an instantaneous control approach to steer an interacting particle system into a certain spatial region by repulsive forces from a few external agents, which might be interpreted as shepherd dogs leading sheep to their home. We introduce an appropriate mathematical model and the corresponding optimization problem. In particular, we are interested in the interaction of numerous particles, which can be approximated by a mean-field equation. Due to the high-dimensional phase space this will require a tailored optimization strategy. The arising control problems are solved using adjoint information to compute the descent directions. Numerical results on the microscopic and the macroscopic level indicate the convergence of optimal controls and optimal states in the mean-field limit, i.e., for an increasing number of particles.\u3c/p\u3

CIDP, myasthenia gravis, and membranous glomerulonephritis – three autoimmune disorders in one patient: a case report

Background We present a patient fulfilling the electrophysiological criteria for definite chronic inflammatory demyelinating polyneuropathy (CIDP), antibody-positive myasthenia gravis (MG), and membranous glomerulonephritis (MGN) confirmed by biopsy. To our knowledge, this is the first case of the concomitant appearance of these three autoimmune diseases in a single patient. Case representation A 42-year-old Caucasian male presented with rapidly progressive gait disturbance, distal weakness of the lower extremities, ascending hypoesthesia, impaired fine motor skills, and beginning cranial nerve palsy showing dysarthrophonia, facial paralysis, and eye movement abnormalities and was diagnosed as rapid onset (atypical) CIDP. After 3 months, the patient complained of increasing physical exhaustion, reduction of his walking distance, worsening of the residual dysphagia, and dysarthria with an inability to swallow. AChR antibodies (17.0 nmol/L, RF < 0.4) and titin antibodies were positive and repetitive nerve stimulation showed an abnormal decrement matching the criteria of myasthenia gravis. Over time the patient developed severe acute-on-chronic renal failure with high-grade proteinuria resulting in generalized edema followed by secondary hyperparathyroidism and dialysis-dependent renal failure. Renal biopsy confirmed beginning anti-phospholipase A2 receptor antibody membranous nephropathy. Conclusion All three diseases are of autoimmune origin with distinctive immunopathogenetic mechanisms. The present case of CIDP, MG, and MGN occurring in one patient indicates a common underlying immune mechanism in these distinct conditions, including the involvement of autoantibodies and T cells

Assessment of Bulbar Function in Adult Patients with 5q-SMA Type 2 and 3 under Treatment with Nusinersen

The antisense oligonucleotide nusinersen has been shown to improve trunk and limb motor function in patients with spinal muscular atrophy (SMA). Bulbar dysfunction, which is regularly present in SMA, is not captured by standard motor scores, and validated measurement instruments to assess it have not yet been established. Data on whether and how bulbar function changes under gene-based therapies in adult SMA patients are also unavailable. Here, we present data on the course of bulbar dysfunction assessed prospectively before nusinersen treatment initiation and 6 and 14 months later in 23 adult SMA patients using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). While no improvement in bulbar scores was observed under treatment with nusinersen, the absence of a decline still implies a therapeutic effect of nusinersen on bulbar dysfunction. The results of this study aim to contribute to a standardized assessment of bulbar function in adult SMA patients, which may show therapeutic effects of gene-based therapies that are not evident from standard motor scores

Neurofilament Heavy Chain and Tau Protein Are Not Elevated in Cerebrospinal Fluid of Adult Patients with Spinal Muscular Atrophy during Loading with Nusinersen

Nusinersen is the first approved drug for the treatment of spinal muscular atrophy (SMA). Treatment of SMA with nusinersen is based on a fixed dosing regimen. For other motoneuron diseases, such as amyotrophic lateral sclerosis (ALS), biomarkers are available for clinical diagnostics; however, no such biomarkers have yet been found for SMA. Serum and cerebrospinal fluid (CSF) samples of 11 patients with adult SMA type 3 were prospectively collected and analyzed during loading with nusinersen. Neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase were investigated as potential biomarkers of motor neuron destruction. No significant pathological alterations in levels of neurofilament heavy chain, tau protein, or S100B protein were detected in the CSF or blood samples under baseline conditions or during loading with nusinersen. Neuron-specific enolase was marginally elevated in CSF and blood samples without significant alteration during treatment. In a mixed cohort of adult patients with SMA type 3, neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase do not serve as potential biomarkers during the loading phase of nusinersen. The slow progression rate of SMA type 3 may not lead to detectable elevation of levels of these common markers of axonal degradation

Nusinersen treatment in adult patients with spinal muscular atrophy: a safety analysis of laboratory parameters

Background!#!Nusinersen is an intrathecally administered antisense oligonucleotide (ASO) that improves motor function in patients with spinal muscular atrophy (SMA). In addition to efficacy, the safety of a therapy is the decisive factor for the success of the treatment. For some ASOs, various organ toxicities have been described, such as thrombocytopenia, renal and liver impairment, or coagulation abnormalities. However, systematic data on laboratory parameters under treatment with nusinersen are mainly available from studies in infants and children. Therefore, our aim was to assess the safety of nusinersen therapy in adult SMA patients.!##!Methods!#!Laboratory data from 404 nusinersen injections performed in 50 adult patients with SMA type 2 and type 3 were retrospectively analyzed.!##!Results!#!The total observation period was 76.9 patient-years, and patients received up to 12 injections. Our data provides no new safety concerns. In cerebrospinal fluid (CSF), the mean white blood cell count and lactate remained stable over time. Total CSF protein increased by 2.9 mg/dL. No change in mean platelet count was observed under therapy. Only one patient showed sporadic mild thrombocytopenia. Coagulation parameters and inflammatory markers were stable. The mean creatinine level decreased by 0.09 mg/dL. Analysis of mean liver enzyme levels revealed no relevant changes during treatment.!##!Conclusion!#!Our data demonstrate a favorable safety profile of nusinersen therapy in adult SMA patients under longer-term 'real-world' conditions. In particular, we found no evidence of clinically relevant platelet declines, coagulopathies, or renal or hepatic organ toxicities, which are common concerns with the use of ASOs