Immunosuppressive therapy in elderly patients with neuromyelitis optica spectrum disorder: a retrospective multicentre study.

BACKGROUND: The risk-benefit relationship of immunosuppressive therapies (ISTs) for elderly patients with neuromyelitis optica spectrum disorder (NMOSD) is not well established. This study aimed to investigate the safety and efficacy of IST in elderly patients with NMOSD. METHODS: This retrospective study analysed IST efficacy and safety in 101 patients with aquaporin-4 antibody-positive NMOSD aged over 65 years, treated for at least 6 months at five Korean referral centres, focusing on relapse rates, infection events and discontinuation due to adverse outcomes. RESULTS: The mean age at disease onset was 59.8 years, and female-to-male ratio was 4:1. Concomitant comorbidities at NMOSD diagnosis were found in 87 patients (86%). The median Expanded Disability Status Scale score at the initiation of IST was 3.5. The administered ISTs included azathioprine (n=61, 60%), mycophenolate mofetil (MMF) (n=48, 48%) and rituximab (n=41, 41%). Over a median of 5.8 years of IST, 58% of patients were relapse-free. The median annualised relapse rate decreased from 0.76 to 0 (p<0.001), and 81% experienced improved or stabilised disability. Patients treated with rituximab had a higher relapse-free rate than those treated with azathioprine or MMF (p=0.022). During IST, 21 patients experienced 25 severe infection events (SIEs) over the age of 65 years, and 3 died from pneumonia. 14 patients (14%) experienced 17 adverse events that led to switching or discontinuation of IST. When comparing the incidence rates of SIEs and adverse events, no differences were observed among patients receiving azathioprine, MMF and rituximab. CONCLUSION: In elderly patients with NMOSD, IST offers potential benefits in reducing relapse rates alongside a tolerable risk of adverse events.

Germinal centers are associated with postthymectomy myasthenia gravis in patients with thymoma.

BACKGROUND AND PURPOSE: Germinal centers (GCs) can be observed in the thymic tissues of patients with thymoma-associated myasthenia gravis (MG). Although an association between thymic GCs and MG has been suggested, it is unknown whether the presence of GCs could predict the development of MG after the resection of thymoma, known as postthymectomy MG. METHODS: We conducted a retrospective analysis of previously nonmyasthenic patients who underwent surgical removal of the thymoma. All available thymic tissue slides were rereviewed by a pathologist to assess for GCs. Patients were classified into GC-positive and GC-negative groups based on the presence of GCs. The incidence of postthymectomy MG was compared between the two groups, and the risk factors for postthymectomy MG were assessed. RESULTS: Of the 196 previously nonmyasthenic patients who underwent thymoma resection, 21 were GC-positive, whereas 175 were GC-negative. Postthymectomy MG developed in 11 (5.6%) patients and showed a higher incidence in the GC-positive group than in the GC-negative group (33.3% vs. 2.3%, p < 0.001). No postoperative radiotherapy and the presence of GCs were risk factors for postthymectomy MG in the univariate analysis. In multivariate analysis, invasive thymoma (hazard ratio [HR] = 9.835, 95% confidence interval [CI] = 1.358-105.372), postoperative radiotherapy (HR = 0.160, 95% CI = 0.029-0.893), and presence of GCs (HR = 15.834, 95% CI = 3.742-67.000) were significantly associated with postthymectomy MG. CONCLUSIONS: Thymic GCs may be a significant risk factor for postthymectomy MG. Even in patients with thymoma who do not show clinical symptoms of MG, postthymectomy MG should be considered, especially if thymic GCs are observed.

Impact of COVID-19 Infection and Its Association With Previous Vaccination in Patients With Myasthenia Gravis in Korea: A Multicenter Retrospective Study.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, patients with myasthenia gravis (MG) were more susceptible to poor outcomes owing to respiratory muscle weakness and immunotherapy. Several studies conducted in the early stages of the COVID-19 pandemic reported higher mortality in patients with MG compared to the general population. This study aimed to investigate the clinical course and prognosis of COVID-19 in patients with MG and to compare these parameters between vaccinated and unvaccinated patients in South Korea. METHODS: This multicenter, retrospective study, which was conducted at 14 tertiary hospitals in South Korea, reviewed the medical records and identified MG patients who contracted COVID-19 between February 2022 and April 2022. The demographic and clinical characteristics associated with MG and vaccination status were collected. The clinical outcomes of COVID-19 infection and MG were investigated and compared between the vaccinated and unvaccinated patients. RESULTS: Ninety-two patients with MG contracted COVID-19 during the study. Nine (9.8%) patients required hospitalization, 4 (4.3%) of whom were admitted to the intensive care unit. Seventy-five of 92 patients were vaccinated before contracting COVID-19 infection, and 17 were not. During the COVID-19 infection, 6 of 17 (35.3%) unvaccinated patients were hospitalized, whereas 3 of 75 (4.0%) vaccinated patients were hospitalized (P < 0.001). The frequencies of ICU admission and mechanical ventilation were significantly lower in the vaccinated patients than in the unvaccinated patients (P = 0.019 and P = 0.032, respectively). The rate of MG deterioration was significantly lower in the vaccinated patients than in the unvaccinated patients (P = 0.041). Logistic regression after weighting revealed that the risk of hospitalization and MG deterioration after COVID-19 infection was significantly lower in the vaccinated patients than in the unvaccinated patients. CONCLUSION: This study suggests that the clinical course and prognosis of patients with MG who contracted COVID-19 during the dominance of the omicron variant of COVID-19 may be milder than those at the early phase of the COVID-19 pandemic when vaccination was unavailable. Vaccination may reduce the morbidity of COVID-19 in patients with MG and effectively prevent MG deterioration induced by COVID-19 infection.

Phase-Locked Synthetic Wavelength Interferometer Using a Femtosecond Laser for Absolute Distance Measurement without Cyclic Error.

We present a phase-locked synthetic wavelength interferometer that enables a complete elimination of cyclic errors in absolute distance measurements. With this method, the phase difference between the reference and measurement paths is fed back into a phase lock-in system, which is then used to control the synthetic wavelength and set the phase difference to zero using an external cavity acousto-optic modulator. We validated the cyclic error removal of the proposed phase-locked method by comparing it with the conventional phase-measuring method of the synthetic wavelength interferometer. By analyzing the locked error signal, we achieved a precision of 0.6 mrad in phase without any observed cyclic errors.

Open-Air Testing of Dual-Comb Time-of-Flight Measurement.

We configured a long-distance ranging apparatus to test the principle of dual-comb time-of-flight measurement using ultrashort lasers. Emphasis was given to the evaluation of open-air performance quantitatively in terms of the measurement resolution and stability. The test results revealed that our dual-comb asynchronous optical pulse sampling permits micrometer-resolved ranging with a repeatability of 2.05 µm over a 648 m distance in dry weather conditions. Further atmospheric effects were evaluated in three different weather conditions with corresponding Allan deviations. Finally, the capability of simultaneous determination of multiple targets was verified with the potential of advanced industrial applications, such as manufacturing, surveying, metrology, and geodesy.

Brighter spotty lesions on spinal MRI help differentiate AQP4 antibody-positive NMOSD from MOGAD.

In a large acute myelitis cohort, we aimed to determine whether brighter spotty lesions (BSLs)-using the refined terminology-on spinal magnetic resonance imaging (MRI) help distinguish aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) from myelin oligodendrocyte glycoprotein antibody disease (MOGAD). An experienced neuro-radiologist and two neurologists independently analyzed 133 spinal MRI scans (65 from MOGAD and 68 from AQP4-NMOSD) acquired within 1 month of attacks. BSLs were observed in 18 of 61 (30%) participants with AQP4-NMOSD, while none of 49 participants with MOGAD showed BSL (p < 0.001). BSL during the acute phase would be useful to differentiate AQP4-NMOSD from MOGAD.

Case Reports of Acute Transverse Myelitis Associated With mRNA Vaccine for COVID-19.

Acute transverse myelitis (ATM) has been reported as rare complication of vaccination. Herein, we report 2 cases of ATM after the administration of an mRNA vaccine for coronavirus disease 2019 (COVID-19). The first one is an 81-year-old man who received the BNT162b2 vaccine. He presented with bilateral hand weakness. Spine magnetic resonance imaging (MRI) showed high signal intensity from the C1 to C3 vertebrae. The second is a 23-year-old woman who received the BNT162b2 vaccine and experienced tingling in her legs. Spine MRI showed a high signal intensity lesion at the conus medullaris. These patients were treated with intravenous methylprednisolone and their symptoms improved slightly. Careful follow-up is needed to identify adverse events after the administration of mRNA vaccines for COVID-19.

Null variants in DYSF result in earlier symptom onset.

We investigated the clinical, laboratory, and genetic spectra in Korean patients with dysferlinopathy to clarify its genotype-phenotype correlation. We retrospectively reviewed 101 patients from 96 unrelated families with pathogenic variants of DYSF. The most common initial phenotype was Miyoshi myopathy in 50 patients. Median ages at examination and symptom onset were 23 [interquartile range (IQR): 18-30] and 36 years [IQR: 27-48], respectively. We observed 38 variants, including nine novel variants. Four variants (c.2494C > T, c.1284 + 2 T > C, c.663 + 1G > C, and c.2997G > T) in DYSF accounted for 62% of total allele frequencies of pathogenic variants. To analyze the genotype-phenotype correlation, we compared the clinical phenotype between patients with null/null (N/N; n = 55) and null/missense variants (N/M; n = 35). The N/N group had an earlier symptom onset age (median: 20 years [IQR: 17-25]) than the N/M group (median: 29 years [IQR: 23-35], p < .001). Total manual muscle testing scores in lower extremities were lower in the N/N group (median: 80 [IQR: 56-92]) than in the N/M group (median: 89 [IQR: 78-98], p = .013). Our study is the first to report that null variants in DYSF result in an earlier symptom onset than missense variants.

Recurrence of clinical events at the same anatomical location in patients with MOG antibody-associated disease.

OBJECTIVES: Likelihood of clinical events occurring within the same anatomical location in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) was retrospectively investigated. METHODS: A total of 236 clinical events in 90 patients with MOGAD from nine referral hospitals were analyzed via logistic regression, and odds ratios (ORs) were calculated. Anatomical lesion location was divided into four groups; optic nerve, spinal cord, cerebral hemisphere, and brainstem/cerebellum. RESULTS: At all locations, there was an increased likelihood of a second attack occurring at the same location as the initial event (cerebral hemisphere OR = 22.14, brainstem/cerebellum OR = 18.4, spinal cord OR = 9.1, and optic nerve OR = 7.8). There was an increased likelihood of a third attack occurring at the same location as the initial event in the optic nerve (OR = 14.9), cerebral hemisphere (OR = 11.7), and spinal cord (OR = 6.7). There were positive trends toward a third clinical event occurring at the same location as the first and/or second events if the event was in the optic nerve (OR = 13.5), cerebral hemisphere (OR = 6.9), or spinal cord (OR = 5.7). CONCLUSIONS: The current study suggests that clinical relapses of MOGAD during early stage tend to recur at the same anatomical locations in the central nervous system.

Comparison of MOG and AQP4 antibody seroprevalence in Korean adults with inflammatory demyelinating CNS diseases.

We aimed to compare seroprevalence of anti-myelin oligodendrocyte glycoprotein (MOG) and anti-aquaporin-4 (AQP4) antibodies in Korean adults with inflammatory demyelinating diseases (IDDs) of the central nervous system (CNS), based on a multicenter nationwide database. Sera were analyzed using a live cell-based assay for MOG and AQP4 antibodies. Of 586 Korean adults with IDDs of the CNS, 36 (6.1%) and 185 (31.6%) tested positive for MOG and AQP4 antibodies, respectively. No participant showed double positivity. Seroprevalence of MOG antibodies was about five times lower than that of AQP4 antibodies in a large cohort of Korean adults with IDDs of the CNS.

Osteopontin heptamer peptide containing the RGD motif enhances the phagocytic function of microglia.

Osteopontin (OPN) is a phosphorylated glycoprotein expressed in various tissues, including brain, and mediates a wide range of cellular activities. In our previous studies, we reported recombinant OPN and RGD and SLAY-containing OPN-peptide icosamer (OPNpt20) exhibited robust neuroprotective activities in an animal model of transient focal ischemia, and attributed these effects to the anti-inflammatory, pro-angiogenic, and phagocytic functions of OPNpt20. In the present study, we truncated OPNpt20 to 13 or 7 amino acid peptides containing RGD (R) and/or SLAY (S) motif (OPNpt13RS, OPNpt7R, OPNpt7RS, and OPNpt7S) and their cell motility and migration inducing activities were examined in BV2 cells (a microglia cell line). All four peptides significantly enhanced BV2 cell motility and migration, but OPNpt7R, an RGD-containing 7-amino-acid OPN peptide (VPNGRGD), was found to be most potent and its potency was comparable to OPNpt20. Phagocytic activity and F-actin polymerization were also significantly enhanced in OPNpt7R-treated BV2 cells. Importantly, studies using two mutant peptides (OPNpt7R-RAA and OPNpt7R-RAD, wherein RGD in OPNpt7R was replaced with RAA or RAD, respectively) revealed that all these effects of OPNpt7R, motility, migration, F-actin polymerization, and phagocytosis induction, were RGD-dependent. Furthermore, the Erk, Fak, and Akt signaling pathways appeared to be involved in the induction of phagocytic activity by OPNpt7R. Co-treating cells with OPNpt7R and D98059 or wortmannin (pharmacological inhibitors of Erk and Akt, respectively) significantly suppressed OPNpt7R-mediated phagocytosis induction. These results indicate the RGD-containing OPN heptamer OPNpt7R triggers microglial motility, migration, and phagocytic activity and that the RGD motif plays a critical role in these activities.

Absolute laser ranging by time-of-flight measurement of ultrashort light pulses [Invited].

Ultrashort pulse lasers are emerging as an advanced tool of distance measurement, with their unique temporal and spectral characteristics being extended to diverse principles of absolute ranging and instrumentation. Here, a systematic methodology is presented for absolute ranging by means of the time-of-flight measurement of ultrashort light pulses using dual-comb asynchronous optical sampling. Based on an elaborate uncertainty analysis, influencing system parameters such as the pulse duration, repetition rate, and averaging time are optimized to achieve a sub-µm measurement accuracy. The absolute ranging system developed in this study demonstrates a combined standard uncertainty of 0.986 µm for a 0.5 ms averaging over a distance range of 3.0 m, with a further reduction to 0.056 µm when the averaging time is increased to 0.5 s. The outstanding performance leads to unprecedented multitarget applications: machine feed control with thermal error compensation in real time as well as the nondestructive inspection of multilens assembly in a production line.

Diverging cyclic radial shearing interferometry for single-shot wavefront sensing.

In this investigation, we describe a simple cyclic radial shearing interferometer for single-shot wavefront sensing. Instead of using the telescope lens system used in typical radial shearing interferometry, a single lens is used to generate two diverging radial shearing beams. This simple modification leads to the advantages of conveniently adjusting the radial shearing ratio, compactness of the system, and practical ease of alignment. With the aid of a polarization pixelated CMOS camera, the spatial phase-shifting technique is used to extract the phase with a single image. The most important feature is the fringe contrast enhancement by reducing the aberrations caused by the complicated optical system even though an incoherent light is used. The experimental results show the fringe contrast enhancement is at least 0.1 better than that of the conventional method, and the wavefronts are properly reconstructed with less than 0.071λ root-mean-squared wavefront error regardless of the coherence of the light.

Improved Self-Calibration of a Multilateration System Based on Absolute Distance Measurement.

Multilateration tracking systems (MLTSs) are used in industrial three-dimensional (3D) coordinate measuring applications. For high-precision measurement, system parameters must be calibrated properly in advance. For an MLTS using absolute distance measurement (ADM), the conventional self-calibration method significantly reduces estimation efficiency because all system parameters are estimated simultaneously using a complicated residual function. This paper presents a novel self-calibration method that optimizes ADM to reduce the number of system parameters via highly precise and separate estimations of dead paths. Therefore, the residual function to estimate the tracking station locations can be simplified. By applying a suitable mathematical procedure and solving the initial guess problem without the aid of an external device, estimation accuracy of the system parameters is significantly improved. In three self-calibration experiments, with ADM repeatability of approximately 3.4 µm, the maximum deviation of the system parameters estimated by the proposed self-calibration method was 68.6 µm, while the maximum deviation estimated by the conventional self-calibration method was 711.9 µm. Validation of 3D coordinate measurements in a 1000 mm × 1000 mm × 1000 mm volume showed good agreement between the proposed ADM-based MLTS and a commercial laser tracker, where the maximum difference based on the standard deviation was 17.7 µm. Conversely, the maximum difference was 98.8 µm using the conventional self-calibration method. These results confirmed the efficiency and feasibility of the proposed self-calibration method.

Adenosine Triphosphate Accumulated Following Cerebral Ischemia Induces Neutrophil Extracellular Trap Formation.

In ischemic stroke, neutrophils infiltrate damaged brain tissue immediately following the ischemic insult and aggravate inflammation via various mechanisms which include neutrophil extracellular traps (NETs) formation. In the present study, we showed that adenosine triphosphate (ATP), a DAMP molecule, accumulates in the brain and induces NETosis in brain parenchyma and in circulating neutrophils (PMNs) isolated from a murine model of stroke induced by middle cerebral artery occlusion (MCAO). Expression of peptidylarginine deiminase-4 (PAD4), which induces citrullination of histones H3 (CitH3) and initiates NETosis, was significantly enhanced in brain parenchyma and blood PMNs following MCAO. ATP or BzATP (a prototypic P2X7R agonist) significantly enhanced the inductions of PAD4 and CitH3 in a P2X7R-dependent manner and intracellular Ca2+ influx, PKCα activation, and NADPH oxidase-dependent reactive oxygen species (ROS) production play critical roles in this ATP-P2X7R-mediated NETosis. In our MCAO animal model, NETosis was markedly suppressed by treatment with apyrase, an enzyme hydrolyzing ATP, but enhanced by co-treatment of BzATP, confirming ATP-P2X7R-mediated NETosis. Since ATP not only induced NETosis but was also extruded after NETosis, our results indicate that ATP accumulated in the ischemic brain induces NETosis, mediating a cross-talk linking NETosis with neuronal damage that might aggravate inflammation and brain damage.

Comb segmentation spectroscopy for rapid detection of molecular absorption lines.

We perform fast comb spectroscopy by dividing the probe comb into several sub-comb segments so as to produce multi-heterodyne beats focused around targeted molecular absorption lines. This concentrated scheme of comb spectroscopy is able to achieve a 30 dB signal-to-noise ratio with just a single shot measurement of 10 µs acquisition time. Such high signal sensitivity is verified by measuring separate absorption lines of H13C14N and 12CO2 gases simultaneously. In addition, atmospheric 12CO2 concentration over a 1.3 km open-air path is traced with a signal repeatability of 15 ppm at a 5 kHz update rate.

Rigorous single pulse imaging for ultrafast interferometric observation.

We discuss how to realize rigorous single pulse imaging using a fiber mode-locked laser for the purpose of ultrafast interferometric observation of fast varying dynamic objects. Sub-picosecond pulses are readily picked up in synchronization with the camera operation, allocating one pulse per frame, but rigorous ultrashort single pulse imaging is disturbed by the accumulation of amplified spontaneous emission (ASE) over the exposure time of the camera. Here, we propose four distinct methods to eliminate the ASE-accumulated disruption in the ultrashort optical gating by pulse interferometry and then evaluate their merits and limitations individually by experiments. The proposed four methods are referred to respectively as the time averaged phase modulation, unbalanced pulse overlapping, tandem pulse picking, and second harmonic generation.

Surface third-harmonic generation at a two-photon-polymerized micro-interferometer for real-time on-chip refractive index monitoring.

A micro-interferometer based on surface third-harmonic generation (THG) at two-photon-polymerized SU-8 cuboids for real-time monitoring of the refractive index changes of target fluids, which can be easily integrated into microfluidic photonic systems, is demonstrated. The third-harmonic (TH) interferogram is selectively generated only from the target volume by a simple vertical pumping, thereby eliminating the needs for complicated coupling and alignments. The dependence of the generated TH to the input pump polarization state is thoroughly investigated. The THG efficiency by linearly polarized excitation is found to be 2.6 × 10-7, which is the most efficient at the SU-8-air interface and independent of the input polarization direction. The THG efficiency from the SU-8-air interface is 12.17 times higher than that from the glass-air interface and 4.93 times higher than that from the SU-8-glass interface. Real-time monitoring of argon gas pressure is demonstrated using the micro- interferometer. The surface TH from two-photon-polymerized 3D structures offers novel design flexibility to the nonlinear optical light sources for microfluidic and microelectronic devices.

DIFFERENTIAL DIAGNOSIS FOR VITREORETINAL LYMPHOMA WITH VITREORETINAL FINDINGS, IMMUNOGLOBULIN CLONALITY TESTS, AND INTERLEUKIN LEVELS.

PURPOSE: To analyze vitreoretinal findings, immunoglobulin clonality tests, and interleukin (IL) levels for diagnosing vitreoretinal lymphoma (VRL). METHODS: Forty-three patients who underwent diagnostic vitrectomy for suspected VRL were retrospectively reviewed. Of those patients finally diagnosed with VRL and nonlymphoma, ophthalmic evaluation and cytology results, IL-6 and IL-10 levels, and immunoglobulin heavy chain and immunoglobulin kappa light chain clonality assays were compared. RESULTS: Sub-retinal pigment epithelium infiltration and veil-pattern vitreous opacity were specific vitreoretinal findings in patients with VRL. The area under the receiver operating characteristic curve of the IL-10-to-IL-6 ratio and of IL-10 levels was 0.972 and 0.931, respectively. A combined immunoglobulin heavy chain and immunoglobulin kappa light chain assay showed increased sensitivity, whereas the determined specificity of immunoglobulin kappa light chain, at 94.12%, was much higher than the 78.95% of immunoglobulin heavy chain. Patients with VRL with atypically elevated IL-6 levels showed extensive and severe sub-retinal pigment epithelium infiltration. CONCLUSION: Newly screened immunoglobulin kappa light chain clonality assays may be useful to distinguish VRL from uveitis with high specificity. When sub-retinal pigment epithelium or retinal infiltration is severe and extensive, the IL-10-to-IL-6 ratio may not be typical and should be carefully interpreted.