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There is a formulation of unimodular gravity (UG) in which the unimodular metric is obtained out of an unrestricted one as γ μ ν = | g | − 1 n g μ ν . This unrestricted metric is only defined up to a Weyl rescaling. Physical charges like ADM energy or horizon entropy, however, are not Weyl invariant in general. In this paper a Weyl invariant definition of some physical charges is given. [ABSTRACT FROM AUTHOR]

This essay addresses some of the relations that can be traced between, on the one hand, J. M. Coetzee and Jorge Luis Borges and, on the other, the concept of the Global South and Coetzee’s recent approach to Latin America. The development of his ideas about the notion of the South or “real South,” as opposed to the “mythic South,” is discussed and illustrated through a brief analysis of Borges’s tale “El Sur” [“The South”] and Coetzee’s novel Disgrace. These two texts help us in focusing Coetzee’s rejection of the so-called “Northern Gaze,” a Westernised world-view dominated by the English language, and his preference for Spanish as the language for the initial publication of his latest books. [ABSTRACT FROM AUTHOR]

Movement slowness is a common and disruptive symptom of multiple sclerosis (MS). A potential cause is that individuals with MS slow down to conserve energy as a behavioral adjustment to heightened metabolic costs of movement. To investigate this prospect, we measured the metabolic costs of both walking and seated arm reaching at five speeds in persons with mild MS (pwMS; n = 13; 46.0 ± 7.7 yr) and sex- and age-matched controls (HCs; n = 13; 45.8 ± 7.8 yr). Notably, the cohort of pwMS was highly mobile and no individuals required a cane or aid when walking. We found that the net metabolic power of walking was approximately 20% higher for pwMS across all speeds (P = 0.0185). In contrast, we found no differences in the gross power of reaching between pwMS and HCs (P = 0.492). Collectively, our results suggest that abnormal slowness of movement in MS--particularly reaching--is not the consequence of heightened effort costs and that other sensorimotor mechanisms are playing a considerable role in slowing. NEW & NOTEWORTHY Individuals with multiple sclerosis (MS) often move more slowly than those without the disease. A possible cause is that movements in MS are more energetically expensive and slowing is an adaptation to conserve metabolic resources. Here, we find that while walking is more costly for persons with MS, arm-reaching movements are not. These results bring into question the driving force of movement slowness in MS and implicate other motor-related networks contributing to slowing. [ABSTRACT FROM AUTHOR]

Ublituximab is a novel anti-CD20 therapy developed for the treatment of patients with multiple sclerosis. It is a glycoengineered chimeric antibody with a novel epitope on CD20, with high antibody-dependent cell-mediated cytotoxicity. Maintenance doses are administered every 6 months over an hour, providing a convenient dosing regimen. The identical phase III randomized, double-blind, active comparator to teriflunomide trials ULTIMATE I and II were completed in early 2022. ULTIMATE I and II, respectively, demonstrated that ublituximab had a strong clinical effect, with annualized relapse rates of 0.08 and 0.09 or reductions of 59% and 49% over teriflunomide. In addition, in ULTIMATE I and II, radiographic efficacy similarly reduced contrast-enhancing lesions by 97% and 96% and new/enlarging T2 lesions by 92% and 90%, respectively. Although ublituximab did not decrease confirmed disability progression in a pooled analysis of both studies, there was an increase in the confirmed disability improvement. Ublituximab was well tolerated, including infusion reactions that were predominantly mild and only seen with the first infusion. Further long-term safety data, as well as relative efficacy compared with current anti-CD20 therapies, will need to be evaluated in the real-world setting if ublituximab is to be approved as expected in December 2022. [ABSTRACT FROM AUTHOR]

This paper is concerned with the structural stability of spherical horizons. By this we mean stability with respect to variations of the second member of the corresponding differential equations, corresponding to the inclusion of the contribution of operators quadratic in curvature. This we do both in the usual second order approach (in which the independent variable is the spacetime metric) and in the first order one (where the independent variables are the spacetime metric and the connection field). In second order, it is claimed that the generic solution in the asymptotic regime (large radius) can be matched not only with the usual solutions with horizons (like Schwarzschildâ€"de Sitter) but also with a more generic (in the sense that it depends on more arbitrary parameters) horizonless family of solutions. It is however remarkable that these horizonless solutions are absent in the restricted (that is, when the background connection is the metric one) first order approach. [ABSTRACT FROM AUTHOR]

Foe (1986) is one of the most ambiguous and controversial novels written by J.M. Coetzee, and has been discussed extensively by criticism from a great variety of theoretical positions. This essay purports to contribute another intertextual reading of the novel, trying to elucidate some of its dark points, particularly section IV, which has been so much debated and for whose ambiguity no wholly satisfactory explanation has so far been produced. Our main contention is that, in addition to Borges's narratives "Pierre Menard, Author of the Quixote" (in Fictions, 1944) and "Borges and I" (in The Maker, 1960), Coetzee's novel can benefit from a parallel reading of other Borgesian tales, particularly "Brodie's Report" (1970) and "The Writing of the God" (1949), among others. Borges's gnosticism is clearly followed by Coetzee, who has explicitly acknowledged his interest in the ethical and esthetic motivations that lie in some of Borges's most mysterious stories. [ABSTRACT FROM AUTHOR]

This article discusses the various shapes, inner structures and roles given to transformative and liberative practices in the work of US Buddhist anarchist authors (1960-2010). Unlike their Chinese and Japanese predecessors, who focused more on discursive parallelisms between Buddhism and anarchism or on historical instances of antiauthoritarianism within the Buddhist tradition(s), US Buddhist anarchists seem to favour practice and experience. This emphasis, characteristic of the way Buddhism has been introduced to the West, sometimes masks the way meditative techniques were used in traditional Buddhist contexts as oppressive technologies of the self. Whereas the emphasis on the inherently revolutionary nature of Buddhist practice represents a radical departure from the way those practices have been conceptualised throughout Buddhist history, it also involves the danger of considering Buddhist practice as an ahistorical sine qua non for social transformation. This is due to the fact that most early Buddhist anarchist writers based their ideas on a highly idealised, Orientalist imagination of Zen Buddhism(s). However, recent contributions based on other traditions have offered a more nuanced, albeit still developing picture. By assessing a number of instances from different US Buddhist anarchist writers, the article traces the brief history of the idea that meditation is revolutionary praxis, while also deconstructing and complicating it through historical and textual analysis. [ABSTRACT FROM AUTHOR]

A ghost free massive deformation of unimodular gravity (UG), in the spirit of mimetic massive gravity, is shown to exist. This construction avoids the no-go theorem for a Fierz–Pauli type of mass term in UG by giving up on Lorentz invariance. In our framework, the mimetic degree of freedom vanishes on-shell. [ABSTRACT FROM AUTHOR]

An introduction to the journal is presented which discusses topics within the issue including issues of sexuality in Egypt; sovereignties of the Syrian civil war; and discourses of nation-building in Burma.

This article discusses how Rojava and its 'Autonomous Administration' simultaneously subvert and reinstate the state(s) they are fighting. Based on Abdullah Öcalan's (b. 1948) conversion to libertarianism after his imprisonment in 1999, the Syrian Kurdish Democratic Union Party (PYD) has been invested in presenting its political experiment as a 'stateless democracy', which has elicited both enthusiasm and suspicion from anarchists worldwide, and from large sections of the Western left. Far from trying to prove or disprove Rojava's own narrative, this article analyses how the construction of Rojava is a complex and often self-contradictory process, both at the rhetorical/propagandist level and in terms of actual military, political and social practices. By engaging many enemies (ISIS, al Nusra, the Free Syrian Army, the Assad regime, Iraqi Kurdistan, Turkey), both discursively and in battle, and trying to obtain support from various potential and mutually conflicting allies (the United States, Russia, Iraqi Kurdistan, the EU, the Western left, the Assad regime) the PYD/YPG-J (People's Protection Units) are entrenched in a fraught space in which subversion and mimicry coexist in uneasy tension. [ABSTRACT FROM AUTHOR]

This work presents a new method for assisting in the identification process of missing persons in several contexts, such as enforced disappearances. We apply a Bayesian technique to incorporate non-genetic variables in the construction of prior information. In that way, we can learn from the already-solved cases of a particular mass event of death, and use that information to guide the search among remaining victims. This paper describes a particular application to the proposed method to the identification of human remains of the so-called disappeared during the last dictatorship in Argentina, which lasted from 1976 until 1983. Potential applications of the techniques presented hereby, however, are much wider. The central idea of our work is to take advantage of the already-solved cases within a certain event to use the gathered knowledge to assist in the investigation process, enabling the construction of prioritized rankings of victims that could correspond to each certain unidentified human remains. [ABSTRACT FROM AUTHOR]

The most general Lagrangian describing spin 2 particles in flat spacetime and containing operators up to (mass) dimension 6 is carefully analyzed, determining the precise conditions for it to be invariant under linearized (transverse) diffeomorphisms, linearized Weyl rescalings, and conformal transformations. [ABSTRACT FROM AUTHOR]

This essay explores the images emerging from the Syrian conflict through the genre of war documentaries by focusing on the performance of sovereignty. Drawing on Foucault’s notion of governmentality and Butler’s performative theory, the author looks at states as performative agents that stage power in front of the camera as a form of self-legitimisation. War documentaries are part of a documentary war in which image, information and emotional involvement have become weaponised. He assesses a few examples of religious and secular sovereignty performed for journalists who are embedded with various militias. This genre is brought about through cooperation between the embedded reporters (i.e. working inside an army or militia) and the fighters assigned to protect and show them around the territory they control. This results in a symbiotic relationship in which both sides co-produce a heavily mediated image of the war from the inside, one that satisfies the journalist’s desire for ‘exclusive access’ and the fighter’s desire for recognition. Such a representational pact contributes a unique feature to the war documentary genre in which the films show the raw reality of war as much they offer an opportunity to perform the state before the camera. From this perspective, the fighters appear not only as destroyers but as builders of a new order, thus complicating the image of the jihadi as an irrational, nihilistic and violent subject. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to determine the feasibility of low-load resistance training with blood flow restriction (BFR) for people with advanced disability due to multiple sclerosis (MS). Methods In this prospective cohort study, 14 participants with MS (Expanded Disability Status Scale [EDSS] score = 6.0 to 7.0; mean age = 55.4 [SD = 6.2] years; 71% women) were asked to perform 3 lower extremity resistance exercises (leg press, calf press, and hip abduction) bilaterally twice weekly for 8 weeks using BFR. Feasibility criteria were as follows: enrollment of 20 participants, ≥80% retention and adherence, ≥90% satisfaction, and no serious adverse events related to the intervention. Other outcomes included knee extensor, ankle plantar flexor, and hip abductor muscle strength, 30-Second Sit-to-Stand Test, Berg Balance Scale, Timed 25-Foot Walk Test, 12-Item MS Walking Scale, Modified Fatigue Impact Scale, Patient-Specific Functional Scale, and daily step count. Results Sixteen participants consented, and 14 completed the intervention, with 93% adherence overall. All participants were satisfied with the intervention. A minor hip muscle strain was the only intervention-related adverse event. There were muscle strength improvements on the more-involved (16%–28%) and less-involved (12%–19%) sides. There were also changes in the 30-Second Sit-to-Stand Test (1.9 repetitions; 95% CI = 1.0 to 2.8), Berg Balance Scale (5.3 points; 95% CI = 3.2 to 7.4), Timed 25-Foot Walk Test (−3.3 seconds; 95% CI = −7.9 to 1.3), Modified Fatigue Impact Scale (−8.8 points; 95% CI = −16.5 to −1.1), 12-Item MS Walking Scale (−3.6 points; 95% CI = −11.5 to 4.4), Patient-Specific Functional Scale (2.9 points; 95% CI = 1.9 to 3.8), and daily step count (333 steps; 95% CI = −191 to 857). Conclusion Low-load resistance training using BFR in people with MS and EDSS scores of 6.0 to 7.0 appears feasible, and subsequent investigation into its efficacy is warranted. Impact Although efficacy data are needed, combining BFR with low-load resistance training may be a viable alternative for people who have MS and who do not tolerate conventional moderate- to high-intensity training because of more severe symptoms, such as fatigue and weakness. Lay Summary Low-load strength training with BFR was feasible in people who have advanced disability due to MS. Using BFR may provide an alternative for people with MS who do not tolerate higher intensity training due to more severe symptoms, such as fatigue and weakness. [ABSTRACT FROM AUTHOR]

The leader protease (L pro ) from foot-and-mouth disease virus (FMDV) has the ability to cleave eIF4G, leading to a blockade of cellular protein synthesis. In contrast to previous reports, our present findings demonstrate that FMDV L pro is able to increase translation driven by FMDV IRES. Additionally, inactivation of eIF2 subsequent to phosphorylation induced by arsenite or thapsigargin in BHK cells blocks protein synthesis directed by FMDV IRES, whereas in the presence of L pro , significant translation is found under these conditions. This phenomenon was also observed in cell-free systems after induction of eIF2 phosphorylation by addition of poly(I:C). [ABSTRACT FROM AUTHOR]

Discrete-time filters represent a promising solution for pulse-processing in high-energy physics experiments due to their flexibility, reliability, and their capability to synthesize weighting functions with virtually any shape. One of the major concerns when designing one of these filters is to calculate the filter parameters that maximize the signal-to-noise ratio. The classic way to address this problem is to perform the noise analysis using a continuous-time domain approach based on the weighting function concept. However, when addressing the problem from an inadequate time domain, the analysis is not insightful and the resulting expressions are complex and difficult to use for design purposes. In this work, a mathematical framework for a design-oriented analysis of discrete-time filters in the discrete-time domain is presented. This analysis is based on treating the sampled noise as a discrete-time signal, which can be manipulated to obtain a closed-form expression for the front-end noise, suitable for computer automatic evaluation and filter optimization procedures. An example of the optimum filter formulation and computation is presented, in addition to several conclusions about optimum digital filtering. [ABSTRACT FROM PUBLISHER]

CXCL13, a B-cell chemokine, has been proposed as a biomarker in a variety of conditions, some of which can mimic multiple sclerosis and can have very high levels. In this case-control study, cerebrospinal fluid (CSF) CXCL13 was elevated in multiple sclerosis, neuromyelitis optica and other inflammatory neurological controls compared with noninflammatory controls. Levels did not differentiate disease groups. For all subjects taken together, CSF CXCL13 correlated with CSF WBC, oligoclonal band numbers, CSF protein, EDSS, and neurofilament levels. In subgroup analyses, CSF CXCL13 correlated with CSF WBC in neuromyelitis optica and IgG index in multiple sclerosis. Additionally, serum CXCL13 was elevated in neuromyelitis optica. [ABSTRACT FROM PUBLISHER]

This paper presents a restructured set of axioms for categorical logic. In virtue of it, the syllogistic with indefinite terms is deduced and proved, within the categorical logic boundaries. As a result, the number of all the conclusive syllogisms is deduced through a simple and axiomatic methodology. Moreover, the distinction between immediate and mediate inferences disappears, which reinstitutes the unity of Aristotelian logic. [ABSTRACT FROM AUTHOR]

Charge amplifiers represent the standard solution to amplify signals from capacitive detectors in high energy physics experiments. In a typical front-end, the noise due to the charge amplifier, and particularly from its input transistor, limits the achievable resolution. The classic approach to attenuate noise effects in MOSFET charge amplifiers is to use the maximum power available, to use a minimum-length input device, and to establish the input transistor width in order to achieve the optimal capacitive matching at the input node. These conclusions, reached by analysis based on simple noise models, lead to sub-optimal results. In this work, a new approach on noise analysis for charge amplifiers based on an extension of the gm/ID methodology is presented. This method combines circuit equations and results from SPICE simulations, both valid for all operation regions and including all noise sources. The method, which allows to find the optimal operation point of the charge amplifier input device for maximum resolution, shows that the minimum device length is not necessarily the optimal, that flicker noise is responsible for the non-monotonic noise versus current function, and provides a deeper insight on the noise limits mechanism from an alternative and more design-oriented point of view. [ABSTRACT FROM PUBLISHER]

A general approach to Bayesian isotonic changepoint problems is developed. Such isotonic changepoint analysis includes trends and other constraint problems and it captures linear, non-smooth as well as abrupt changes. Desired marginal posterior densities are obtained using a Markov chain Monte Carlo method. The methodology is exemplified using one simulated and two real data examples, where it is shown that our proposed Bayesian approach captures the qualitative conclusion about the shape of the trend change. [ABSTRACT FROM AUTHOR]

To investigate the pharmacological properties of the CR011-vcMMAE fully human antibody–drug conjugate (ADC), such as dose titrations, quantitation of the time (days) to complete regression, pharmacokinetics, and schedule dependency. Our prior study characterized a fully human antibody to GPNMB covalently linked to monomethylauristatin E, CR011-vcMMAE, and further demonstrated cell surface staining of melanoma lines susceptible to the immunoconjugate’s cytotoxicity (Clin Cancer Res 2005; 12(4): 1373–1382). The human SK-MEL-2 and SK-MEL-5 melanoma xenografts were used in athymic mice to assess anti-tumor efficacy. After s.c. implantation, tumors became established (60–100 mg), and treatment commenced by i.v. injection of the immunoconjugate or vinblastine or paclitaxel. Short-term anti-tumor effects (inhibition of tumor growth) and long-term effects (complete regression) were observed. CR011-vcMMAE induced regression of established human SK-MEL-2 and SK-MEL-5 xenografts at doses from 1.25 to 80 mg/kg treatment when administered intravenously every 4 days (4 treatments); strikingly, regressions were not associated with re-growth during the observation period (200 days). The disappearance rate of implants was dose dependent (minimum time, 18.5 days). Detectable serum CR011-vcMMAE ≥1 μg/mL (∼0.01 μM) was observed for >30 days post-dose; CR011-vcMMAE showed an elimination half-life of 10.3 days. A low volume of distribution suggested that CR011-vcMMAE was confined to blood and interstitial fluid. CR011-vcMMAE could be delivered by either a single bolus dose or by intermittent dosing (i.e., every 1, 2, 4, 8, or 16 days) with no discernible differences in the proportion of tumor-free survivors, indicating a lack of schedule dependency. The antibody–drug conjugate produced complete regressions, but the equivalent doses of free monomethylauristatin E or unconjugated antibody did not show anti-tumor effects. In addition, decreases in plasma tumor-derived human interleukin-8 coincided with tumor nodule disappearance. Short-term anti-tumor effects and long-term effects (complete regression) were observed with CR011-vcMMAE, but not with the reference agents. These results suggest that CR011-vcMMAE may provide therapeutic benefit in malignant melanoma. [ABSTRACT FROM AUTHOR]

Two isoforms of the translation initiation factor eIF4G, eIF4GI and eIF4GII, have been described in eukaryotic cells. The exact function of each isoform during the initiation of protein synthesis is still under investigation. We have developed an efficient and reliable method of expressing poliovirus 2Apro, which differentially proteolyzes eIF4GI and eIF4GII in a time- and dose-dependent manner. This system is based on the electroporation of an in vitro transcribed mRNA that contains the encephalomyocarditis virus internal ribosome entry site followed by the sequence of poliovirus 2Apro. In contrast to HeLa cells, expression of this protease in BHK-21 cells induces delayed hydrolysis kinetics of eIF4GI with respect to eIF4GII. Moreover, under these conditions the polyadenylate binding protein is not cleaved. Interestingly, translation of de novo synthesized luciferase mRNA is highly dependent on eIF4GI integrity, whereas ongoing translation is inhibited at the same time as eIF4GII cleavage. Moreover, reinitiation of a preexisting mRNA translation after polysome run-off is dependent on the integrity of eIF4GII. Notably, de novo translation of heat shock protein 70 mRNA depends little on eIF4GI integrity but is more susceptible to eIF4GII hydrolysis. Finally, translation of an mRNA containing encephalomyocarditis virus internal ribosome entry site when the two isoforms of eIF4G are differentially hydrolyzed has been examined. [ABSTRACT FROM AUTHOR]

Abstract: To better understand the development of ventral mesencephalic dopamine neurons, we performed subtractive hybridization screens to find ventral mesencephalic genes expressed at rat embryonic day 10 when these neurons begin to differentiate. The most commonly identified genes in these screens were members of the Bex (Brain expressed X-linked) gene family, rat Bex1 (Rex3), and a novel gene, rat Bex4. After identifying these genes, we then sought to characterize the Bex gene family. Two additional novel Bex genes (human Bex5 and mouse Bex6) were discovered through genomic databases. Bex5 is present in humans and monkeys, but not rodents, while Bex6 exists in mice, but not humans. Bex4 and Bex5 are localized to the X chromosome, are expressed in brain, and are similar in sequence. Bex4 and Bex5 are 54% and 56% identical to human Bex3 (pHGR74, NADE). Mouse Bex6 is on chromosome 16 and is 67% identical to mouse Bex4. Human Bex gene expression was studied with tissue expression arrays probed with specific oligonucleotides. Human Bex1 and Bex2 have similar expression patterns in the central nervous system with high levels in pituitary, cerebellum, and temporal lobe, and Bex1 is widely expressed outside of the central nervous system with high expression in the liver. Human Bex4 is highly expressed in heart, skeletal muscle, and liver, while Bex3 and Bex5 are more widely expressed. The subcellular localization of the Bex proteins varies from nuclear (rat Bex1) to cytoplasmic (rat Bex3, human Bex5, and mouse Bex6) and to both nuclear and cytoplasmic (rat Bex2 and rat Bex4). Rat Bex3, rat Bex4, human Bex5, and mouse Bex6 are degraded by the proteasome, while rat Bex1 or Bex2 are not. Rat Bex3 protein can likely bind transition metals through a histidine-rich domain. Because this gene family was originally named Bex and because these genes are unified by sequence similarity and gene structure, we believe the Bex nomenclature should prevail over nomenclature based on function (NADE) that has not been extended to the other Bex genes. We conclude that the Bex gene family members are highly homologous but differ in their expression patterns, subcellular localization, and degradation by the proteasome. [Copyright &y& Elsevier]

Consider a process that jumps among a finite set of states, with random times spent in between. In semi-Markov processes transitions follow a Markov chain and the sojourn distributions depend only on the connecting states. Suppose that the process started far in the past, achieving stationary. We consider non-parametric estimation by modelling the log-hazard of the sojourn times through linear splines; and we obtain maximum penalized likelihood estimators when data consist of several i.i.d. windows. We prove consistency using Grenander''s method of sieves. [Copyright &y& Elsevier]

Background: Conventional antipsychotics although effective in treating acute psychotic and behavioural symptoms are subject to certain limitations due to the high incidence of side effects associated, mainly extrapyramidal symptoms (EPS), and insufficient response shown in some cases. EPS are a major factor in neuroleptic non compliance and high relapse rates among patients. This study was designed to assess the safety and effectiveness of olanzapine compared to typical antipsychotics drugs in the treatment of schizophrenic inpatients at acute psychiatric in-patient units. Method: Data from 904 patients schizophrenic patients (F20 of ICD10, WHO) were collected in this prospective, comparative, non-randomized, open and observational study. Patients were followed during their entire hospital stay. Safety was assessed through the collection of spontaneous adverse events and a specific extrapyramidal symptoms questionnaire (EPS). Clinical status was measured through the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression of Severity (CGI-S), Patient Global Impression of Improvement (PGI) and the Nursing Observational Scale for In-patient Evaluation (NOSIE). Results: A total of 483 patients received olanzapine (olanzapine group, OG), and 421 received typical antipsychotics (control group, CG). Treatment emergent EPS, or worsening of previous EPS were statistically significantly higher in the CG (P=0.001). Responder rate was statistically greater in the OG (P<0.001). Mean change in BPRS-total, BPRS-negative, BPRS-agitation subscales and PGI was significantly higher in the OG (P<0.001). Mean decrease in CGI, BPRS positive and BPRS depression sub-scales was also significantly lower (P≤0.05). Mean change in the NOSIE scale was similar between both groups. Conclusion: Olanzapine has been shown to be better tolerated in comparison with conventional antipsychotics in a large unselected sample of acutely psychotic schizophrenic in-patients. Its effectiveness may be greater than that of conventional antipsychotics. [Copyright &y& Elsevier]

Cellular parameters of the seminogram have been previously shown to correlate with L-carnitine concentration in the seminal fluid. Carnitine is involved in a variety of metabolic processes playing an important role in maintaining an active oxidative phosphorylation (OXPHOS). Recently, we have found a significant association between the specific activities of the respiratory chain complexes and the seminogram parameters and here we have studied the relationship between the spermatozoa OXPHOS activities and L-carnitine concentration in the seminal plasma. Carnitine, but not prostatic secretions, positive and significantly correlate with mitochondrial respiratory complex activities and the citric acid cycle enzymes citrate synthase and succinate dehydrogenase. It is remarkable that the ratios of the respiratory chain complexes to citrate synthase or succinate dehydrogenase, significant but negatively correlated with L-carnitine concentration. As carnitine in seminal plasma is secreted from the epididymis our results strongly suggest that relationships between carnitine secretion, seminal quality and OXPHOS activities could be because of a parallel response to the same regulatory event. [ABSTRACT FROM AUTHOR]

Presents information on a study which discussed a modeling approach for integrated capacitors based on the partial-element-equivalent-circuit formulation. Modeling methodology; Electrical measurements and model verification; Simulation case studies on the 3M C-Ply technology.

Psoriatic disease (PsD) affects multiple clinical domains and causes a significant inflammatory burden in patients, requiring comprehensive evaluation and treatment. In recent years, new molecules such as JAK inhibitors (JAKinhibs) have been developed. These have very clear advantages: they act quickly, have a beneficial effect on pain, are well tolerated and the administration route is oral. Despite all this, there is still little scientific evidence in daily clinical practice. This observational, retrospective, single-center study was carried out in patients diagnosed with PsA in the last two years, who started treatment with Tofacitinib or Upadacitinib due to failure of a DMARD. The data of 32 patients were analyzed, and the majority of them (75%) started treatment with Tofacitinib. Most had moderate arthritis activity and mild psoriasis involvement according to activity indices. Both Tofacitinib and Upadacitinib demonstrated significant efficacy, with rapid and statistically significant improvement in joint and skin activity indices, C-reactive protein reduction, and objective measures of disease activity such as the number of painful and inflamed joints. Although there was some difference in the baseline characteristics of the cohort, treatment responses were comparable or even superior to those in the pivotal clinical trials. In addition, there was a low frequency of mild adverse events leading to treatment discontinuation and no serious adverse events. These findings emphasize the strong efficacy and tolerability of JAKinhibs in daily clinical practice, supporting their role as effective therapeutic options for patients with PsD. [ABSTRACT FROM AUTHOR]

The article presents arguments supporting the need for randomized clinical trials for testing disease-modifying therapies (DMTs) for treating multiple sclerosis (MS) in pregnant women. It talks about topics including DMT guidance for managing MS in women who wish to conceive, the impact of DMTs on breastfeeding, and testing the safety of DMTs to pregnant women and fetuses.

We have recently undergone an analysis of gravitational theories as defined in first order formalism, where the metric and the connection are treated as independent fields. The physical meaning of the connection field has historically been somewhat elusive. In this paper, a complete spin analysis of the torsionless connection field is performed, and its consequences are explored. The main properties of a hypothetical consistent truncation of the theory are discussed as well. [ABSTRACT FROM AUTHOR]

Based on the quasi-local energy definition of Brown and York, we compute the integral of the trace of the extrinsic curvature over a codimension-2 hypersurface. In particular, we study the difference between the uncompactified Minkowski spacetime and the toroidal Kaluza-Klein compactification. For the latter, we find that this quantity interpolates between zero and the value for the uncompactified spacetime, as the size of the compact dimension increases. Thus, the quasi-local energy is able to discriminate between the two spacetimes. [ABSTRACT FROM AUTHOR]

Introduction: Delayed-release dimethyl fumarate (DMF) is an effective treatment for multiple sclerosis (MS). Some patients experience gastrointestinal (GI) adverse events (AEs) that may lead to premature DMF discontinuation. This study characterized the impact of site-specific GI management strategies on the occurrence of GI events and discontinuation patterns. Methods: Data on GI events and DMF persistence were retrospectively abstracted from medical records of patients treated with DMF in routine medical practice in the EFFECT study (NCT02776072). GI management strategies were assessed via a study site questionnaire. Discontinuation rates were analyzed according to counseling patterns. Results: Of 826 DMF-treated patients at 66 sites, 809 from 65 sites were eligible for the GI analysis; of these, 27% experienced GI AEs. Within 1 year of treatment, 14% (118/826) of patients discontinued DMF, 5% (44/809) due to GI events. Most sites (92%) reported that patients were very likely (> 75% of the time) to be counseled about GI events at/before DMF treatment initiation and/or to be recommended that DMF be taken with food (86%); 48% of sites reported to be very likely to recommend using symptomatic therapies for GI AEs. Lower discontinuation rates were reported at sites very likely versus not very likely (≤ 75% of the time) to (1) provide counseling; (2) provide specific details regarding GI events; or (3) recommend taking DMF with food, and/or using symptomatic GI therapies. Conclusion: Counseling and other GI management strategies at initiation of DMF treatment appear to reduce the burden of GI events, and a variety of GI management strategies may improve DMF persistence. Trial Registration: NCT02776072. Funding: Biogen (Cambridge, MA, USA). [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate safety (infusion‐related reactions [IRRs]) and patient satisfaction (patient‐reported outcomes [PROs]) for at‐home ocrelizumab administration for patients with multiple sclerosis (MS). Methods: This open‐label study included adult patients with an MS diagnosis who had completed a ≥ 600‐mg ocrelizumab dose, had a patient‐determined disease steps score of 0 to 6 and had completed PROs. Eligible patients received a 600‐mg ocrelizumab home‐based infusion over 2 h, followed by 24‐h and 2‐week post‐infusion follow‐up calls. IRRs and adverse events (AEs) were documented during infusions and follow‐up calls. PROs were completed before and 2 weeks post infusion. Results: Overall, 99 of 100 expected patients were included (mean [SD] age, 42.3 [7.7] years; 72.7% female; 91.9% White). The mean (SD) infusion time was 2.5 (0.6) hours, and 75.8% of patients completed their ocrelizumab infusion between 2 to 2.5 h. The IRR incidence rate was 25.3% (95% CI: 16.7%, 33.8%)—similar to other shorter ocrelizumab infusion studies—and all AEs were mild/moderate. In total, 66.7% of patients experienced AEs, including itch, fatigue, and grogginess. Patients reported significantly increased satisfaction with the at‐home infusion process and confidence in the care provided. Patients also reported a significant preference for at‐home infusion compared with prior infusion center experiences. Interpretation: IRRs and AEs occurred at acceptable rates during in‐home infusions of ocrelizumab over a shorter infusion time. Patients reported increased confidence and comfort with the home infusion process. Findings from this study provide evidence of the safety and feasibility of home‐based ocrelizumab infusion over a shorter infusion period. [ABSTRACT FROM AUTHOR]

Background: The monoclonal antibody ublituximab enhances antibody-dependent cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated for the treatment of relapsing multiple sclerosis.Methods: In two identical, phase 3, double-blind, double-dummy trials (ULTIMATE I and II), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72) and oral placebo or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary end point was the annualized relapse rate. Secondary end points included the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) by 96 weeks and worsening of disability.Results: A total of 549 participants were enrolled in the ULTIMATE I trial, and 545 were enrolled in the ULTIMATE II trial; the median follow-up was 95 weeks. In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (rate ratio, 0.41; 95% confidence interval [CI], 0.27 to 0.62; P<0.001); in the ULTIMATE II trial, the annualized relapse rate was 0.09 and 0.18, respectively (rate ratio, 0.51; 95% CI, 0.33 to 0.78; P = 0.002). The mean number of gadolinium-enhancing lesions was 0.02 in the ublituximab group and 0.49 in the teriflunomide group (rate ratio, 0.03; 95% CI, 0.02 to 0.06; P<0.001) in the ULTIMATE I trial and 0.01 and 0.25, respectively (rate ratio, 0.04; 95% CI, 0.02 to 0.06; P<0.001), in the ULTIMATE II trial. In the pooled analysis of the two trials, 5.2% of the participants in the ublituximab group and 5.9% in the teriflunomide group had worsening of disability at 12 weeks (hazard ratio, 0.84; 95% CI, 0.50 to 1.41; P = 0.51). Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group. Serious infections occurred in 5.0% in the ublituximab group and in 2.9% in the teriflunomide group.Conclusions: Among participants with relapsing multiple sclerosis, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not result in a significantly lower risk of worsening of disability. Ublituximab was associated with infusion-related reactions. (Funded by TG Therapeutics; ULTIMATE I and II ClinicalTrials.gov numbers, NCT03277261 and NCT03277248.). [ABSTRACT FROM AUTHOR]

The multi-domain non-structural protein 3 of SARS-coronavirus is a component of the viral replication/transcription complex (RTC). Among other domains, it contains three sequentially arranged macrodomains: the X domain and subdomains SUD-N as well as SUD-M within the “SARS-unique domain”. The X domain was proposed to be an ADP-ribose-1”-phosphatase or a poly(ADP-ribose)-binding protein, whereas SUD-NM binds oligo(G)-nucleotides capable of forming G-quadruplexes. Here, we describe the application of a reverse genetic approach to assess the importance of these macrodomains for the activity of the SARS-CoV RTC. To this end, Renilla luciferase-encoding SARS-CoV replicons with selectively deleted macrodomains were constructed and their ability to modulate the RTC activity was examined. While the SUD-N and the X domains were found to be dispensable, the SUD-M domain was crucial for viral genome replication/transcription. Moreover, alanine replacement of charged amino-acid residues of the SUD-M domain, which are likely involved in G-quadruplex-binding, caused abrogation of RTC activity. [ABSTRACT FROM AUTHOR]

Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS). Objective: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion. Methods: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUC τ ) and maximum plasma concentration (C max) for Weeks 8–12. B-cell depletion and safety/tolerability were assessed. Results: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUC τ , 487.7 vs 474.1 h × µg/mL (ratio 1.03); C max, 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated. Conclusion: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion. [ABSTRACT FROM AUTHOR]

Three different matrix (M) proteins termed M1, M2 and M3 have been described in cells infected with vesicular stomatitis virus (VSV). Individual expression of VSV M proteins induces an evident cytopathic effect including cell rounding and detachment, in addition to a partial inhibition of cellular protein synthesis, likely mediated by an indirect mechanism. Analogous to viroporins, M1 promotes the budding of new virus particles; however, this process does not produce an increase in plasma membrane permeability. In contrast to M1, M2 and M3 neither interact with the cellular membrane nor promote the budding of double membrane vesicles at the cell surface. Nonetheless, all three species of M protein interfere with the transport of cellular mRNAs from the nucleus to the cytoplasm and also modulate the redistribution of the splicing factor. The present findings indicate that all three VSV M proteins share some activities that interfere with host cell functions. [ABSTRACT FROM AUTHOR]

Objective To assess the efficacy and safety of abatacept (ABA) in monotherapy (ABAMONO) vs combined ABA [ABA plus MTX (ABAMTX) or ABA plus non-MTX conventional synthetic DMARDs (csDMARDs) (ABANON-MTX)] in RA patients with interstitial lung disease (ILD) (RA-ILD). Methods This was a restrospective multicentre study of RA-ILD Caucasian patients treated with ABA. We analysed in the three groups (ABAMONO, ABAMTX, ABANON-MTX) the following outcome variables: (i) dyspnoea; (ii) forced vital capacity (FVC) and diffusion capacity of the lung for the carbon monoxide (DLCO); (iii) chest high-resolution CT (HRCT); (iv) DAS28-ESR; (v) CS-sparing effect; and (vi) ABA retention and side-effects. Differences between basal and final follow-up were evaluated. Multivariable linear regression was used to assess the differences between the three groups. Results We studied 263 RA-ILD patients (mean ± s. d. age 64.6 ± 10 years) [ABAMONO (n  = 111), ABAMTX (n  = 46) and ABANON-MTX (n  = 106)]. At baseline, ABAMONO patients were older (67 ± 10 years) and took higher prednisone dose [10 (interquartile range 5–15) mg/day]. At that time, there were no statistically significant differences in sex, seropositivity, ILD patterns, FVC and DLCO, or disease duration. Following treatment, in all groups, most patients experienced stabilization or improvement in FVC, DLCO, dyspnoea and chest HRCT as well as improvement in DAS28-ESR. A statistically significant difference between basal and final follow-up was only found in CS-sparing effect in the group on combined ABA (ABAMTX or ABANON-MTX). However, in the multivariable analysis, there were no differences in any outcome variables between the three groups. Conclusion In Caucasian individuals with RA-ILD, ABA in monotherapy or combined with MTX or with other conventional-DMARDs seems to be equally effective and safe. However, a CS-sparing effect is only observed with combined ABA. [ABSTRACT FROM AUTHOR]

Abstract: Recombinant severe acute respiratory virus (SARS-CoV) variants lacking the group specific genes 6, 7a, 7b, 8a, 8b and 9b (rSARS-CoV-Δ[6–9b]), the structural gene E (rSARS-CoV-ΔE), and a combination of both sets of genes (rSARS-CoV-Δ[E,6–9b]) have been generated. All these viruses were rescued in monkey (Vero E6) cells and were also infectious for human (Huh-7, Huh7.5.1 and CaCo-2) cell lines and for transgenic (Tg) mice expressing the SARS-CoV receptor human angiotensin converting enzyme-2 (hACE-2), indicating that none of these proteins is essential for the viral cycle. Furthermore, in Vero E6 cells, all the viruses showed the formation of particles with the same morphology as the wt virus, indicating that these proteins do not have a high impact in the final morphology of the virions. Nevertheless, in the absence of E protein, release of virus particles efficacy was reduced. Viruses lacking E protein grew about 100-fold lower than the wt virus in lungs of Tg infected mice but did not grow in the brains of the same animals, in contrast to the rSARS-CoV-Δ[6–9b] virus, which grew almost as well as the wt in both tissues. Viruses lacking E protein were highly attenuated in the highly sensitive hACE-2 Tg mice, in contrast to the minimal rSARS-CoV-Δ[6–9b] and wt viruses. These data indicate that E gene might be a virulence factor influencing replication level, tissue tropism and pathogenicity of SARS-CoV, suggesting that ΔE attenuated viruses are promising vaccine candidates. [Copyright &y& Elsevier]

Background: Irinotecan is a common cytotoxic agent used in advanced colorectal cancers. However, a major clinical problem with this cytotoxic is that it causes gastrointestinal mucositis manifest by severe diarrhoea. To date there is no established single dose of irinotecan in rats to enable determination of changes occurring following administration. Therefore, the primary aim of this study was to determine a single dose of irinotecan that induced reproducible gastrointestinal mucositis in DA rats. The secondary aim was to determine if the presence of tumour altered the development of mucositis. Methods: Eighty-eight rats were divided into two groups, 44 received tumours and 44 remained tumour naïve. These were randomized to receive a single dose of irinotecan at 150, 200, 250 or 300 mg/kg. Two control groups of rats received either no treatment or 2 doses of 150 mg/kg irinotecan, shown previously to induce reproducible gastrointestinal mucositis. Rats were monitored closely for incidence and severity of diarrhoea, and mortality, before being killed 48 and 144 h following treatment. Results: Rats administered 250 and 300 mg/kg of irinotecan all developed diarrhoea, and this was associated with high mortality rates (up to 100%). Necropsies revealed that many of these rats had duodenal perforations and fatty lysis consistent with peritonitis. The lower doses of 150 and 200 mg/kg irinotecan also caused diarrhoea, but were not associated with high mortality rates. Histopathological examination confirmed small and large intestinal damage in all rats that received irinotecan, regardless of dose. Tumour-bearing rats had worse diarrhoea and higher mortality compared to tumour-naïve rats. Conclusions: We find that a single dose of 200 mg/kg irinotecan causes reproducible gastrointestinal mucositis as measured by levels of diarrhoea, and small and large intestinal histology. Importantly this dose has a low mortality. The response to irinotecan is more pronounced in tumour-bearing rats. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Available data involve neurotrophins and their receptors in carcinomas. Quantitative evaluation of these molecules in these tumors might be useful as prognostic marker and eventual treatments. Our study on 40 mammary tumors tries to correlate expression of these molecules and prognosis. Immunohistochemistry for NGF, BDNF, NT3, TrkA, TrkB, TrkC, and p75 was used. Patient's age, histopathology, Bloom-Richardson grading, estrogen and progesterone receptors, Ki-67 index, HER-2, p53 were evaluated. Statistics found inverse relationship between grading and TrkC expression. We found significantly higher TrkC expression in Grade I than in Grade III tumors. Rise in TrkC expression could indicate good prognosis. [ABSTRACT FROM AUTHOR]

Marigold flowers are the main natural source of xanthophylls, and marigold saponified extract is used as an additive in several food and pharmaceutical industries. In this work, the use of a solid-state fermentation (ensilage) process for increasing the yield of xanthophylls extracted from fermented marigold flowers was examined. The process consisted of a mixed culture of three microorganisms (Flavobacterium IIb,Acinetobacter anitratus, andRhizopus nigricans), part of the normal microbiota associated with the marigold flower. These microorganisms had been previously isolated, and were identified as relevant for the ensilage process due to their capacity to produce cellulolytic enzymes. Based on experimental design strategies, optimum operation values were determined for aeration, moisture, agitation, and marigold-to-inoculum ratio in the proposed solid-state fermentation equipment, leading to a xanthophylls yield of 17.8-g/kg dry weight. The optimum achieved represents a 65% increase with respect to the control. HPLC analysis indicated conservation of extracted oleoresin. Based on the experimental results, interactions were identified that could be associated with the heat and mass-transfer reactions taking place within the bioreactor. The insight gained allows conditions that limit growth and metabolic activity to be avoided. [ABSTRACT FROM AUTHOR]

Background: The biomechanical mechanisms underlying stair climbing limitations are poorly understood in people with multiple sclerosis (MS).Research Questions: Are trunk and pelvis motion and lower extremity joint moments during step ascent different between MS and control groups? Are step ascent biomechanics and stair climbing performance associated in people with MS?Methods: 20 people with MS (49 ± 12 years, EDSS range: 1.5-5.5) and ten control participants (48 ± 12 years) underwent three-dimensional motion analysis while ascending a 15.2-cm step and also completed a timed Functional Stair Test. Main effects of group (MS vs Control) and limb (Stronger/Dominant vs Weaker/Non-dominant) and interactions were assessed using two-way analyses of variance. Associations between movement patterns during the step ascent and Functional Stair Test performance were performed using Pearson's correlations and backward stepwise linear regression.Results: Significant group main effects were observed in greater sagittal pelvis excursion (p < 0.001), greater sagittal (p = 0.013) and frontal (p = 0.001) trunk excursion, and lower trail limb peak ankle plantar flexion moment (p < 0.001) of the MS group. Significant limb main effects were observed with greater sagittal trunk excursion (p = 0.037) and peak trail limb ankle plantar flexion moment (p = 0.037) in the stronger/dominant limb. A significant interaction was observed in peak knee extensor moment (p = .002). Stair climbing performance in the MS group correlated with sagittal (r = .607, p=<0.001) and frontal pelvis excursions (r = 0.385, p = 0.014), sagittal trunk excursion (r = .411, p = 0.008), and ankle plantar flexion moments (r=-0.415, p = 0.008). Sagittal and frontal pelvis excursion and bilateral handrail use explained a significant amount of variability in stair climbing performance (Adj R2 = 0.775).Significance: In conclusion, despite the presence of proximal and distal lower extremity movement pattern compensations during a step ascent task, larger pelvis angular excursions are associated with impaired stair climbing performance in people with MS and may serve as targets for future rehabilitation interventions. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is highly responsive to neoadjuvant polychemotherapy regimens including anthracyclines, taxanes, and, more recently, carboplatin. However, there is inadequate information on the individual contribution of each of these agents to the global activity of the combinations, and the use of combinations of up to four of these drugs is associated with relevant toxicity. Identifying single-drug activity in the clinical neoadjuvant setting is challenging. We developed patient-derived xenografts (PDXs) from several chemotherapy-naïve TNBC samples to assess the antitumor activity of single drugs and combinations of drugs. PDXs were established from chemotherapy-naïve TNBC samples. Nine TNBC PDX models (all of which corresponded to a basal-like phenotype according to the PAM50 classifier) were treated with carboplatin, docetaxel, and doxorubicin and the combination of docetaxel and carboplatin. Only one of nine PDX models showed sensitivity to doxorubicin, while eight of nine PDX models showed sensitivity to docetaxel and carboplatin as single agents. The 3 PDX models derived from patients with gBRCA-1 or gPALB2 mutations were very sensitive to carboplatin single agent. All 6 PDX models from patients without hereditary germ-line mutations showed increased sensitivity to the combination of docetaxel and carboplatin. In the present study, docetaxel and carboplatin single agents were active drugs against basal-like TNBC, while doxorubicin monotherapy showed low activity. The combination of docetaxel and carboplatin was more effective than the drugs used as single agents, except in the PDX from patients with gBRCA1/PALB2 mutations. [ABSTRACT FROM AUTHOR]

We recently reported that multiple sclerosis (MS) plasma contains IgG aggregates and induces complement-dependent neuronal cytotoxicity (Zhou et al., 2023). Using ELISA, we report herein that plasma IgG levels in the aggregates can be used as biomarkers for MS. We enriched the IgG aggregates from samples of two cohorts (190 MS and 160 controls) by collecting flow-through after plasma binding to Protein A followed by detection of IgG subclass. We show that there are significantly higher levels of IgG1, IgG3, and total IgG antibodies in MS IgG aggregates, with an AUC >90%; higher levels of IgG1 distinguish secondary progressive MS from relapsing-remitting MS (AUC = 91%). Significantly, we provided the biological rationale for MS plasma IgG biomarkers by demonstrating the strong correlation between IgG antibodies and IgG aggregate-induced neuronal cytotoxicity. These non-invasive, simple IgG-based blood ELISA assays can be adapted into clinical practice for diagnosing MS and SPMS and monitoring treatment responses. • Enriched the IgG aggregates by collecting flow-through after plasma binding to Protein A (A-FT). • Significantly higher levels of IgG1, IgG3, and total IgG antibodies in MS plasma A-FT. • Higher plasma IgG1 can distinguish secondary progressive MS (SPMS) from relapsing-remitting MS (RRMS). • Strong correlation between IgG antibodies and IgG-induced neuronal cytotoxicity. • Provided evidence for a noninvasive blood-based IgG biomarker for MS. [ABSTRACT FROM AUTHOR]

Introduction: Studies investigating rates and risk factors for serious safety events (SSEs) during rituximab treatment of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and related disorders are limited. Methods: Rituximab‐treated patients with MS, NMOSD, or related disorders at the Rocky Mountain and New York University MS Care Centers were included. The follow‐up period was defined as the time from the initial dose of rituximab up to 12 months of last dose of rituximab or ocrelizumab (in patients who switched). Clinician‐reported and laboratory data were retrospectively collected from electronic medical records. Results: One‐thousand patients were included comprising 907 MS, 77 NMOSD, and 16 related disorders. Patients had a mean follow‐up of 31.1 months and a mean cumulative rituximab dose of 4012 mg. Of the 169 patients who switched to ocrelizumab, the mean ocrelizumab dose was 1141 mg. Crude incidence rate per 1000 person‐years (PY) for lymphopenia was 19.2, neutropenia 5.6, and hypogammaglobulinemia 17.8. Infections resulting in either hospitalization, IV antibiotics, or using antibiotics ≥14 days occurred at a rate of 38.6/1000 PY. Risk factors for infection were duration of therapy, male gender, increased disability, prior exposure to immunosuppression/chemotherapy, lymphopenia, and hypogammaglobulinemia. Particularly, wheelchair‐bound patients had 8.56‐fold increased odds of infections. Crude incidence rates of malignant cancer were 3.5, new autoimmune disease 2.3, thromboembolic event 3.1, and mortality of 5.4 per 1000 PY. Interpretation: Rates of SSEs in patients with MS, NMOSD, and related disorders were low. Through properly assessing risk:benefit of B‐cell depleting therapy in neuroinflammatory disorders and continual monitoring, clinicians may decrease the risk of serious infections. [ABSTRACT FROM AUTHOR]