Neuromyelitis Optica spectrum disorders in Argentina: A hospital-based study.

BACKGROUND: Neuromyelitis Optica spectrum disorder (NMOSD) is an antibody-mediated autoimmune disease of the CNS, which especially affects the optic nerves and spinal cord. There is little known in Latin America (LATAM) about NMOSD, and few reports have been published in the literature so far. We aimed to describe an NMOSD study in a single center from Argentina. METHODS: A retrospective cross sectional study was carried out in a single reference center in the city of Buenos Aires, Argentina. Data were collected from January 2000 through December 2021 using medical records from patients attending Ramos Mejia Hospital in Buenos Aires, Argentina. Here we describe the clinical, laboratory, MRI, disability course, and treatment of 92 NMOSD patients. RESULTS: Mean age at the onset of symptoms was 31 years (range 2-68) with a female/male ratio of 4.8:1. 71.7 % had an early onset before the age of 50 years old, 8.7 % had a late onset of the disease and 19.6 % had an onset at pediatric age. The first symptom of NMOSD was optic neuritis in 47.8 % of the patients, followed by transverse myelitis, 33.7 % and area postrema syndrome, 5.4 %. 96.7 % of patients relapsed at least once during the follow-up period. The mean of the expanded disability status scale (EDSS) was 4.0 (range 2-8). 34,8 % had one or more associated autoimmune diseases. 78,6 % had a positive result for AQP4-IgG. The ratio of male to female was 1:8.4 vs.1:1.2 in the seropositive group vs. the seronegative. CSF results showed OCB type 2 in 6.3 %. The brain MRI did not show brain lesions in 71,7 % of the patients. 17 % presented spinal cord lesions with less than 3 vertebral segments. All patients received treatment with immunosuppressive drugs. Rituximab and azathioprine were the most used. CONCLUSIONS: This is the largest hospital-based study in an Argentina cross-sectional study of patients with NMOSD. Recurrent disease, early age at onset, female prevalence in AQP4-IgG+ patients, and the difficulty to assess new treatments, are the highlight features in our study of patients. Further Argentinian and LATAM studies will provide more information.

Secuelas cognitivas en encefalitis inmunomediadas: cohorte de pacientes en Argentina / Cognitive sequelae in immunomediated encephalitis: cohort of patients in Argentina

Resumen Introducción: Las encefalitis inmunomediadas son un desorden neurológico de origen autoinmune. Actual mente es escasa la descripción de las secuelas cognitivas crónicas. El objetivo del presente trabajo fue caracterizar la secuela cognitiva de diferentes tipos de encefalitis inmunomediadas en una cohorte de un centro único de Argentina. Métodos: Estudio prospectivo, observacional, trans versal, de pacientes en seguimiento en un hospital de la Ciudad de Buenos Aires, con diagnóstico de encefalitis inmunomediada probable y definitiva. Se evaluaron variables epidemiológicas, clínicas, paraclínicas y tra tamiento. Se determinó la secuela cognitiva a través de una evaluación neurocognitiva realizada a partir del año de la presentación clínica. Resultados: Fueron incluidos 15 pacientes, todos con resultado disminuido en al menos un test. La memoria fue el dominio más afectado. Aquellos que se encon traban bajo tratamiento inmunosupresor al momento de evaluarse presentaron menores resultados en el aprendizaje seriado (media -2.94; desvío estándar 1.54) versus los que se encontraban sin tratamiento (media -1.18; desvío estándar 1.40; p = 0.05) y en la prueba de reconocimiento (media -10.34; desvío estándar 8.02) ver sus sin tratamiento (media -1.39; desvío estándar 2.21; p = 0.003). Los pacientes con estatus epiléptico tuvieron resultados deficitarios en la prueba de reconocimiento (media -7.2; desvío estándar 7.91) en comparación a los que no lo tenían (media -1.47; desvío estándar 2.34; p = 0.05). Conclusión: Nuestros resultados demuestran que, a pesar del curso monofásico de la enfermedad, todos los pacientes presentan daño cognitivo persistente más allá del año del inicio del cuadro. Estudios prospectivos de mayor envergadura serían necesarios para confirmar nuestros hallazgos.

Abstract Introduction: Autoimmune encephalitis represents a group of immune-mediated neurological disorders. At present, the description of the chronic cognitive sequela is scarce. The objective of this study was to characterize the cognitive after effects of different types of autoimmune encephalitis in a cohort from a single center in Argentina. Methods: Prospective, observational, cross-sectional study of patients under follow-up at a hospital in Buenos Aires city, with a diagnosis of probable and definitive immune-mediated encephalitis. Epidemiological, clini cal, paraclinical and treatment related variables were evaluated. Cognitive sequela was determined through a neurocognitive evaluation performed at least a year after the clinical presentation. Results: Fifteen patients were included. All had di minished results in at least one test. Memory was the most affected domain. Patients who were under im munosuppressive treatment at the time of evaluation presented lower results in serial learning (mean -2.94; standard deviation 1.54) versus those who weren't under treatment (mean -1.18; standard deviation 1.40; p = 0.05). The same pattern was observed on the recognition test of treatment group (mean -10.34; standard deviation 8.02) versus treatment-free group (mean -1.39; standard deviation 2.21; p =0.003). Patients with status epilepticus had poorer results in the recognition test (mean -7.2; standard deviation 7.91) compared to those without it (mean -1.47; standard deviation 2.34; p = 0.05). Conclusion: Our results show that, despite the mo nophasic course of this disease, all patients had persis tent cognitive damage beyond the year of onset. Larger prospective studies are required to confirm our findings.

Evidence for spontaneous regulation of the humoral IgM anti-GM1 autoimmune response by IgG antibodies in multifocal motor neuropathy patients.

BACKGROUND AND AIMS: Multifocal motor neuropathy (MMN) is a peripheral nerve disorder characterized by slow progressive distal asymmetric weakness with minimal or no sensory impairment. Currently, a vast evidence supports a direct pathogenic role of IgM anti-GM1 antibodies on disease pathogenesis. Patients with MMN seropositive for GM1-specific IgM antibodies have significantly more weakness, disability and axon loss than patients without these antibodies. During the screening for IgM anti-GM1 antibodies in a cohort of patients with neuropathy we noticed an absence or significant reduction of natural IgM anti-GM1 autoreactivity in some patients with MMN, suggesting a mechanism of self-control of autoreactivity. We aim to understand the lack of natural reactivity against GM1 in MMN patients. METHODS: The presence of free IgM anti-GM1 reactivity or its complex to blocking IgG was analysed by combining high performance thin layer chromatography-immunostaining, soluble binding inhibition assays, Protein-G or GM1-affinity columns and dot blot assays. RESULTS: We identified in MMN patients an immunoregulation of IgM anti-GM1 antibodies mediated by IgG immunoglobulins characterized by: (i) lack of natural IgM anti-GM1 autoreactivity as a result of a immunoregulatory IgG-dependent mechanism; (ii) presence of natural and disease-associated IgM anti-GM1/IgG blocking Ab complexes in sera; and (iii) high levels of IgG blocking against natural IgM anti-GM1 antibodies (Abs. INTERPRETATION: Our observations unmask a spontaneous IgG-dependent mechanism of immunoregulation against IgM anti-GM1 antibodies that could explain, in part, fluctuations in the usually slowly progressive clinical course that characterizes the disease and, at the same time, allows the identification of an autoimmune response against GM1 ganglioside in seronegative patients.

[Cognitive sequelae in immunomediated encephalitis: cohort of patients in Argentina]. / Secuelas cognitivas en encefalitis inmunomediadas: cohorte de pacientes en Argentina.

INTRODUCTION: Autoimmune encephalitis represents a group of immune-mediated neurological disorders. At present, the description of the chronic cognitive sequela is scarce. The objective of this study was to characterize the cognitive after effects of different types of autoimmune encephalitis in a cohort from a single center in Argentina. METHODS: Prospective, observational, cross-sectional study of patients under follow-up at a hospital in Buenos Aires city, with a diagnosis of probable and definitive immune-mediated encephalitis. Epidemiological, clinical, paraclinical and treatment related variables were evaluated. Cognitive sequela was determined through a neurocognitive evaluation performed at least a year after the clinical presentation. RESULTS: Fifteen patients were included. All had diminished results in at least one test. Memory was the most affected domain. Patients who were under immunosuppressive treatment at the time of evaluation presented lower results in serial learning (mean -2.94; standard deviation 1.54) versus those who weren't under treatment (mean -1.18; standard deviation 1.40; p = 0.05). The same pattern was observed on the recognition test of treatment group (mean -10.34; standard deviation 8.02) versus treatment-free group (mean -1.39; standard deviation 2.21; p =0.003). Patients with status epilepticus had poorer results in the recognition test (mean -7.2; standard deviation 7.91) compared to those without it (mean -1.47; standard deviation 2.34; p = 0.05). CONCLUSION: Our results show that, despite the monophasic course of this disease, all patients had persistent cognitive damage beyond the year of onset. Larger prospective studies are required to confirm our findings.

Introducción: Las encefalitis inmunomediadas son un desorden neurológico de origen autoinmune. Actualmente es escasa la descripción de las secuelas cognitivas crónicas. El objetivo del presente trabajo fue caracterizar la secuela cognitiva de diferentes tipos de encefalitis inmunomediadas en una cohorte de un centro único de Argentina. Métodos: Estudio prospectivo, observacional, transversal, de pacientes en seguimiento en un hospital de la Ciudad de Buenos Aires, con diagnóstico de encefalitis inmunomediada probable y definitiva. Se evaluaron variables epidemiológicas, clínicas, paraclínicas y tratamiento. Se determinó la secuela cognitiva a través de una evaluación neurocognitiva realizada a partir del año de la presentación clínica. Resultados: Fueron incluidos 15 pacientes, todos con resultado disminuido en al menos un test. La memoria fue el dominio más afectado. Aquellos que se encontraban bajo tratamiento inmunosupresor al momento de evaluarse presentaron menores resultados en el aprendizaje seriado (media -2.94; desvío estándar 1.54) versus los que se encontraban sin tratamiento (media -1.18; desvío estándar 1.40; p = 0.05) y en la prueba de reconocimiento (media -10.34; desvío estándar 8.02) versus sin tratamiento (media -1.39; desvío estándar 2.21; p = 0.003). Los pacientes con estatus epiléptico tuvieron resultados deficitarios en la prueba de reconocimiento (media -7.2; desvío estándar 7.91) en comparación a los que no lo tenían (media -1.47; desvío estándar 2.34; p = 0.05). Conclusión: Nuestros resultados demuestran que, a pesar del curso monofásico de la enfermedad, todos los pacientes presentan daño cognitivo persistente más allá del año del inicio del cuadro. Estudios prospectivos de mayor envergadura serían necesarios para confirmar nuestros hallazgos.

C5a complement levels in clinical remission AQP4-IgG-positive NMO patients.

BACKGROUND: Neuromyelitis Optica Spectrum Disorders (NMOSD) is an antibody-mediated disorder of the Central Nervous System where a leading role of the complement system has been demonstrated. OBJECTIVE: To measure the levels of complement factors C3, C4 and C5a in serum and plasma of clinical remission patients with AQP4-IgG + NMOSD. METHODS: Twelve patients with NMOSD AQP4 + according to 2015 criteria from a General Hospital in Buenos Aires, Argentina, were included in the study, and 19 age- and sex-matched healthy volunteers as a control group (HC). AQP4 antibodies were measured in serum by CBA analysis. Fresh blood samples were centrifuged to obtain serum and plasma. C3, C4, and AQP4 antibodies were measured in the serum, whereas C5a was measured in the plasma, which was obtained using Futhan (BD FUT-175®, BD Biosciences, San Jose, CA, USA). RESULTS: The complement factors, C3, C4, and C5a were measured in all samples. The mean concentration of C3 was 130.7 mg/dl (SD 16.1 mg/dl), and the mean concentration of C4 was 21.6 mg/dl (SD 4.8 mg/dl); both values were within the normal reference range (C3: 84-193 mg/dl; C4: 20-40 mg/dl) and were not significantly different (p > 0.05) from the mean levels in healthy controls (C3: 116.9 mg/dl; C4: 21.9 mg/dl). When analyzing the mean plasma level of C5a, we found a statistically significant difference (p = 0.0444) between the mean concentration of C5a in NMOSD patients (43.1 ng/ml; SD 48.7 ng/ml) and the HC group (17.7 ng/ml; SD 16.7 ng/ ml). CONCLUSIONS: In conclusion, the present study demonstrates that plasma C5a may be interesting to investigate as a potential biomarker of disease activity in NMOSD, in a larger and prospective cohort.

Revealing the complexity of vampire bat rabies "spillover transmission".

BACKGROUND: The term virus 'spillover' embodies a highly complex phenomenon and is often used to refer to viral transmission from a primary reservoir host to a new, naïve yet susceptible and permissive host species. Spillover transmission can result in a virus becoming pathogenic, causing disease and death to the new host if successful infection and transmission takes place. MAIN TEXT: The scientific literature across diverse disciplines has used the terms virus spillover, spillover transmission, cross-species transmission, and host shift almost indistinctly to imply the complex process of establishment of a virus from an original host (source/donor) to a naïve host (recipient), which have close or distant taxonomic or evolutionary ties. Spillover transmission may result in unsuccessful onward transmission, if the virus dies off before propagation. Alternatively, successful viral establishment in the new host can occur if subsequent secondary transmission among individuals of the same novel species and among other sympatric susceptible species occurred. As such, virus spillover transmission is a common yet highly complex phenomenon that encompasses multiple subtle stages that can be deconstructed to be studied separately to better understand the drivers of disease emergence. Rabies virus (RABV) is a well-documented viral pathogen which still inflicts heavy impact on humans, companion animals, wildlife, and livestock throughout Latin America due substantial spatial temporal and ecological-natural and expansional-overlap with several virus reservoir hosts. Thereby, the rabies disease system represents a robust avenue through which the drivers and uncertainties surrounding spillover transmission can be unravel at its different subtle stages to better understand how they may be affected by coarse, medium, and fine scale variables. CONCLUSIONS: The continued study of viral spillover transmission necessitates the elucidation of its complexities to better assess the cross-scale impacts of ecological forces linked to the propensity of spillover success. Improving capacities to reconstruct and predict spillover transmission would prevent public health impacts on those most at risk populations across the globe.

Posterior Malleolar Fracture Assessment: An Independent Interobserver and Intraobserver Validation of Three Computed Tomography-Based Classifications.

BACKGROUND: Posterior malleolus fractures occur in up to 50% of all ankle fractures. Several classification systems exist for their characterization, especially under CT. However, those classifications do not report the level of agreement or do it incompletely. This study aims to independently assess three posterior malleolus fracture classifications (Haraguchi, Bartonícek/Rammelt, and Mason). METHODS: This study was designed according to the Guidelines for Reporting Reliability and Agreement Studies. Ninety-four CT scans of patients with ankle fractures that had posterior malleolus fractures were included. Posterior malleolus fractures were assessed by six evaluators (three attending foot and ankle surgeons and three orthopaedic surgery residents) according to Haraguchi, Bartonícek/Rammelt, and Mason classifications. All images were reassessed by the same evaluators in a random sequence 3 weeks later. The kappa (k) coefficient was used to determine the interobserver and intraobserver agreement. Statistical significance was established using P < 0.05 with a 95% confidence interval (CI). RESULTS: The interobserver agreement was moderate for Haraguchi, Bartonícek/Rammelt, and Mason classifications with a global k value of 0.52 (95% CI, 0.43 to 0.60), 0.53 (95% CI, 0.46 to 0.61), and 0.54 (95% CI, 0.47 to 0.62), respectively. The intraobserver agreement was substantial for Haraguchi, Bartonícek/Rammelt, and Mason classifications, with an overall k value of 0.70 (95% CI, 0.64 to 0.74), 0.73 (95% CI, 0.68 to 0.78), and 0.73 (95% CI, 0.69 to 0.78), respectively. Interobserver and intraobserver agreement among orthopaedic surgeons and residents had no significant difference. CONCLUSION: The current classifications for posterior malleolus fractures showed a substantial intraobserver agreement. Nevertheless, the interobserver agreement obtained was just moderate for all classifications, independent of the level of expertise of the evaluators.

Training Program for Orthopedic Residents in Forefoot Osteotomy Skills: Transference From a Simulator to a Cadaveric Surgical Scenario.

INTRODUCTION: An effective simulation program allows both the acquisition of surgical skills on the simulated model and the transfer of these skills to a surgical scenario. We designed a forefoot osteotomy training program and sought to determine the transferability to a cadaveric surgical scenario. METHODS: Eleven orthopedic residents and 2 foot and ankle surgeons were included. A foot simulator was used. All residents were instructed on the surgical techniques of Chevron, Akin, and triple Weil osteotomies. Eight junior residents (trainees) were enrolled in a supervised simulation program. Baseline assessment was performed on the simulator with the Objective Structured Assessment of Technical Skills (OSATS) and the Imperial College Surgical Assessment Device (ICSAD). After baseline, trainees completed a training program and had a final evaluation of proficiency on the simulator and on cadaveric specimens. Three senior residents with no simulated training (controls) and experts were assessed for comparison. RESULTS: All trainees improved from a baseline OSATS score of 11 points (9-20) to a final score of 35 points (33-35) in the simulator and 34 points (32-34) in the cadaveric specimen ( P < 0.01). Compared with baseline, the ICSAD results improved in path length (391 [205-544] to 131 [73-278] meters, P < 0.01) and number of movements (2756 [1258-3338] to 992 [478-1908], P < 0.01). The final OSATS and ICSAD scores did not differ from experts ( P = 0.1) and were significantly different from untrained residents ( P = 0.02). CONCLUSIONS: Simulated training of Chevron, Akin, and triple Weil osteotomies in orthopedic residents improved procedural proficiency, enabling successful skill transfer to a surgical scenario in cadavers. LEVEL OF EVIDENCE: II (Prospective Cohort Study).

A recombinant rabies vaccine that prevents viral shedding in rabid common vampire bats (Desmodus rotundus).

Vampire bat transmitted rabies (VBR) is a continuing burden to public health and agricultural sectors in Latin America, despite decades-long efforts to control the disease by culling bat populations. Culling has been shown to disperse bats, leading to an increased spread of rabies. Thus, non-lethal strategies to control VBR, such as vaccination, are desired. Here, we evaluated the safety and efficacy of a viral-vectored recombinant mosaic glycoprotein rabies vaccine candidate (RCN-MoG) in vampire bats (Desmodus rotundus) of unknown history of rabies exposure captured in México and transported to the United States. Vaccination with RCN-MoG was demonstrated to be safe, even in pregnant females, as no evidence of lesions or adverse effects were observed. We detected rabies neutralizing antibodies in 28% (8/29) of seronegative bats post-vaccination. Survival proportions of adult bats after rabies virus (RABV) challenge ranged from 55-100% and were not significantly different among treatments, pre- or post-vaccination serostatus, and route of vaccination, while eight pups (1-2.5 months of age) used as naïve controls all succumbed to challenge (P<0.0001). Importantly, we found that vaccination with RCN-MoG appeared to block viral shedding, even when infection proved lethal. Using real-time PCR, we did not detect RABV nucleic acid in the saliva samples of 9/10 vaccinated bats that succumbed to rabies after challenge (one was inconclusive). In contrast, RABV nucleic acid was detected in saliva samples from 71% of unvaccinated bats (10/14 sampled, plus one inconclusive) that died of the disease, including pups. Low seroconversion rates post-vaccination and high survival of non-vaccinated bats, perhaps due to earlier natural exposure, limited our conclusions regarding vaccine efficacy. However, our findings suggest a potential transmission-blocking effect of vaccination with RCN-MoG that could provide a promising strategy for controlling VBR in Latin America beyond longstanding culling programs.

Divergent Rabies Virus Variant of Probable Bat Origin in 2 Gray Foxes, New Mexico, USA.

In the Western Hemisphere, bat-associated rabies viruses (RABVs) have established independent transmission cycles in multiple mammal hosts, forming genetically distinct lineages. In New Mexico, USA, skunks, bats, and gray foxes are rabies reservoir hosts and represent a public health risk because of encounters with humans. During 2015 and 2019, two previously undescribed RABVs were detected in 2 gray foxes (Urocyon cinereoargenteus) in Lincoln County, New Mexico. Phylogenetic analysis of the nucleoprotein gene indicated that the isolates are a novel RABV variant. These 2 cases probably represent repeated spillover events from an unknown bat reservoir to gray foxes. Molecular analysis of rabies cases across New Mexico identified that other cross-species transmission events were the result of viral variants previously known to be enzootic to New Mexico. Despite a robust rabies public health surveillance system in the United States, advances in testing and surveillance techniques continue to identify previously unrecognized zoonotic pathogens.

Self-Care of Chronic Illness Inventory: An Initial Psychometric Evaluation in People Living With HIV in Italy.

ABSTRACT: Self-care is essential to achieve positive clinical outcomes in patients with chronic diseases; however, self-care behaviors of people living with HIV (PLWH) have not been extensively studied due to the lack of validated measurements. We performed preliminary psychometric analyses of the structural validity and internal consistency of the Self-Care of Chronic Illness Inventory among 108 PLWH living in Italy and assessed self-care levels. Our findings largely replicate the instrument's original factor structure and indicated high internal consistency and reliability. Additionally, we found that PLWH performed self-care behaviors at suboptimal levels. Recommendations for clinical care and future investigations are advanced.

The Importance of Accurate Host Species Identification in the Framework of Rabies Surveillance, Control and Elimination.

Accurate host identification is paramount to understand disease epidemiology and to apply appropriate control measures. This is especially important for multi-host pathogens such as the rabies virus, a major and almost invariably fatal zoonosis that has mobilized unanimous engagement at an international level towards the final goal of zero human deaths due to canine rabies. Currently, diagnostic laboratories implement a standardized identification using taxonomic keys. However, this method is challenged by high and undiscovered biodiversity, decomposition of carcasses and subjective misevaluation, as has been attested to by findings from a cohort of 242 archived specimens collected across Sub-Saharan Africa and submitted for rabies diagnosis. We applied two simple and cheap methods targeting the Cytochrome b and Cytochrome c oxidase subunit I to confirm the initial classification. We therefore suggest prioritizing a standardized protocol that includes, as a first step, the implementation of taxonomic keys at a family or subfamily level, followed by the molecular characterization of the host species.

Acute optic neuritis: What do complementary tests add to diagnosis?

INTRODUCTION: Optic neuritis (ON) is the inflammation of the optic nerve due in many cases, to a pathological immune response. Since its symptoms can be subtle, diagnosis is sometimes challenging. The value of complementary tests for diagnosis and prognosis of ON was demonstrated in retrospective analysis, but their utility in the acute period of ON has been scarcely studied. The aim of this study is to determine the usefulness of clinical assessment, optical coherence tomography (OCT), visual evoked potentials (VEP) and orbit magnetic resonance imaging (MRI) for making diagnosis and prognosis of acute ON (AON). MATERIALS AND METHODS: A cross-sectional study was conducted including patients with ON within 90 days of symptom onset. A complete neuro-ophthalmological evaluation, OCT, VEP and MRI were carried out, determining in each case its sensitivity, specificity and predictive values in the diagnosis of ON and the assessment of its severity. RESULTS: 75 eyes of 34 patients with ON were included. Regarding diagnosis, low contrast visual acuity (LCVA) displayed the highest sensitivity (100%), being superior than the sensitivity of all complementary tools, always below 80%. Orbit MRI abnormal findings has a Specificity of 100% to confirm diagnosis. Regarding severity assessment and prognosis, Ganglion cell +inner plexiform layer (GCIP) thickness, but not retinal nerve fibre layer (RNFL), correlates significantly with patients' visual acuity (VA) (p < 0.05). Furthermore, both P100latency and VEP's amplitude showed to be significantly associated with VA (p < 0.05) in the acute period. The combination of two predictors (measurement of RNFL and GCIP) are capable of explaining 60% of the variation of the patient's visual acuity, with statistical significance (p = 0.02) CONCLUSIONS: In depth neuro-ophthalmological assessment during the acute phase of ON, including contrast sensitivity measurement, proved to be superior to complementary tests for diagnosis, surpassing the performance of OCT and VEP. However, these tools can add to prognosis, as GCIP thickness and VEP's amplitude correlate with disease severity and its findings could encourage prompt aggressive treatments in AON.

Severe Acute Respiratory Syndrome Coronavirus 2 Transmission in a Georgia School District-United States, December 2020-January 2021.

BACKGROUND: To inform prevention strategies, we assessed the extent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and settings in which transmission occurred in a Georgia public school district. METHODS: During 1 December 2020-22 January 2021, SARS-CoV-2-infected index cases and their close contacts in schools were identified by school and public health officials. For in-school contacts, we assessed symptoms and offered SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) testing; performed epidemiologic investigations and whole-genome sequencing to identify in-school transmission; and calculated secondary attack rate (SAR) by school setting (eg, sports, elementary school classroom), index case role (ie, staff, student), and index case symptomatic status. RESULTS: We identified 86 index cases and 1119 contacts, 688 (61.5%) of whom received testing. Fifty-nine of 679 (8.7%) contacts tested positive; 15 of 86 (17.4%) index cases resulted in ≥2 positive contacts. Among 55 persons testing positive with available symptom data, 31 (56.4%) were asymptomatic. Highest SARs were in indoor, high-contact sports settings (23.8% [95% confidence interval {CI}, 12.7%-33.3%]), staff meetings/lunches (18.2% [95% CI, 4.5%-31.8%]), and elementary school classrooms (9.5% [95% CI, 6.5%-12.5%]). The SAR was higher for staff (13.1% [95% CI, 9.0%-17.2%]) vs student index cases (5.8% [95% CI, 3.6%-8.0%]) and for symptomatic (10.9% [95% CI, 8.1%-13.9%]) vs asymptomatic index cases (3.0% [95% CI, 1.0%-5.5%]). CONCLUSIONS: Indoor sports may pose a risk to the safe operation of in-person learning. Preventing infection in staff members, through measures that include coronavirus disease 2019 vaccination, is critical to reducing in-school transmission. Because many positive contacts were asymptomatic, contact tracing should be paired with testing, regardless of symptoms.

The Case of an Agricultural Crop Business Association in Navarra as Circular Economy Intermediary.

The circular economy (CE) is an alternative economic system based on closing energy and material cycles to achieve sustainable development and create value based on innovation. In this sense, business associations (BAs) can work as intermediaries to promote CE in industrial sectors. They bring together many companies, generate trust-based relationships, support companies' strategy and collaborative innovation to construct closed-loop material flows, and increase competitiveness in sectors and regions. This study aims to show the BA's role as intermediaries of CE and promoters of industrial symbiosis (IS) as a value creation strategy among its affiliated companies (AC). Thus, this work takes the form of an exploratory case study of five different companies of the Union of Agricultural Cooperatives of Navarra (UCAN) in Spain. Researchers collected this study's data through a focus group and surveys. As a result, an original serious game was developed in 2016 and a survey in 2016 and 2020, which considers the CE's six fields of action (take, make, manufacture, distribution, use, recovery, and IS). Finally, this study proposes a methodology to promote the CE through the BAs, based on the performance of the UCAN as an intermediary of the CE and IS. Likewise, BAs' potential to promote the closure of energy and materials cycles in regions and commercial sectors such as agribusiness is demonstrated. The study also demonstrated the organizations' evolution and the improved perception of economic benefits and reduced barriers to implementing CE. This long-term analysis is valuable in novel topics such as CE.

Acting centrally or peripherally: A renewed interest in the central nervous system penetration of disease-modifying drugs in multiple sclerosis.

With the recent approval of cladribine tablets, siponimod and ozanimod, there has been a renewed interest into the extent to which these current generation disease-modifying therapies (DMTs) are able to cross into the central nervous system (CNS), and how this penetration of the blood-brain barrier (BBB) may influence their ability to treat multiple sclerosis (MS). The integrity of the CNS is maintained by the BBB, blood-cerebrospinal fluid barrier, and the arachnoid barrier, which all play an important role in preserving the immunological environment and homeostasis within the CNS. The integrity of the BBB decreases during the course of MS, with a putative temporal relationship to disease worsening. Furthermore, it is currently considered that progression of the disease is mediated mainly by resident cells of the CNS. The existing literature provides evidence to show that some of the current generation DMTs for MS are able to penetrate the CNS and potentially exert direct effects on CNS-resident cells, in particular the CNS-penetrating prodrugs cladribine and fingolimod, and other sphingosine-1 phosphate receptor modulators; siponimod and ozanimod. Other current generation DMTs appear to be restricted to the periphery due to their high molecular weight or physicochemical properties. As more effective brain penetrant therapies are developed for the treatment of MS, there is a need to understand whether the potential for direct effects within the CNS are of significance, and whether this brings additional benefits over and above treatment effects mediated in the periphery. In turn, this will require an improved understanding of the structure and function of the BBB, the role it plays in MS and subsequent treatments. This narrative review summarizes the data supporting the biological plausibility of a potential benefit from therapeutic molecules entering the CNS, and discusses the potential significance in the current and future treatment of MS.

Status of the neuromyelitis optica spectrum disorder in Latin America.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) is an increasing diagnostic and therapeutic challenge in Latin America (LATAM). Despite the heterogeneity of this population, ethnic and socioeconomic commonalities exist, and epidemiologic studies from the region have had a limited geographic and population outreach. Identification of some aspects from the entire region are lacking. OBJECTIVES: To determine ethnic, clinical characteristics, and utilization of diagnostic tools and types of therapy for patients with NMOSD in the entire Latin American region. METHODS: The Latin American Committee for Treatment and Research in MS (LACTRIMS) created an exploratory investigational survey addressed by Invitation to NMOSD Latin American experts identified through diverse sources. Data input closed after 30 days from the initial invitation. The questionnaire allowed use of absolute numbers or percentages. Multiple option responses covering 25 themes included definition of type of practice; number of NMOSD cases; ethnicity; utilization of the 2015 International Panel criteria for the diagnosis of Neuromyelitis optica (IPDN); clinical phenotypes; methodology utilized for determination of anti-Aquaporin-4 (anti- AQP4) antibodies serological testing, and if this was performed locally or processed abroad; treatment of relapses, and long-term management were surveyed. RESULTS: We identified 62 investigators from 21 countries reporting information from 2154 patients (utilizing the IPDN criteria in 93.9% of cases), which were categorized in two geographical regions: North-Central, including the Caribbean (NCC), and South America (SA). Ethnic identification disclosed Mestizos 61.4% as the main group. The most common presenting symptoms were concomitant presence of optic neuritis and transverse myelitis in 31.8% (p=0.95); only optic neuritis in 31.4% (more common in SA), p<0.001); involvement of the area postrema occurred in 21.5% and brain stem in 8.3%, both were more frequent in the South American cases (p<0.001). Anti-AQP4 antibodies were positive in 63.9% and anti-Myelin Oligodendrocyte Glycoprotein (MOG) antibodies in 4.8% of total cases. The specific laboratorial method employed was not known by 23.8% of the investigators. Acute relapses were identified in 81.6% of cases, and were treated in 93.9% of them with intravenous steroids (IVS); 62.1% with plasma exchange (PE), and 40.9% with intravenous immunoglobulin-G (IVIG). Therapy was escalated in some cases due to suboptimal initial response. Respondents favored Rituximab as long-term therapy (86.3%), whereas azathioprine was also utilized on 81.8% of the cases, either agent used indistinctly by the investigators according to treatment accessibility or clinical judgement. There were no differences among the geographic regions. CONCLUSIONS: This is the first study including all countries of LATAM and the largest cohort reported from a multinational specific world area. Ethnic distributions and phenotypic features of the disease in the region, challenges in access to diagnostic tools and therapy were identified. The Latin American neurological community should play a determinant role encouraging and advising local institutions and health officials in the availability of more sensitive and modern diagnostic methodology, in facilitating the the access to licensed medications for NMOSD, and addressing concerns on education, diagnosis and management of the disease in the community.

Use of partial N-gene sequences as a tool to monitor progress on rabies control and elimination efforts in Ethiopia.

Ethiopia is one of the African countries most affected by rabies. A coarse catalog of rabies viruses (RABV) was created as a benchmark to assess the impact of control and elimination activities. We evaluated a 726 bp amplicon at the end of the N-gene to infer viral lineages in circulation using maximum likelihood and Bayesian methods for phylogenetic reconstruction. We sequenced 228 brain samples from wild and domestic animals collected in five Ethiopian regions during 2010-2017. Results identified co-circulating RABV lineages that are causing recurrent spillover infections into wildlife and domestic animals. We found no evidence of importation of RABVs from other African countries or vaccine-induced cases in the area studied. A divergent RABV lineage might be involved in an independent rabies cycle in jackals. This investigation provides a feasible approach to assess rabies control and elimination efforts in resource-limited countries.

Low Vitamin D Serum Levels in a Cohort of Myasthenia Gravis Patients in Argentina.

There are limited and controversial studies that address the role of vitamin D (vitD), a vitamin with immunomodulatory effects, in myasthenia gravis (MG), a neuromuscular autoimmune disease. We aimed to assess 25-hydroxy vitamin D (25(OH)D) levels and to evaluate possible associations with the clinical severity and other biomarkers of the disease. Serum levels of 25(OH)D, anti-acetylcholine receptor antibodies and complement factor C5a were measured in MG patients (n = 66) and healthy volunteers (HV) (n = 25). Participants were evaluated through questionnaires to determine vitD intake and sunlight exposure. Severity scores were registered for MG patients. We found an 89.4% of MG individuals with nonsufficient levels of vitD, in comparison with 68.0% in the group of HV (OR = 3.96; P = 0.024). In addition, there was an inverse correlation between 25(OH)D levels and one of the scores (P = 0.037 r = -0.26, CI95  = -0.49 to -0.0087). However, when we compared 25(OH)D median serum levels between MG patients and HV, no statistically significant differences have been found. This is the first report of vitD status in a cohort of Argentinean MG patients, where we found that patients are more likely to have nonsufficient levels of vitD compared to healthy people and that patients with more severe disease have lower levels of vitD.