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Multiple sclerosis (MS) is characterized by focal inflammatory activity in the central nervous system and a diffuse, compartmentalized inflammation that is the primary driver of neuroaxonal damage and worsening disability. It is now recognized that higher-efficacy disease-modifying therapies (HE-DMT) are often required to treat the complex neuropathological changes that occur during the disease course and improve long-term outcomes. The optimal use of HE-DMTs in practice was addressed by a Canadian panel of 12 MS experts who used the Delphi method to develop 27 consensus recommendations. The HE-DMTs that were considered were the monoclonal antibodies (natalizumab, ocrelizumab, ofatumumab) and the immune reconstitution agents (alemtuzumab, cladribine). The issues addressed included defining aggressive/severe disease, patient selection of the most appropriate candidates for HE-DMTs, baseline investigations and efficacy monitoring, defining suboptimal treatment response, use of serum neurofilament-light chain in evaluating treatment response, safety monitoring, aging and immunosenescence and when to consider de-escalating or discontinuing treatment. The goals of the consensus recommendations were to provide guidelines to clinicians on their use of HE-DMTs in practice and to improve long-term outcomes in persons with MS.
In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety.
Methods:
A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites.
Results:
We performed 1,351 transfusions in 16 months. The transparency of the digital inventory at each site was critical to facilitate qualification, randomization, and overnight shipments of blood group-compatible plasma for transfusions into trial participants. While inventory challenges were heightened with COVID-19 convalescent plasma, the cloud-based system, and the flexible approach of the plasma coordination center staff across the blood bank network enabled decentralized procurement and distribution of investigational products to maintain inventory thresholds and overcome local supply chain restraints at the sites.
Conclusion:
The rapid creation of a plasma coordination center for outpatient transfusions is infrequent in the academic setting. Distributing more than 3,100 plasma units to blood banks charged with managing investigational inventory across the U.S. in a decentralized manner posed operational and regulatory challenges while providing opportunities for the plasma coordination center to contribute to research of global importance. This program can serve as a template in subsequent public health emergencies.
Understanding the factors contributing to optimal cognitive function throughout the aging process is essential to better understand successful cognitive aging. Processing speed is an age sensitive cognitive domain that usually declines early in the aging process; however, this cognitive skill is essential for other cognitive tasks and everyday functioning. Evaluating brain network interactions in cognitively healthy older adults can help us understand how brain characteristics variations affect cognitive functioning. Functional connections among groups of brain areas give insight into the brain’s organization, and the cognitive effects of aging may relate to this large-scale organization. To follow-up on our prior work, we sought to replicate our findings regarding network segregation’s relationship with processing speed. In order to address possible influences of node location or network membership we replicated the analysis across 4 different node sets.
Participants and Methods:
Data were acquired as part of a multi-center study of 85+ cognitively normal individuals, the McKnight Brain Aging Registry (MBAR). For this analysis, we included 146 community-dwelling, cognitively unimpaired older adults, ages 85-99, who had undergone structural and BOLD resting state MRI scans and a battery of neuropsychological tests. Exploratory factor analysis identified the processing speed factor of interest. We preprocessed BOLD scans using fmriprep, Ciftify, and XCPEngine algorithms. We used 4 different sets of connectivity-based parcellation: 1)MBAR data used to define nodes and Power (2011) atlas used to determine node network membership, 2) Younger adults data used to define nodes (Chan 2014) and Power (2011) atlas used to determine node network membership, 3) Older adults data from a different study (Han 2018) used to define nodes and Power (2011) atlas used to determine node network membership, and 4) MBAR data used to define nodes and MBAR data based community detection used to determine node network membership.
Segregation (balance of within-network and between-network connections) was measured within the association system and three wellcharacterized networks: Default Mode Network (DMN), Cingulo-Opercular Network (CON), and Fronto-Parietal Network (FPN). Correlation between processing speed and association system and networks was performed for all 4 node sets.
Results:
We replicated prior work and found the segregation of both the cortical association system, the segregation of FPN and DMN had a consistent relationship with processing speed across all node sets (association system range of correlations: r=.294 to .342, FPN: r=.254 to .272, DMN: r=.263 to .273). Additionally, compared to parcellations created with older adults, the parcellation created based on younger individuals showed attenuated and less robust findings as those with older adults (association system r=.263, FPN r=.255, DMN r=.263).
Conclusions:
This study shows that network segregation of the oldest-old brain is closely linked with processing speed and this relationship is replicable across different node sets created with varied datasets. This work adds to the growing body of knowledge about age-related dedifferentiation by demonstrating replicability and consistency of the finding that as essential cognitive skill, processing speed, is associated with differentiated functional networks even in very old individuals experiencing successful cognitive aging.
The association between sleep quality and cognition is widely established, but the role of aging in this relationship is largely unknown.
Objective:
To examine how age impacts the sleep–cognition relationship and determine whether there are sensitive ranges when the relationship between sleep and cognition is modified. This investigation could help identify individuals at risk for sleep-related cognitive impairment.
Subjects:
Sample included 711 individuals (ages 36.00–89.83, 59.66 ± 14.91, 55.7 % female) from the Human Connectome Project-Aging (HCP-A).
Methods:
The association between sleep quality (Pittsburgh Sleep Quality Index, PSQI) and cognition (Crystallized Cognition Composite and Fluid Cognition Composite from the NIH Toolbox, the Trail Making Test, TMT, and the Rey Auditory Verbal Learning Test, RAVLT) was measured using linear regression models, with sex, race, use of sleep medication, hypertension, and years of education as covariates. The interaction between sleep and age on cognition was tested using the moderation analysis, with age as both continuous linear and nonlinear (quadratic) terms.
Results:
There was a significant interaction term between the PSQI and nonlinear age term (age2) on TMT-B (p = 0.02) and NIH Toolbox crystallized cognition (p = 0.02), indicating that poor sleep quality was associated with worse performance on these measures (sensitive age ranges 50–75 years for TMT-B and 66–70 years for crystallized cognition).
Conclusions:
The sleep–cognition relationship may be modified by age. Individuals in the middle age to early older adulthood age band may be most vulnerable to sleep-related cognitive impairment.
Throughout the world, the Catholic Church has been in ferment since the Second Vatican Council. In Latin America, traditionally a Catholic region, the application of the council's ideas has stimulated dramatic changes in the outlook and practices of Church groups. These changes are particularly visible in the development of a new language for describing and evaluating temporal action (“the world”), and in the emergence of novel perspectives on the Church's proper relation to “the world.” What is the import of such changes for the student of politics?
Here, we revise Pietraszewski's model of groups by assigning participant pairs with two triplets, denoting: (1) the type of game that models the interaction, (2) its critical switching point between alternatives (i.e., the game's similarity threshold), and (3) the perception of strategic similarity with the opponent. These triplets provide a set of primitives that accounts for individuals' strategic motivations and observed behaviors.
To assess reasons for noncompliance with COVID-19 vaccination among healthcare workers (HCWs).
Design:
Cohort observational and surveillance study.
Setting:
Sheba Medical Center, a 1,600-bed tertiary-care medical center in Israel.
Participants:
The study included 10,888 HCWs including all employees, students, and volunteers.
Intervention:
The BNT162b2 mRNA COVID-19 vaccine was offered to all HCWs of the hospital. Noncompliance was assessed, and pre-rollout and post-rollout surveys were conducted. Data regarding uptake of the vaccine as well as demographic data and compliance with prior influenza vaccination were collected, and 2 surveys were distributed. The survey before the rollout pertained to the intention to receive the vaccine, and the survey after the rollout pertained to all unvaccinated HCWs regarding causes of hesitancy.
Results:
In the pre-rollout survey, 1,673 (47%) of 3,563 HCWs declared their intent to receive the vaccine. Overall, 8,108 (79%) HCWs received the COVID-19 vaccine within 40 days of rollout. In a multivariate logistic regression model, the factors that were significant predictors of vaccine uptake were male sex, age 40–59 years, occupation (paramedical professionals and doctors), high socioeconomic level, and compliance with flu vaccine. Among 425 unvaccinated HCWs who answered the second survey, the most common cause for hesitancy was the risk during pregnancy (31%).
Conclusions:
Although vaccine uptake among HCWs was higher than expected, relatively low uptake was observed among young women and those from lower socioeconomic levels and educational backgrounds. Concerns regarding vaccine safety during pregnancy were common and more data about vaccine safety, especially during pregnancy, might improve compliance.
Producing parallel narratives of the fall of Kaifeng in 1127 and the sack of Constantinople in 1204, Ye Mengde 葉夢得 (1077–1148) and Niketas Choniates (c.1155–1217) chronicled the collapse of these imperial centres in an effort to reconstruct post-conquest political communities in exile. While Ye and Niketas were deploying different conceptual frameworks of political authority and literary blueprints for memoirs, their writings documented personal displacement as well as cultural and political trauma writ large. By recording and commemorating the chain of events that culminated in the collapse of the Northern Song and Byzantine Empires, both authors were converting oral anecdotes into cultural memory. Ye and Niketas devised ex post facto explanations for the fall of Kaifeng and Constantinople as the consequence of the actions of failed monarchs and corrupt courtiers — and, to a lesser extent — the forces of divine punishment.
Keywords: Ye Mengde, Niketas Choniates, Kaifeng, Constantinople, imperial collapse, cultural memory
After Jurchen invaders from Inner Asia besieged and conquered Kaifeng in 1126–1127, and Constantinople fell to the Latin armies of the Fourth Crusade in 1204, political information about these courts and capitals was preserved and retransmitted by elite scholars, whose accounts of imperial collapse circulated amongst communities of diasporic literati. Producing parallel narratives of the fall of Kaifeng and the sack of Constantinople, Ye Mengde 葉夢得 (1077–1148) and Niketas Choniates (c.1155–1217) chronicled the collapse of these imperial centres in an effort to reconstruct post-conquest political communities. While Ye and Niketas were operating within separate conceptual frameworks of imperial authority and structuring their narratives according to different literary blueprints, their surviving memoirs documented personal displacement as well as cultural and political trauma writ large. By recording and commemorating the chain of events that culminated in the collapse of the Northern Song and Byzantine Empires from exile, both authors were converting orally transmitted anecdotes into enduring textual representations; in other words, they were transmuting communicative memory into cultural memory. Braiding dynastic history with personal recollection, their texts commemorated the breaching of imperial frontiers by ‘barbarian’ invaders, who had dislocated educated men like themselves into the hinterland, where dispersed networks of elites could be reconnected through the sharing of narratives about the recent dynastic past.
This chapter explores the effects of the Trump presidency in human rights foreign policy. Taking into account the mixed character of U.S. foreign policy in previous decades, it provides a measured account of how the populist rhetoric of “America First” was translated into concrete actions, initially under Secretary of State Rex Tillerson, and more intensely under National Security Adviser John Bolton and Secretary of State Mike Pompeo. The disorganization of the administration has left room for career officers to implement a relatively traditional human rights policy in some areas. The Trump administration has departed most significantly from past administrations in declining to embrace the core principles on which human rights policy is based. Its support of strongmen because of – not in spite of – their authoritarian qualities may leave its most distinct (and damaging) human rights legacy.
We prove in generic situations that the lattice in a tame type induced by the completed cohomology of a $U(3)$-arithmetic manifold is purely local, that is, only depends on the Galois representation at places above $p$. This is a generalization to $\text{GL}_{3}$ of the lattice conjecture of Breuil. In the process, we also prove the geometric Breuil–Mézard conjecture for (tamely) potentially crystalline deformation rings with Hodge–Tate weights $(2,1,0)$ as well as the Serre weight conjectures of Herzig [‘The weight in a Serre-type conjecture for tame $n$-dimensional Galois representations’, Duke Math. J.149(1) (2009), 37–116] over an unramified field extending the results of Le et al. [‘Potentially crystalline deformation 3985 rings and Serre weight conjectures: shapes and shadows’, Invent. Math.212(1) (2018), 1–107]. We also prove results in modular representation theory about lattices in Deligne–Lusztig representations for the group $\text{GL}_{3}(\mathbb{F}_{q})$.