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Background: Treatment of generalized myasthenia gravis (gMG) with reduced steroid dosages may minimize steroid-associated AEs. Corticosteroid dosage changes were not permitted during the 26-week, CHAMPION MG study of ravulizumab in adults with anti-acetylcholine receptor antibody-positive (AChRAb+) gMG. Participants who completed the study could receive ravulizumab in the open-label extension (OLE; NCT03920293); corticosteroid adjustments were permitted. Methods: Patients could receive intravenous ravulizumab (blind induction or bridging dose at Week 26 [OLE start] for those previously receiving placebo or ravulizumab, respectively, then 3000–3600 mg at Week 28 and every 8 weeks thereafter) for ≤4 years. Results: Among 161 patients (78 ravulizumab, 83 placebo) who entered the OLE and received ravulizumab for ≤164 weeks, 113 received oral or enteral corticosteroids during the OLE; the proportion treated with >10 mg/day corticosteroids decreased from 58% (n=66) at first OLE dose to 37% (n=42) (35 [31%] received ≤5 mg/day and 71 [63%] received ≤10 mg/day) at last reported dose. Fourteen patients (12%) discontinued corticosteroids. The mean (SD) corticosteroid dosage/patient decreased from 17.5 (11.9) mg/day at first OLE dose to 11.7 (10.9) mg/day at last assessment. Conclusions: Ravulizumab decreased corticosteroid use in patients with AChRAb+ gMG, suggesting a steroid-sparing role for ravulizumab.
The knowledge, skills, and abilities needed for clinical research professionals (CRPs) are described in the Joint Task Force (JTF) for Clinical Trial Competencies Framework as a basis for leveled educational programs, training curricula, and certification. There is a paucity of literature addressing team science competencies tailored to CRPs. Gaps in training, research, and education can restrict their capability to effectively contribute to team science.
Materials/Methods:
The CRP Team Science team consisted of 18 members from 7 clinical and translational science awarded institutions. We employed a multi-stage, modified Delphi approach to define “Smart Skills” and leveled team science skills examples using individual and team science competencies identified by Lotrecchiano et al.
Results:
Overall, 59 team science Smart Skills were identified resulting in 177 skills examples across three levels: fundamental, skilled, and advanced. Two examples of the leveled skillsets for individual and team competencies are illustrated. Two vignettes were created to illustrate application for training.
Discussion:
This work provides a first-ever application of team science for CRPs by defining specific individual and team science competencies for each level of the CRP career life course. This work will enhance the JTF Domains 7 (Leadership and Professionalism) and 8 (Communication and Teamwork) which are often lacking in CRP training programs. The supplement provides a full set of skills and examples from this work.
Conclusion:
Developing team science skills for CRPs may contribute to more effective collaborations across interdisciplinary clinical research teams. These skills may also improve research outcomes and stabilize the CRP workforce.
Little is known about the life cycle and mode of transmission of Dientamoeba fragilis. Recently it was suggested that fecal–oral transmission of cysts may play a role in the transmission of D. fragilis. In order to establish an infection, D. fragilis is required to remain viable when exposed to the pH of the stomach. In this study, we investigated the ability of cultured trophozoites to withstand the extremes of pH. We provide evidence that trophozoites of D. fragilis are vulnerable to highly acidic conditions. We also investigated further the ultrastructure of D. fragilis cysts obtained from mice and rats by transmission electron microscopy. These studies of cysts showed a clear cyst wall surrounding an encysted parasite. The cyst wall was double layered with an outer fibrillar layer and an inner layer enclosing the parasite. Hydrogenosomes, endoplasmic reticulum and nuclei were present in the cysts. Pelta-axostyle structures, costa and axonemes were identifiable and internal flagellar axonemes were present. This study therefore provides additional novel details and knowledge of the ultrastructure of the cyst stage of D. fragilis.
Hospital-treated self-harm is common, costly and associated with repeated self-harm and suicide. Providing a comprehensive psychosocial assessment following self-harm is recommended by professional bodies and may improve outcomes.
Aims
To review the provision of psychosocial assessments after hospital-presenting self-harm and the extent to which macro-level factors indicative of service provision explain variability in these estimates.
Method
We searched five electronic databases to 3 January 2023 for studies reporting data on the proportion of patients and/or events that were provided a psychosocial assessment. Pooled weighted prevalence estimates were calculated with the random-effects model. Random-effects meta-regression was used to investigate between-study variability.
Results
119 publications (69 unique samples) were included. Across ages, two-thirds of patients had a psychosocial assessment (0.67, 95% CI 0.58–0.76). The proportion was higher for young people and older adults (0.75, 95% CI 0.36–0.99 and 0.83, 95% CI 0.48–1.00, respectively) compared with adults (0.64, 95% CI 0.54–0.73). For events, around half of all presentations had these assessments across the age range. No macro-level factor explained between-study heterogeneity.
Conclusions
There is room for improvement in the universal provision of psychosocial assessments for self-harm. This represents a missed opportunity to review and tailor aftercare supports for those at risk. Given the marked unexplained heterogeneity between studies, the person- and system-level factors that influence provision of psychosocial assessments after self-harm should be studied further.
Cognitive training has shown promise for improving cognition in older adults. Aging involves a variety of neuroanatomical changes that may affect response to cognitive training. White matter hyperintensities (WMH) are one common age-related brain change, as evidenced by T2-weighted and Fluid Attenuated Inversion Recovery (FLAIR) MRI. WMH are associated with older age, suggestive of cerebral small vessel disease, and reflect decreased white matter integrity. Higher WMH load associates with reduced threshold for clinical expression of cognitive impairment and dementia. The effects of WMH on response to cognitive training interventions are relatively unknown. The current study assessed (a) proximal cognitive training performance following a 3-month randomized control trial and (b) the contribution of baseline whole-brain WMH load, defined as total lesion volume (TLV), on pre-post proximal training change.
Participants and Methods:
Sixty-two healthy older adults ages 65-84 completed either adaptive cognitive training (CT; n=31) or educational training control (ET; n=31) interventions. Participants assigned to CT completed 20 hours of attention/processing speed training and 20 hours of working memory training delivered through commercially-available Posit Science BrainHQ. ET participants completed 40 hours of educational videos. All participants also underwent sham or active transcranial direct current stimulation (tDCS) as an adjunctive intervention, although not a variable of interest in the current study. Multimodal MRI scans were acquired during the baseline visit. T1- and T2-weighted FLAIR images were processed using the Lesion Segmentation Tool (LST) for SPM12. The Lesion Prediction Algorithm of LST automatically segmented brain tissue and calculated lesion maps. A lesion threshold of 0.30 was applied to calculate TLV. A log transformation was applied to TLV to normalize the distribution of WMH. Repeated-measures analysis of covariance (RM-ANCOVA) assessed pre/post change in proximal composite (Total Training Composite) and sub-composite (Processing Speed Training Composite, Working Memory Training Composite) measures in the CT group compared to their ET counterparts, controlling for age, sex, years of education and tDCS group. Linear regression assessed the effect of TLV on post-intervention proximal composite and sub-composite, controlling for baseline performance, intervention assignment, age, sex, years of education, multisite scanner differences, estimated total intracranial volume, and binarized cardiovascular disease risk.
Results:
RM-ANCOVA revealed two-way group*time interactions such that those assigned cognitive training demonstrated greater improvement on proximal composite (Total Training Composite) and sub-composite (Processing Speed Training Composite, Working Memory Training Composite) measures compared to their ET counterparts. Multiple linear regression showed higher baseline TLV associated with lower pre-post change on Processing Speed Training sub-composite (ß = -0.19, p = 0.04) but not other composite measures.
Conclusions:
These findings demonstrate the utility of cognitive training for improving postintervention proximal performance in older adults. Additionally, pre-post proximal processing speed training change appear to be particularly sensitive to white matter hyperintensity load versus working memory training change. These data suggest that TLV may serve as an important factor for consideration when planning processing speed-based cognitive training interventions for remediation of cognitive decline in older adults.
Interventions using a cognitive training paradigm called the Useful Field of View (UFOV) task have shown to be efficacious in slowing cognitive decline. However, no studies have looked at the engagement of functional networks during UFOV task completion. The current study aimed to (a) assess if regions activated during the UFOV fMRI task were functionally connected and related to task performance (henceforth called the UFOV network), (b) compare connectivity of the UFOV network to 7 resting-state functional connectivity networks in predicting proximal (UFOV) and near-transfer (Double Decision) performance, and (c) explore the impact of network segregation between higher-order networks and UFOV performance.
Participants and Methods:
336 healthy older adults (mean age=71.6) completed the UFOV fMRI task in a Siemens 3T scanner. UFOV fMRI accuracy was calculated as the number of correct responses divided by 56 total trials. Double Decision performance was calculated as the average presentation time of correct responses in log ms, with lower scores equating to better processing speed. Structural and functional MRI images were processed using the default pre-processing pipeline within the CONN toolbox. The Artifact Rejection Toolbox was set at a motion threshold of 0.9mm and participants were excluded if more than 50% of volumes were flagged as outliers. To assess connectivity of regions associated with the UFOV task, we created 10 spherical regions of interest (ROIs) a priori using the WFU PickAtlas in SPM12. These include the bilateral pars triangularis, supplementary motor area, and inferior temporal gyri, as well as the left pars opercularis, left middle occipital gyrus, right precentral gyrus and right superior parietal lobule. We used a weighted ROI-to-ROI connectivity analysis to model task-based within-network functional connectivity of the UFOV network, and its relationship to UFOV accuracy. We then used weighted ROI-to-ROI connectivity analysis to compare the efficacy of the UFOV network versus 7 resting-state networks in predicting UFOV fMRI task performance and Double Decision performance. Finally, we calculated network segregation among higher order resting state networks to assess its relationship with UFOV accuracy. All functional connectivity analyses were corrected at a false discovery threshold (FDR) at p<0.05.
Results:
ROI-to-ROI analysis showed significant within-network functional connectivity among the 10 a priori ROIs (UFOV network) during task completion (all pFDR<.05). After controlling for covariates, greater within-network connectivity of the UFOV network associated with better UFOV fMRI performance (pFDR=.008). Regarding the 7 resting-state networks, greater within-network connectivity of the CON (pFDR<.001) and FPCN (pFDR=. 014) were associated with higher accuracy on the UFOV fMRI task. Furthermore, greater within-network connectivity of only the UFOV network associated with performance on the Double Decision task (pFDR=.034). Finally, we assessed the relationship between higher-order network segregation and UFOV accuracy. After controlling for covariates, no significant relationships between network segregation and UFOV performance remained (all p-uncorrected>0.05).
Conclusions:
To date, this is the first study to assess task-based functional connectivity during completion of the UFOV task. We observed that coherence within 10 a priori ROIs significantly predicted UFOV performance. Additionally, enhanced within-network connectivity of the UFOV network predicted better performance on the Double Decision task, while conventional resting-state networks did not. These findings provide potential targets to optimize efficacy of UFOV interventions.
Nonpathological aging has been linked to decline in both verbal and visuospatial memory abilities in older adults. Disruptions in resting-state functional connectivity within well-characterized, higherorder cognitive brain networks have also been coupled with poorer memory functioning in healthy older adults and in older adults with dementia. However, there is a paucity of research on the association between higherorder functional connectivity and verbal and visuospatial memory performance in the older adult population. The current study examines the association between resting-state functional connectivity within the cingulo-opercular network (CON), frontoparietal control network (FPCN), and default mode network (DMN) and verbal and visuospatial learning and memory in a large sample of healthy older adults. We hypothesized that greater within-network CON and FPCN functional connectivity would be associated with better immediate verbal and visuospatial memory recall. Additionally, we predicted that within-network DMN functional connectivity would be associated with improvements in delayed verbal and visuospatial memory recall. This study helps to glean insight into whether within-network CON, FPCN, or DMN functional connectivity is associated with verbal and visuospatial memory abilities in later life.
Participants and Methods:
330 healthy older adults between 65 and 89 years old (mean age = 71.6 ± 5.2) were recruited at the University of Florida (n = 222) and the University of Arizona (n = 108). Participants underwent resting-state fMRI and completed verbal memory (Hopkins Verbal Learning Test - Revised [HVLT-R]) and visuospatial memory (Brief Visuospatial Memory Test - Revised [BVMT-R]) measures. Immediate (total) and delayed recall scores on the HVLT-R and BVMT-R were calculated using each test manual’s scoring criteria. Learning ratios on the HVLT-R and BVMT-R were quantified by dividing the number of stimuli (verbal or visuospatial) learned between the first and third trials by the number of stimuli not recalled after the first learning trial. CONN Toolbox was used to extract average within-network connectivity values for CON, FPCN, and DMN. Hierarchical regressions were conducted, controlling for sex, race, ethnicity, years of education, number of invalid scans, and scanner site.
Results:
Greater CON connectivity was significantly associated with better HVLT-R immediate (total) recall (ß = 0.16, p = 0.01), HVLT-R learning ratio (ß = 0.16, p = 0.01), BVMT-R immediate (total) recall (ß = 0.14, p = 0.02), and BVMT-R delayed recall performance (ß = 0.15, p = 0.01). Greater FPCN connectivity was associated with better BVMT-R learning ratio (ß = 0.13, p = 0.04). HVLT-R delayed recall performance was not associated with connectivity in any network, and DMN connectivity was not significantly related to any measure.
Conclusions:
Connectivity within CON demonstrated a robust relationship with different components of memory function as well across verbal and visuospatial domains. In contrast, FPCN only evidenced a relationship with visuospatial learning, and DMN was not significantly associated with memory measures. These data suggest that CON may be a valuable target in longitudinal studies of age-related memory changes, but also a possible target in future non-invasive interventions to attenuate memory decline in older adults.
After Viceroy Don Luis de Velasco died in 1564, royal officials watched with trepidation as the conquistadores’ descendants adopted heraldry, hereditary titles, and royal ceremony, supposedly in jest. Scholars have argued that the royal judges used these over-the-top fiestas to frame powerful settlers for sedition. This article instead argues that the royal judges’ obsession with how wealthy settlers adopted royal pomp and circumstance, on the one hand, and refusal to recognize how they imprecisely imitated the Mexica nobility, on the other, helped to consolidate Spanish power—symbolic and literal—in New Spain.
In this chapter, we illustrate a wide variety of conditions affecting the bone marrow not described in other chapters of this book. These include inherited or acquired anemias, bone marrow failure syndromes not described in the germline disorders, therapy-related changes, metastatic malignancy, and storage disorders.
Myelodysplastic/myeloproliferative neoplasm (MDS/MPNs) constitute a group of clonal hematopoietic disorders with hybrid features; those of a myeloproliferative neoplasm (MPN) include bone marrow hypercellularity due to proliferation of one or more of the myeloid (as opposed to lymphoid) lineages with effective hematopoiesis, leading to a peripheral “cytosis” or “cytoses.” At the same time, these disorders show variable morphologic or functional dysplasia with ineffective hematopoiesis, resulting in cytopenia(s), findings more characteristic of myelodysplastic syndrome (MDS). The blast percentage is always less than 20, though sometimes transformation to acute myeloid leukemia (AML) occurs.
Two independent temporal-spatial clusters of hospital-onset Rhizopus infections were evaluated using whole-genome sequencing (WGS). Phylogenetic analysis confirmed that isolates within each cluster were unrelated despite epidemiological suspicion of outbreaks. The ITS1 region alone was insufficient for accurate analysis. WGS has utility for rapid rule-out of suspected nosocomial Rhizopus outbreaks.
High-quality evidence from prospective longitudinal studies in humans is essential to testing hypotheses related to the developmental origins of health and disease. In this paper, the authors draw upon their own experiences leading birth cohorts with longitudinal follow-up into adulthood to describe specific challenges and lessons learned. Challenges are substantial and grow over time. Long-term funding is essential for study operations and critical to retaining study staff, who develop relationships with participants and hold important institutional knowledge and technical skill sets. To maintain contact, we recommend that cohorts apply multiple strategies for tracking and obtain as much high-quality contact information as possible before the child’s 18th birthday. To maximize engagement, we suggest that cohorts offer flexibility in visit timing, length, location, frequency, and type. Data collection may entail multiple modalities, even at a single collection timepoint, including measures that are self-reported, research-measured, and administrative with a mix of remote and in-person collection. Many topics highly relevant for adolescent and young adult health and well-being are considered to be private in nature, and their assessment requires sensitivity. To motivate ongoing participation, cohorts must work to understand participant barriers and motivators, share scientific findings, and provide appropriate compensation for participation. It is essential for cohorts to strive for broad representation including individuals from higher risk populations, not only among the participants but also the staff. Successful longitudinal follow-up of a study population ultimately requires flexibility, adaptability, appropriate incentives, and opportunities for feedback from participants.
This chapter presents a comprehensive review of the interaction between circum-Caribbean indigenous peoples and nonhuman primates before and at early European contact. It fills significant gaps in contemporary scholarly literature by providing an updated archaeological history of the social and symbolic roles of monkeys in this region. We begin by describing the zooarchaeological record of primates in the insular and coastal circum-Caribbean Ceramic period archaeological sites. Drawing from the latest archaeological investigations that use novel methods and techniques, we also review other biological evidence of the presence of monkeys. In addition, we compile a list of indigenously crafted portable material imagery and review rock art that allegedly depicts primates in the Caribbean. Our investigation is supplemented by the inclusion of written documentary sources, specifically, ethnoprimatological information derived from early ethnohistorical sources on the multifarious interactions between humans and monkeys in early colonial societies. Finally, we illustrate certain patterns that may have characterized interactions between humans and monkeys in past societies of the circum-Caribbean region (300–1500 CE), opening avenues for future investigations of this topic.
Keywords:
Archaeoprimatology, Ceramic period, Greater and Lesser Antilles, Island and coastal archaeology, Saladoid, Taíno, Trinidad, Venezuela
We examined the possible sex and age differences in the proportion of experienced Coronavirus Disease 2019 (COVID-19) symptoms in unaware (previously) infected adults, and their uninfected counterparts, estimated by serostatus prior to vaccination, at the end of 2020 (Wuhan strain). A cross-sectional community-based study using a convenience sample of 10 001 adult inhabitants of a southern Dutch province, heavily affected by COVID-19, was conducted. Participants donated a blood sample to indicate past infection by serostatus (positive/negative). Experienced symptoms were assessed by questionnaire, before the availability of the serological test result. Only participants without confirmed SARS-CoV-2 infection were included (n = 9715, age range 18–90 years). The seroprevalence was comparable between men (17.3%) and women (18.0%), and participants aged 18–60 years (17.3%) and aged 60 years and older (18.6%). We showed sex and age differences in the proportion experienced symptoms by serostatus in a large cohort of both unaware (untested) seropositive compared with seronegative reference participants. Irritability only differed by serostatus in men (independent of age), while stomach ache, nausea and dizziness only differed by serostatus in women aged 60 years and older. Besides, the proportion of experiencing pain when breathing and headache differed by serostatus in men aged 18–60 years only. Our study highlights the importance of taking possible sex and age differences into account with respect to acute and long-term COVID-19 outcomes. Identifying symptom profiles for sex and age subgroups can contribute to timely identification of infection, gaining importance once governments currently move away from mass testing again.
It has been shown that there is disparity in access to long-term care and other services for minority populations. This study assessed long-term care access among older individuals belonging to minority populations including visible, ethnocultural, linguistic, and sexual minorities. Barriers and facilitators influencing admission were identified and evaluated.
A search for articles from 10 databases published between January 2000 and January 2021 was conducted. Included studies evaluated factors affecting minority populations’ admission to long-term care, and non-residents’ perceptions of future admission. This review was registered with PROSPERO: CRD42018038662. Sixty included quantitative and qualitative studies, ranging in quality from fair to excellent. Findings suggest minority status is associated with reduced admission to long-term care, controlling for confounding variables. Barriers identified include discordant language, fear of discrimination, lack of information, and family obligations. Findings suggest that minority populations experienced barriers accessing long-term care and had unmet cultural and language needs while receiving care in this setting.
We present the case of a 4-month-old, former 23-week premature baby who underwent patent ductus arteriosus device closure in the cardiac catheterisation lab with an Amplatzer Piccolo™ device at 12 weeks of life. This was complicated by late migration of the device into the aorta resulting in severe obstruction and requiring surgical intervention.
Dementia assessment includes cognitive and behavioral testing with informant verification. Conventional testing is resource-intensive, with uneven access. Online unsupervised assessments could reduce barriers to risk assessment. The aim of this study was to assess the relationship between informant-rated behavioral changes and participant-completed neuropsychological test performance in older adults, both measured remotely via an online unsupervised platform, the Brain Health Registry (BHR).
Design:
Observational cohort study.
Setting:
Community-dwelling older adults participating in the online BHR. Informant reports were obtained using the BHR Study Partner Portal.
Participants:
The final sample included 499 participant–informant dyads.
Measurements:
Participants completed online unsupervised neuropsychological assessment including Forward Memory Span, Reverse Memory Span, Trail Making B, and Go/No-Go tests. Informants completed the Mild Behavioral Impairment Checklist (MBI-C) via the BHR Study Partner portal. Cognitive performance was evaluated in MBI+/− individuals, as was the association between cognitive scores and MBI symptom severity.
Results:
Mean age of the 499 participants was 67, of which 308/499 were females (61%). MBI + status was associated with significantly lower memory and executive function test scores, measured using Forward and Reverse Memory Span, Trail Making Errors and Trail Making Speed. Further, significant associations were found between poorer objectively measured cognitive performance, in the domains of memory and executive function, and MBI symptom severity.
Conclusion:
These findings support the feasibility of remote, informant-reported behavioral assessment utilizing the MBI-C, supporting its validity by demonstrating a relationship to online unsupervised neuropsychological test performance, using a previously validated platform capable of assessing early dementia risk markers.