Cognitive and affective perspective-taking in conduct-disordered children high and low on callous-unemotional traits

<p>Abstract</p> <p>Background</p> <p>Deficits in cognitive and/or affective perspective-taking have been implicated in Conduct-Disorder (CD), but empirical investigations produced equivocal results. Two factors may be implicated: (a) distinct deficits underlying the antisocial conduct of CD subgroups, (b) plausible disjunction between cognitive and affective perspective-taking with subgroups presenting either cognitive or affective-specific deficits.</p> <p>Method</p> <p>This study employed a second-order false-belief paradigm in which the cognitive perspective-taking questions tapped the character's thoughts and the affective perspective-taking questions tapped the emotions generated by these thoughts. Affective and cognitive perspective-taking was compared across three groups of children: (a) CD elevated on Callous-Unemotional traits (<it>CD-high-CU</it>, <it>n </it>= 30), (b) CD low on CU traits (<it>CD-low-CU</it>, <it>n </it>= 42), and (c) a 'typically-developing' comparison group (<it>n </it>= 50), matched in age (7.5 – 10.8), gender and socioeconomic background.</p> <p>Results</p> <p>The results revealed deficits in <it>CD-low-CU </it>children for both affective and cognitive perspective-taking. In contrast <it>CD-high-CU </it>children showed relative competency in cognitive, but deficits in affective-perspective taking, a finding that suggests an affective-specific defect and a plausible dissociation of affective and cognitive perspective-taking in <it>CD-high-CU </it>children.</p> <p>Conclusion</p> <p>Present findings indicate that deficits in cognitive perspective-taking that have long been implicated in CD appear to be characteristic of a subset of CD children. In contrast affective perspective-taking deficits characterise both CD subgroups, but these defects seem to be following diverse developmental paths that warrant further investigation.</p

Study protocol for the recreational stimulation for elders as a vehicle to resolve delirium superimposed on dementia (Reserve For DSD) trial

<p>Abstract</p> <p>Background</p> <p>Delirium is a state of confusion characterized by an acute and fluctuating decline in cognitive functioning. Delirium is common and deadly in older adults with dementia, and is often referred to as delirium superimposed on dementia, or DSD. Interventions that treat DSD are not well-developed because the mechanisms involved in its etiology are not completely understood. We have developed a theory-based intervention for DSD that is derived from the literature on cognitive reserve and based on our prior interdisciplinary work on delirium, recreational activities, and cognitive stimulation in people with dementia. Our preliminary work indicate that use of simple, cognitively stimulating activities may help resolve delirium by helping to focus inattention, the primary neuropsychological deficit in delirium. Our primary aim in this trial is to test the efficacy of Recreational Stimulation for Elders as a Vehicle to resolve DSD (RESERVE- DSD).</p> <p>Methods/Design</p> <p>This randomized repeated measures clinical trial will involve participants being recruited and enrolled at the time of admission to post acute care. We will randomize 256 subjects to intervention (RESERVE-DSD) or control (usual care). Intervention subjects will receive 30-minute sessions of tailored cognitively stimulating recreational activities for up to 30 days. We hypothesize that subjects who receive RESERVE-DSD will have: decreased severity and duration of delirium; greater gains in attention, orientation, memory, abstract thinking, and executive functioning; and greater gains in physical function compared to subjects with DSD who receive usual care. We will also evaluate potential moderators of intervention efficacy (lifetime of complex mental activities and APOE status). Our secondary aim is to describe the costs associated with RESERVE-DSD.</p> <p>Discussion</p> <p>Our theory-based intervention, which uses simple, inexpensive recreational activities for delivering cognitive stimulation, is innovative because, to our knowledge it has not been tested as a treatment for DSD. This novel intervention for DSD builds on our prior delirium, recreational activity and cognitive stimulation research, and draws support from cognitive reserve theory.</p> <p>Trial registration</p> <p>ClinicalTrials.gov identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01267682">NCT01267682</a></p

Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors.

Arrival of the novel SARS-CoV-2 has launched a worldwide effort to identify both pre-approved and novel therapeutics targeting the viral proteome, highlighting the urgent need for efficient drug discovery strategies. Even with effective vaccines, infection is possible, and at-risk populations would benefit from effective drug compounds that reduce the lethality and lasting damage of COVID-19 infection. The CoV-2 MacroD-like macrodomain (Mac1) is implicated in viral pathogenicity by disrupting host innate immunity through its mono (ADP-ribosyl) hydrolase activity, making it a prime target for antiviral therapy. We therefore solved the structure of CoV-2 Mac1 from non-structural protein 3 (Nsp3) and applied structural and sequence-based genetic tracing, including newly determined A.&nbsp;pompejana MacroD2 and GDAP2 amino acid sequences, to compare and contrast CoV-2 Mac1 with the functionally related human DNA-damage signaling factor poly (ADP-ribose) glycohydrolase (PARG). Previously, identified targetable features of the PARG active site allowed us to develop a pharmacologically useful PARG inhibitor (PARGi). Here, we developed a focused chemical library and determined 6 novel PARGi X-ray crystal structures for comparative analysis. We applied this knowledge to discovery of CoV-2 Mac1 inhibitors by combining computation and structural analysis to identify PARGi fragments with potential to bind the distal-ribose and adenosyl pockets of the CoV-2 Mac1 active site. Scaffold development of these PARGi fragments has yielded two novel compounds, PARG-345 and PARG-329, that crystallize within the Mac1 active site, providing critical structure-activity data and a pathway for inhibitor optimization. The reported structural findings demonstrate ways to harness our PARGi synthesis and characterization pipeline to develop CoV-2 Mac1 inhibitors targeting the ADP-ribose active site. Together, these structural and computational analyses reveal a path for accelerating development of antiviral therapeutics from pre-existing drug optimization pipelines

Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors.

Arrival of the novel SARS-CoV-2 has launched a worldwide effort to identify both pre-approved and novel therapeutics targeting the viral proteome, highlighting the urgent need for efficient drug discovery strategies. Even with effective vaccines, infection is possible, and at-risk populations would benefit from effective drug compounds that reduce the lethality and lasting damage of COVID-19 infection. The CoV-2 MacroD-like macrodomain (Mac1) is implicated in viral pathogenicity by disrupting host innate immunity through its mono (ADP-ribosyl) hydrolase activity, making it a prime target for antiviral therapy. We therefore solved the structure of CoV-2 Mac1 from non-structural protein 3 (Nsp3) and applied structural and sequence-based genetic tracing, including newly determined A.&nbsp;pompejana MacroD2 and GDAP2 amino acid sequences, to compare and contrast CoV-2 Mac1 with the functionally related human DNA-damage signaling factor poly (ADP-ribose) glycohydrolase (PARG). Previously, identified targetable features of the PARG active site allowed us to develop a pharmacologically useful PARG inhibitor (PARGi). Here, we developed a focused chemical library and determined 6 novel PARGi X-ray crystal structures for comparative analysis. We applied this knowledge to discovery of CoV-2 Mac1 inhibitors by combining computation and structural analysis to identify PARGi fragments with potential to bind the distal-ribose and adenosyl pockets of the CoV-2 Mac1 active site. Scaffold development of these PARGi fragments has yielded two novel compounds, PARG-345 and PARG-329, that crystallize within the Mac1 active site, providing critical structure-activity data and a pathway for inhibitor optimization. The reported structural findings demonstrate ways to harness our PARGi synthesis and characterization pipeline to develop CoV-2 Mac1 inhibitors targeting the ADP-ribose active site. Together, these structural and computational analyses reveal a path for accelerating development of antiviral therapeutics from pre-existing drug optimization pipelines

Depressive Symptoms, Bone Loss, and Fractures in Postmenopausal Women

BackgroundOsteoporosis and depression may be associated through common physiologic systems or risk factors.ObjectiveTo assess the associations between depressive symptoms (Burnam's scale) or antidepressant use and bone outcomes.DesignProspective cohort study.ParticipantsA total of 93,676 postmenopausal women (50 to 79 years old) enrolled in the Women's Health Initiative Observational Study.MeasurementsSelf-reported fractures (n = 14,982) (hip [adjudicated], spine, wrist, and "other"). Analyses included 82,410 women with complete information followed on average for 7.4 years. Bone mineral density (BMD) of the hip (n = 4539), spine (n = 4417), and whole body (n = 4502) was measured at baseline and 3 years in women enrolled at 3 densitometry study sites.ResultsOverall, there were no statistically significant associations between depressive symptoms or antidepressant therapy and 3-year change in BMD. In a subset of women not using antidepressants, there was a significant difference in whole-body BMD change between women with and without depressive symptoms (P = .05). Depressive symptoms (hazard ratio [HR] 1.08; 95% CI = 1.02 to 1.14) and antidepressant therapy (HR = 1.22; CI = 1.15 to 1.30) independently increased risk of any fracture, the majority of which occurred at "other" anatomic sites. Antidepressant therapy increased the risk of spine fracture (HR = 1.36; CI = 1.14 to 1.63). No associations were observed between depressive symptoms or antidepressant therapy and hip or wrist fracture.ConclusionIn this study of postmenopausal women, average age 64, we observed minimal association between depressive symptoms and 3-year changes in either BMD or fracture risk. Antidepressant use was not associated with changes in BMD, but was associated with increased risk of fractures at the spine and "other " anatomic sites

Risk of COVID-19 after natural infection or vaccinationResearch in context

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health