Associations between social connections and cognition: a global collaborative individual participant data meta-analysis.

BACKGROUND: Poor social connections (eg, small networks, infrequent interactions, and loneliness) are modifiable risk factors for cognitive decline. Existing meta-analyses are limited by reporting aggregate responses, a focus on global cognition, and combining social measures into single constructs. We aimed to investigate the association between social connection markers and the rate of annual change in cognition (ie, global and domain-specific), as well as sex differences, using an individual participant data meta-analysis. METHODS: We harmonised data from 13 longitudinal cohort studies of ageing in North America, South America, Europe, Africa, Asia, and Australia. Studies were eligible for inclusion if they had baseline data for social connection markers and at least two waves of cognitive scores. Follow-up periods ranged from 0 years to 15 years across cohorts. We included participants with cognitive data for at least two waves and social connection data for at least one wave. We then identified and excluded people with dementia at baseline. Primary outcomes were annual rates of change in global cognition and cognitive domain scores over time until final follow-up within each cohort study analysed by use of an individual participant data meta-analysis. Linear mixed models within cohorts used baseline social connection markers as predictors of the primary outcomes. Effects were pooled in two stages using random-effects meta-analyses. We assessed the primary outcomes in the main (partially adjusted) and fully adjusted models. Partially adjusted models controlled for age, sex, and education; fully adjusted models additionally controlled for diabetes, hypertension, smoking, cardiovascular risk, and depression. FINDINGS: Of the 40 006 participants in the 13 cohort studies, we excluded 1392 people with dementia at baseline. 38 614 individual participants were included in our analyses. For the main models, being in a relationship or married predicted slower global cognitive decline (b=0·010, 95% CI 0·000-0·019) than did being single or never married; living with others predicted slower global cognitive (b=0·007, 0·002-0·012), memory (b=0·017, 0·006-0·028), and language (b=0·008, 0·000-0·015) decline than did living alone; and weekly interactions with family and friends (b=0·016, 0·006-0·026) and weekly community group engagement (b=0·030, 0·007-0·052) predicted slower memory decline than did no interactions and no engagement. Never feeling lonely predicted slower global cognitive (b=0·047, 95% CI 0·018-0·075) and executive function (b=0·047, 0·017-0·077) decline than did often feeling lonely. Degree of social support, having a confidante, and relationship satisfaction did not predict cognitive decline across global cognition or cognitive domains. Heterogeneity was low (I2=0·00-15·11%) for all but two of the significant findings (association between slower memory decline and living with others [I2=58·33%] and community group engagement, I2=37·54-72·19%), suggesting robust results across studies. INTERPRETATION: Good social connections (ie, living with others, weekly community group engagement, interacting weekly with family and friends, and never feeling lonely) are associated with slower cognitive decline. FUNDING: EU Joint Programme-Neurodegenerative Disease Research grant, funded by the National Health and Medical Research Council Australia, and the US National Institute on Aging of the US National Institutes of Health.

Scoping review of health outcomes for people with disabilities in user-led organisations.

A user-led organisation (ULO) may be defined as an organisation that is run and controlled by the people who use the services provided by that organisation. ULOs provide services to their members, such as information, advice, support, treatment and training. ULOs may also be involved in advocacy, influencing local service provision, government policy and public perceptions of disability. This scoping review concentrated on health outcomes achieved by ULOs for people with disabilities, including physical, sensory, cognitive, intellectual, neurological or mental health impairments. Based on a search of the academic literature up to 30 June 2020, 26 articles were included. Twenty-four articles were on ULOs for mood disorders, schizophrenia or psychosis, and there was one article each on ULOs for cross-disability and chronic non-malignant pain. There was some evidence that peer-run and inclusive ULOs for members with mood disorders, schizophrenia or psychosis can reduce the number of times people with these illnesses access traditional mental health services. There was no evidence that ULOs can replace traditional mental health services. Therefore, ULOs for mood disorders, schizophrenia or psychosis could be considered an adjunct to traditional mental health services, not a replacement. For other disabilities, a lack of evidence means that no recommendation can be made. However, the organisational structure of ULOs may be as important as the support and services offered.

Correlates of deep brain stimulation consensus conference decision to treat primary dystonia.

BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for motor disturbance in people with primary dystonia (PWD). Numerous factors are considered by an interdisciplinary consensus conference before deciding candidacy for DBS surgery (e.g., demographic, medical, cognitive, and behavioral factors). However, little is known about which of these factors are associated with PWD DBS surgery consensus conference decisions. OBJECTIVE: Our goal was to examine whether pre-operative demographic, medical, and cognitive/behavioral variables are associated DBS consensus conference decisions in patients with dystonia. METHODS: Thirty-two PWD completed comprehensive presurgery workup included neurological and neuropsychological exams, and neuroimaging in consideration for DBS surgery. An interdisciplinary conference committee either recommended or did not recommend DBS surgery based upon these data. Demographic and medical data (e.g., dystonia disease characteristics, medical comorbidities, medications) were also collected. We also examined impact from cardiovascular disease factors, using a Revised Cardiac Risk Index. PWD were grouped based on DBS conference decision (eligible: n = 21, ineligible: n = 11) and compared across demographic, medical, and cognitive/behavioral variables. RESULTS: Across clinical variables, PWD who were deemed ineligible for DBS surgery had a higher Revised Cardiac Risk Index. PWD who were classified as ineligible displayed lower global cognitive functioning, working memory, phonemic fluency, memory retrieval, and cognitive flexibility. CONCLUSIONS: Consensus decision making regarding DBS surgery eligibility involves a multifactorial process. We found that deficits in executive functioning were associated with the DBS consensus committee decision. We also observed elevated cardiac risk among these individuals, likely reflecting the relation between vascular health and cognition. Implications, and clinical and scientific applications of these findings are discussed.

An examination of the neurocognitive profile and base rate of performance impairment in primary dystonia.

BACKGROUND: Primary dystonia has been traditionally viewed as a motor disorder. However, non-motor symptoms are frequently present and significantly quality of life. Neuropsychiatric and cognitive symptoms have been identified, but prior studies have been limited in sample size and lack of control groups. This study examined the neurocognitive profile of a sample of persons with primary dystonia (PWD) as compared to demographically matched healthy control group. METHODS: A cognitive test battery was administered to 25 PWD who presented for pre-surgical candidacy evaluation for deep brain stimulation surgery. The test battery domains included global cognitive function, attention, expressive language, visuospatial skills, memory, and executive functioning. Twenty-five age, gender, education-matched healthy control participants were compared to the PWD. RESULTS: Compared to demographically matched healthy controls, PWD performed worse on measures of global cognitive function, attention, memory, and conceptualization. Based on normative comparison, a large portion of PWD were impaired on tasks of executive functioning and expressive language. Over 80% of the PWD showed impairment on at least one neurocognitive measure and over 60% showed impairment on 3 or more tests. CONCLUSIONS: Neurocognitive deficits were prevalent among our PWD sample. These impairments were present across a broad range of cognitive domains. Given the degree of cognitive impairment found in this study, our results have implications for health care providers with providing interventions to PWD.

Myomaker and Myomerger Work Independently to Control Distinct Steps of Membrane Remodeling during Myoblast Fusion.

Classic mechanisms for membrane fusion involve transmembrane proteins that assemble into complexes and dynamically alter their conformation to bend membranes, leading to mixing of membrane lipids (hemifusion) and fusion pore formation. Myomaker and Myomerger govern myoblast fusion and muscle formation but are structurally divergent from traditional fusogenic proteins. Here, we show that Myomaker and Myomerger independently mediate distinct steps in the fusion pathway, where Myomaker is involved in membrane hemifusion and Myomerger is necessary for fusion pore formation. Mechanistically, we demonstrate that Myomerger is required on the cell surface where its ectodomains stress membranes. Moreover, we show that Myomerger drives fusion completion in a heterologous system independent of Myomaker and that a Myomaker-Myomerger physical interaction is not required for function. Collectively, our data identify a stepwise cell fusion mechanism in myoblasts where different proteins are delegated to perform unique membrane functions essential for membrane coalescence.

Meta-analysis of cognitive performance in fibromyalgia.

INTRODUCTION: Fibromyalgia is a condition with symptoms of pain, physical function difficulties, and emotional problems, but is also characterized by complaints of poor cognition (often called "FibroFog"). Over the last two decades, a number of studies have examined cognitive differences between individuals with and without fibromyalgia. The purpose of the current study was to conduct a quantitative synthesis of these differences across multiple cognitive domains. METHOD: Following Cochrane guidelines, we identified 37 eligible studies for analysis where persons with fibromyalgia (total n = 964) were compared to participants from age-matched control groups without fibromyalgia (total n = 1025) on a range of neuropsychological measures. Group differences between persons with fibromyalgia and healthy controls were examined for cognitive domains including processing speed, long- and short-term memory, and executive functions (inhibitory control, set shifting, updating, and accessing). Random-effect meta-analyses were conducted to determine effect sizes for these differences in cognitive performance. RESULTS: Fibromyalgia was significantly and negatively associated with performance on all domains of cognitive function. The largest effect size was found for inhibitory control (g = 0.61), followed by memory (g = 0.51 for short-term, 0.50 for long-term memory). The smallest cognitive difference between those with fibromyalgia and controls was for set shifting (g = 0.30). CONCLUSION: These findings support the hypothesis that the self-reported cognitive impact of fibromyalgia is also found in objective neuropsychological measures. Routine screening for cognitive dysfunction in those with fibromyalgia may be warranted in addition to assessment of the traditional fibromyalgia symptoms.

Effect of Frequency-Dependent Attenuation on Predicted Histotripsy Waveforms in Tissue-Mimicking Phantoms.

Tissue-mimicking phantoms are employed for the assessment of shocked histotripsy pulses in vitro. These broadband shock waves are critical for tissue ablation and are influenced by the frequency-dependent attenuation of the medium. The density, sound speed and attenuation spectra (2-25 MHz) were measured for phantoms that mimic key histotripsy targets. The influence of non-linear propagation relative to the attenuation was described in terms of Gol'dberg number. An expression was derived to estimate the bandwidth of shocked histotripsy pulses for power law-dependent attenuation. The expression is independent of the fundamental frequency of the histotripsy pulse for linear frequency-dependent attenuation.

Vitrification of a small number of spermatozoa in normozoospermic and severely oligozoospermic samples.

Despite broad utilization of sperm cryopreservation, little progress has been made to modify freezing protocols or to improve rates of sperm survival. Vitrification is an alternative method for freezing human spermatozoa without toxic permeable cryoprotectants (CPAs). The purpose of our study was to optimize the vitrification and post thaw recovery of a small number of spermatozoa using only nonpermeating CPAs in a closed straw system in normozoospermic and severely oligozoospermic samples. Individual motile spermatozoa (n = 295) were selected from semen samples of 15 normozoospermic and 10 severe oligozoospermia patients. Overall sperm recovery after vitrification was 80% (n = 236) with 80% (n = 189) viability and 41.5% (n = 98) retained post-warming motility. Two different loading techniques were compared to transfer selected spermatozoa into straws in preparation for vitrification: by spontaneous capillary action (CA) and with the aid of a polar body biopsy (PBB) pipette. There was evidence that the PBB loading technique increases the odds of spermatozoa recovery in both subsets (p = 0.01 and p = 0.04) in the normal and abnormal subsamples, respectively.

The impact of inflammation on cognitive function in older adults: implications for healthcare practice and research.

Accumulating evidence suggests that levels of inflammation, an immune response, increase with age throughout the body and the brain. The effects of inflammation on the brain, both acute and chronic, have been associated with cognitive decline and risk of dementia in older adults. Factors believed to increase inflammation include certain health-related behaviors, such as smoking, poor diet, and inactivity as well as health conditions like diabetes, hypertension, and chronic obstructive pulmonary disease, most of which require medical intervention and monitoring. As such, nurses and healthcare professionals are likely to encounter patients who are at a high risk for future development of inflammation-related cognitive decline. A review of inflammatory processes and their relation to cognitive function in older adults is provided, along with factors that may increase or reduce inflammation. Implications for practice and research are discussed.

Incident cognitive impairment is elevated in the stroke belt: the REGARDS study.

OBJECTIVE: To determine whether incidence of impaired cognitive screening status is higher in the southern Stroke Belt region of the United States than in the remaining United States. METHODS: A national cohort of adults age ≥45 years was recruited by the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study from 2003 to 2007. Participants' global cognitive status was assessed annually by telephone with the Six-Item Screener (SIS) and every 2 years with fluency and recall tasks. Participants who reported no stroke history and who were cognitively intact at enrollment (SIS >4 of 6) were included (N = 23,913, including 56% women; 38% African Americans and 62% European Americans; 56% Stroke Belt residents and 44% from the remaining contiguous United States and the District of Columbia). Regional differences in incident cognitive impairment (SIS score ≤4) were adjusted for age, sex, race, education, and time between first and last assessments. RESULTS: A total of 1,937 participants (8.1%) declined to an SIS score ≤4 at their most recent assessment, over a mean of 4.1 (±1.6) years. Residents of the Stroke Belt had greater adjusted odds of incident cognitive impairment than non-Belt residents (odds ratio, 1.18; 95% confidence interval, 1.07-1.30). All demographic factors and time independently predicted impairment. INTERPRETATION: Regional disparities in cognitive decline mirror regional disparities in stroke mortality, suggesting shared risk factors for these adverse outcomes. Efforts to promote cerebrovascular and cognitive health should be directed to the Stroke Belt.

Physical exercise at midlife and risk of dementia three decades later: a population-based study of Swedish twins.

BACKGROUND: With the number of people with dementia increasing, identifying potential protective factors has become more important. We explored the association between physical exercise at midlife and subsequent risk of dementia among members of the HARMONY study. METHODS: Measures of exercise were obtained by the Swedish Twin Registry an average of 31 years prior to dementia assessment. Dementia was diagnosed using a two-stage procedure--screening for cognitive impairment followed by full clinical evaluation. We used two study designs: case-control analyses included 264 cases with dementia (176 had Alzheimer's disease) and 2870 controls; co-twin control analyses included 90 twin pairs discordant for dementia. RESULTS: In case-control analyses, controlling for age, sex, education, diet (eating fruits and vegetables), smoking, drinking alcohol, body mass index, and angina, light exercise such as gardening or walking and regular exercise involving sports were associated with reduced odds of dementia compared to hardly any exercise (odds ratio [OR] = 0.63, 95% confidence interval [CI], 0.43-0.91 for light exercise; OR = 0.34, 95% CI, 0.16-0.72 for regular exercise). Findings were similar for Alzheimer's disease alone. In co-twin control analyses, controlling for education, the association between higher levels of exercise and lower odds of dementia approached significance (OR = 0.50, 95% CI, 0.23-1.06; p =.072). CONCLUSIONS: Exercise at midlife may reduce the odds of dementia in older adulthood, suggesting that exercise interventions should be explored as a potential strategy for delaying disease onset.

Do work-related stress and reactivity to stress predict dementia more than 30 years later?

The purpose of this study was to examine associations for work-related stress, reactivity to stress, and subsequent risk of dementia. The sample consisted of members of the population-based Swedish Twin Registry who were participants in the HARMONY study (n=2,049). We used case control and cotwin control designs, with information on work-related stress and reactivity to stress collected as part of a questionnaire completed in 1967. Dementia was diagnosed approximately 30 years later using a 2-stage procedure-screening for cognitive impairment followed by full clinical evaluation. We found that measures of work-related stress (job dissatisfaction and high job demands) were not associated with dementia risk. Greater reactivity to stress predicted higher risk of dementia controlling for age, education, sex, occupational status, alcohol use, and smoking status (odds ratio=1.57, 95% confidence interval 1.08-2.31). Cotwin control analyses also showed that dementia probands were more likely to report high reactivity to stress than their nondemented cotwins. We did not find evidence of an interaction between work stress and reactivity in predicting dementia. Overall, indicators of stress due to environment (ie, work) were not associated with dementia, whereas the individual characteristic of reactivity to stress predicted dementia risk.

Exploratory studies to investigate a linked prebiotic origin of RNA and coded peptides. 4th Communication. Further observations concerning pyrimidine nucleoside synthesis by stepwise nucleobase assembly.

As part of an ongoing investigation into a possible linked origin of RNA and coded peptides, we have (further) investigated the potentially prebiotic synthesis of pyrimidine ribonucleosides (ribonucleotides), by stepwise nucleobase assembly on sugar (sugar phosphate) scaffolds. In this paper, we complete our description of this assembly process on aldopentose scaffolds. Treatment of D-ribose (14) and D-xylose (20) with cyanamide smoothly produces the furanosylamino-oxazolines 15 and 21, respectively (Schemes 1 and 3). Similar treatment of D-lyxose (26) also produces the furanosylamino-oxazoline 29, but as a minor component of an equilibrating mixture in which the pyranosylamino-oxazoline 28 predominates (Scheme 4). Treatment of the various amino-oxazolines with cyanoacetylene gives furanosylcytidines 16, 25, and 31, and the lyxopyranosylcytidine 30 (Schemes 1-4). Minor by-products of the cyanoacetylene reaction include imino lactone 17, acetals 19, 22, and 24, and cyanovinyl adducts 22 and 23 resulting from initial addition of nucleoside OH groups to the terminal acetylenic C-atom of cyanoacetylene (Schemes 2-4).

Exploratory studies to investigate a linked prebiotic origin of RNA and coded peptides.

An introduction to the premise that RNA and genetically coded proteins should not be viewed as etiologically discrete entities in the origin of life is presented. This premise follows from the mutual interdependence of RNA and coded proteins in biology and the lack of prebiotically plausible constitutional self-assembly processes leading to either polymeric species. The RNA:coded peptides subsystem and its informational core, the genetic code, are then analysed retrosynthetically to suggest a (replicative) synthesis involving the intermediacy of aminoacyl-RNA trimers (cf. Scheme 5). A number of potential candidate aminoacyl-RNA trimers are identified (23-26; Scheme 6) and a chemical strategy to assess their validity is outlined. Experimental investigation of potential aminoacylation chemistry, nucleobase assembly and phosphate activation rules out three of the trimers but suggests that 26 is worthy of further investigation.