Reliability of dynamic causal modelling of resting-state magnetoencephalography.

This study assesses the reliability of resting-state dynamic causal modelling (DCM) of magnetoencephalography (MEG) under conductance-based canonical microcircuit models, in terms of both posterior parameter estimates and model evidence. We use resting-state MEG data from two sessions, acquired 2 weeks apart, from a cohort with high between-subject variance arising from Alzheimer's disease. Our focus is not on the effect of disease, but on the reliability of the methods (as within-subject between-session agreement), which is crucial for future studies of disease progression and drug intervention. To assess the reliability of first-level DCMs, we compare model evidence associated with the covariance among subject-specific free energies (i.e., the 'quality' of the models) with versus without interclass correlations. We then used parametric empirical Bayes (PEB) to investigate the differences between the inferred DCM parameter probability distributions at the between subject level. Specifically, we examined the evidence for or against parameter differences (i) within-subject, within-session, and between-epochs; (ii) within-subject between-session; and (iii) within-site between-subjects, accommodating the conditional dependency among parameter estimates. We show that for data acquired close in time, and under similar circumstances, more than 95% of inferred DCM parameters are unlikely to differ, speaking to mutual predictability over sessions. Using PEB, we show a reciprocal relationship between a conventional definition of 'reliability' and the conditional dependency among inferred model parameters. Our analyses confirm the reliability and reproducibility of the conductance-based DCMs for resting-state neurophysiological data. In this respect, the implicit generative modelling is suitable for interventional and longitudinal studies of neurological and psychiatric disorders.

Sex-specific Long-term Outcomes of Watchman Left Atrial Appendage Closure for Stroke Prevention in Atrial Fibrillation.

Background: A recent analysis of a large registry showed differences in periprocedural outcomes of the Watchman left atrial appendage closure device in males compared with females. The objective of our study was to investigate the 5-year event rate in males and females enrolled in the Watchman device premarket clinical studies submitted for US Food and Drug Administration review. Methods: We conducted a patient-level meta-analysis of 2256 patients from 4 studies: the PROTECT AF (Embolic Protection in Patients with Atrial Fibrillation) and PREVAIL (Prospective Randomized Evaluation of the Watchman Left Atrial Appendage Closure Device in Patients with Atrial Fibrillation vs Long-Term Warfarin Therapy) randomized controlled trials and their continued-access registries-CAP1 (Continued Access to PROTECT AF) and CAP2 (Continued Access to PREVAIL). The outcomes evaluated were ischemic stroke (IS), IS/systemic embolism, hemorrhagic stroke (HS), and all-cause mortality. Mixed-effects Cox regression models and statistical testing for treatment-by-sex interaction were used to compare left atrial appendage closure vs warfarin in males and females. Hazard ratios adjusted (aHRs) for CHADS2 scores were generated using the same model with CHADS2 score as a covariate. Time-to-event end points were evaluated using the Kaplan-Meier method and log-rank test. Results: For Watchman vs warfarin in the 2 randomized controlled trials, there was no significant interaction between sex and treatment for IS, IS/systemic embolism, HS, and all-cause mortality (P > .05); both males and females in the Watchman group had a lower aHR for HS than that in the warfarin group, which was statistically significant for males (aHR, 0.163; 95% CI, 0.045-0.593). In addition, there were no differences in outcomes between females and males treated with the Watchman device when pooling all studies. Conclusions: These data suggest that sex does not significantly affect the long-term safety and effectiveness of the Watchman device in patients with nonvalvular atrial fibrillation; however, further studies are needed.

New Therapeutics in Alzheimer's Disease Longitudinal Cohort study (NTAD): study protocol.

INTRODUCTION: With the pressing need to develop treatments that slow or stop the progression of Alzheimer's disease, new tools are needed to reduce clinical trial duration and validate new targets for human therapeutics. Such tools could be derived from neurophysiological measurements of disease. METHODS AND ANALYSIS: The New Therapeutics in Alzheimer's Disease study (NTAD) aims to identify a biomarker set from magneto/electroencephalography that is sensitive to disease and progression over 1 year. The study will recruit 100 people with amyloid-positive mild cognitive impairment or early-stage Alzheimer's disease and 30 healthy controls aged between 50 and 85 years. Measurements of the clinical, cognitive and imaging data (magnetoencephalography, electroencephalography and MRI) of all participants will be taken at baseline. These measurements will be repeated after approximately 1 year on participants with Alzheimer's disease or mild cognitive impairment, and clinical and cognitive assessment of these participants will be repeated again after approximately 2 years. To assess reliability of magneto/electroencephalographic changes, a subset of 30 participants with mild cognitive impairment or early-stage Alzheimer's disease will also undergo repeat magneto/electroencephalography 2 weeks after baseline. Baseline and longitudinal changes in neurophysiology are the primary analyses of interest. Additional outputs will include atrophy and cognitive change and estimated numbers needed to treat each arm of simulated clinical trials of a future disease-modifying therapy. ETHICS AND DATA STATEMENT: The study has received a favourable opinion from the East of England Cambridge Central Research Ethics Committee (REC reference 18/EE/0042). Results will be disseminated through internal reports, peer-reviewed scientific journals, conference presentations, website publication, submission to regulatory authorities and other publications. Data will be made available via the Dementias Platform UK Data Portal on completion of initial analyses by the NTAD study group.

Comparing Longitudinal Sarcopenia Trends by Definitions Across Men and Women After Hip Fracture.

OBJECTIVES: While sarcopenia is prevalent after hip fracture in the acute postfracture period, little is known about the prevalence after discharge. This study assessed longitudinal trends in sarcopenia prevalence over 12 months after hip fracture using three different operational definitions. DESIGN: Prospective observational study. SETTING: Baltimore Hip Studies seventh cohort. PARTICIPANTS: A total of 82 men and 78 women, aged 65 years and older, with surgical repair of a nonpathological hip fracture. MEASUREMENTS: Baseline assessment included a dual-energy X-ray absorptiometry scan and interview. Follow-up assessments, which additionally included performance measures, occurred 2, 6, and 12 months after admission. Using these measures, three sarcopenia definitions were assessed over the year following hip fracture: European Working Group on Sarcopenia in Older Persons (EWGSOP), International Working Group on Sarcopenia (IWGS), and Foundation for the National Institutes of Health (FNIH). RESULTS: EWGSOP and IWGS provided the highest prevalence of sarcopenia (62%-69% in men, 42%-62% in women), while prevalence by FNIH was much lower for men (15%-19%) and women (5%-12%). For both men and women, the agreement between EWGSOP and IWGS definitions was excellent, and FNIH showed poor agreement with them, supported by various statistical measures across first-year follow-up. Prevalence was stable over time in men by all definitions, while the prevalence in women by FNIH was lowest at 2 months, significantly increased at 6 months (P = .03), and remained higher at 12 months. Whether sarcopenia prevalence differed significantly by sex varied by time point and definition; however, when different, men had a higher prevalence than women (P < .05). While some participants recovered from sarcopenia over time, some also became newly sarcopenic. CONCLUSION: The prevalence of sarcopenia after fracture differed greatly for EWGSOP and IWGS compared to FNIH. Overall, there appeared to be no reduction in sarcopenia over the year after hip fracture, regardless of definition. Future research should examine the relationship between sarcopenia prevalence and functional recovery. J Am Geriatr Soc 68:1537-1544, 2020.

Cerebral autoregulation in premature infants during the first 96 hours of life and relationship to adverse outcomes.

OBJECTIVE: To test the hypothesis that impaired cerebral autoregulation (ICA) increases the susceptibility of premature infants to adverse outcomes, we determined the relationship of ICA and cerebral reactivity (CR) measured in the first 96 hours of life to the outcome of grade 3 or 4 intraventricular haemorrhage (IVH) and/or death within 1 month. SETTING: Single-centre level IV neonatal intensive care unit. PATIENTS: Neonates 24-29 weeks' gestation less than 12 hours old with invasive blood pressure monitoring. DESIGN: Cerebral saturations and mean arterial blood pressure were recorded every 30 s for 96 hours. For each 10 min epoch, the correlation coefficient (r) was calculated for mean arterial blood pressure versus cerebral saturations. The epoch was considered to have ICA if r>0.5 and CR if r<0. RESULTS: Sixty-one subjects were included. During the first 96 hours, ICA occurred 17.6% and CR occurred 41% of recorded time. In those without adverse outcomes, ICA decreased and CR increased by postnatal day (p<0.05). Adjusted for birth weight and gestational age, those with IVH and those who died spent more time with ICA and less time with CR (p<0.05) over the entire recording period. Those with IVH had 1.5-fold increase in time with ICA on day 2 (p=0.021), and decrease in time with CR on day 3 (p=0.036). Compared with survivors, non-survivors spent more time with ICA on days 3 and 4 (p<0.005), and less with CR on day 3 (p=0.032). CONCLUSION: ICA and CR vary by postnatal day and these patterns are associated with adverse outcomes.

Sequestration-Mediated Downregulation of de Novo Purine Biosynthesis by AMPK.

Dynamic partitioning of de novo purine biosynthetic enzymes into multienzyme compartments, purinosomes, has been associated with increased flux of de novo purine biosynthesis in human cells. However, we do not know of a mechanism by which de novo purine biosynthesis would be downregulated in cells. We have investigated the functional role of AMP-activated protein kinase (AMPK) in the regulation of de novo purine biosynthesis because of its regulatory action on lipid and carbohydrate biosynthetic pathways. Using pharmacological AMPK activators, we have monitored subcellular localizations of six pathway enzymes tagged with green fluorescent proteins under time-lapse fluorescence single-cell microscopy. We revealed that only one out of six pathway enzymes, formylglycinamidine ribonucleotide synthase (FGAMS), formed spatially distinct cytoplasmic granules after treatment with AMPK activators, indicating the formation of single-enzyme self-assemblies. In addition, subsequent biophysical studies using fluorescence recovery after photobleaching showed that the diffusion kinetics of FGAMS were slower when it localized inside the self-assemblies than within the purinosomes. Importantly, high-performance liquid chromatographic studies revealed that the formation of AMPK-promoted FGAMS self-assembly caused the reduction of purine metabolites in HeLa cells, indicating the downregulation of de novo purine biosynthesis. Collectively, we demonstrate here that the spatial sequestration of FGAMS by AMPK is a mechanism by which de novo purine biosynthesis is downregulated in human cells.

[Cancer nursing care education programs: the effectiveness of different teaching methods].

BACKGROUND: In-service education affects the quality of cancer care directly. Using classroom teaching to deliver in-service education is often ineffective due to participants' large workload and shift requirements. PURPOSE: This study evaluated the learning effectiveness of different teaching methods in the dimensions of knowledge, attitude, and learning satisfaction. METHODS: This study used a quasi-experimental study design. Participants were cancer ward nurses working at one medical center in northern Taiwan. Participants were divided into an experimental group and control group. The experimental group took an e-learning course and the control group took a standard classroom course using the same basic course material. Researchers evaluated the learning efficacy of each group using a questionnaire based on the quality of cancer nursing care learning effectiveness scale. All participants answered the questionnaire once before and once after completing the course. RESULTS: (1) Post-test "knowledge" scores for both groups were significantly higher than pre-test scores for both groups. Post-test "attitude" scores were significantly higher for the control group, while the experimental group reported no significant change. (2) after a covariance analysis of the pre-test scores for both groups, the post-test score for the experimental group was significantly lower than the control group in the knowledge dimension. Post-test scores did not differ significantly from pre-test scores for either group in the attitude dimension. (3) Post-test satisfaction scores between the two groups did not differ significantly with regard to teaching methods. The e-learning method, however, was demonstrated as more flexible than the classroom teaching method. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Study results demonstrate the importance of employing a variety of teaching methods to instruct clinical nursing staff. We suggest that both classroom teaching and e-learning instruction methods be used to enhance the quality of cancer nursing care education programs. We also encourage that interactivity between student and instructor be incorporated into e-learning course designs to enhance effectiveness.