Safety, immunogenicity and efficacy of the self-amplifying mRNA ARCT-154 COVID-19 vaccine: pooled phase 1, 2, 3a and 3b randomized, controlled trials.

Combination of waning immunity and lower effectiveness against new SARS-CoV-2 variants of approved COVID-19 vaccines necessitates new vaccines. We evaluated two doses, 28 days apart, of ARCT-154, a self-amplifying mRNA COVID-19 vaccine, compared with saline placebo in an integrated phase 1/2/3a/3b controlled, observer-blind trial in Vietnamese adults (ClinicalTrial.gov identifier: NCT05012943). Primary safety and reactogenicity outcomes were unsolicited adverse events (AE) 28 days after each dose, solicited local and systemic AE 7 days after each dose, and serious AEs throughout the study. Primary immunogenicity outcome was the immune response as neutralizing antibodies 28 days after the second dose. Efficacy against COVID-19 was assessed as primary and secondary outcomes in phase 3b. ARCT-154 was well tolerated with generally mild-moderate transient AEs. Four weeks after the second dose 94.1% (95% CI: 92.1-95.8) of vaccinees seroconverted for neutralizing antibodies, with a geometric mean-fold rise from baseline of 14.5 (95% CI: 13.6-15.5). Of 640 cases of confirmed COVID-19 eligible for efficacy analysis most were due to the Delta (B.1.617.2) variant. Efficacy of ARCT-154 was 56.6% (95% CI: 48.7- 63.3) against any COVID-19, and 95.3% (80.5-98.9) against severe COVID-19. ARCT-154 vaccination is well tolerated, immunogenic and efficacious, particularly against severe COVID-19 disease.

Prognostic value of exercise longitudinal right ventricular free wall strain in patients with sickle cell disease.

Longitudinal right ventricular free wall strain (RVFWS) has been identified as an independent prognostic marker in patients with pulmonary hypertension. Little is known however about the prognostic value of RVFWS in patients with sickle cell (SC) disease, particularly during exercise. We therefore examined the prognostic significance of RVFWS both at rest and with exercise in patients with SC disease and normal resting systolic pulmonary artery pressure (SPAP). Consecutive patients with SC disease referred for bicycle ergometer stress echocardiography (SE) were enrolled ftom July 2019 to January 2021. All patients had measurable tricuspid regurgitation velocity (TRV). Conventional echocardiography parameters, left ventricular global longitudinal strain (LVGLS), RVFWS, and ventriculoarterial coupling indices (TAPSE/SPAP and RVFWS/SPAP) were assessed at rest and peak exercise. Repeat SE was performed at a median follow-up of 2 years. The cohort consisted of 87 patients (mean age was 31 ± 11 years, 66% females). All patients had normal resting TRV < 2.8 m/s, RVFWS and LVGLS at baseline. There were 23 (26%) patients who had peak stress RVFWS < 20%. They had higher resting and peak stress TRV and SPAP, but lower resting and peak stress TAPSE/SPAP, RVFWS/SPAP, and LVGLS as well as lower peak stress cardiac output when compared to patients with peak stress RVFWS ≥ 20% (p < 0.05). Patients with baseline peak stress RVFWS < 20% had a significant decrease in exercise performance at follow-up (7.5 ± 2.7 min at baseline vs. 5.5 ± 2.8 min at follow-up, p < 0.001). In the multivariate analysis, baseline peak stress RVFWS was the only independent predictor of poorer exercise performance at follow-up [odds ratio 8.2 (1.2, 56.0), p = 0.033]. Among patients with SC disease who underwent bicycle ergometer SE, a decreased baseline value of RVFWS at peak stress predicted poorer exercise time at follow-up.

Distinguishing four types of Person × Situation interactions: An integrative framework and empirical examination.

People differ in their reaction to situations, resulting in Person × Situation interactions. These interactions have been emphasized by many theoretical accounts of personality. Nevertheless, empirical progress on Person × Situation interactions has been slow. This is in part attributable to an insufficient distinction of person and situation variables and of different types of interaction effects. We propose a framework distinguishing four nested types of interaction effects varying in specificity: (a) P × S: broad Person × Situation interaction variance, (b) P × Sspec: between-person differences in situation variable-outcome associations, (c) Pspec × S: between-situation differences in person variable-outcome associations, and (d) Pspec × Sspec: specific Person Variable × Situation Variable interactions. We conducted two large online studies (N = 622 and N = 818) with standardized situation stimuli (N = 62 pictures and N = 62 first-person perspective videos) and assessed Big Five traits, DIAMONDS situation characteristics, and Big Five states. Using preregistered multilevel models, we systematically quantified the different interaction types. We found (a) large Person × Situation interaction variance in personality states, (b) sizable individual differences in situation characteristic-state contingencies, (c) consistent but smaller between-situation differences in trait-state associations, and (d) some significant but (very) small Personality Trait × Situation Characteristic interactions. Our findings highlight Person × Situation interactions as potentially important predictors of psychological states, although the explanation of these interactions through specific person variables remains difficult. Individual differences in the reaction to situations should be incorporated into our models of personality. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

In Situ Measurements of Dynamic Bacteria Transport and Attachment in Heterogeneous Sand-Packed Columns.

Prevention, mitigation, and regulation of bacterial contaminants in groundwater require a fundamental understanding of the mechanisms of transport and attachment in complex geological materials. Discrepancies in bacterial transport behaviors observed between field studies and laboratory experiments indicate an incomplete understanding of dynamic bacterial transport and immobilization processes in realistic heterogeneous geologic systems. Here, we develop a new experimental approach for in situ quantification of dynamic bacterial transport and attachment distribution in geologic media that relies on radiolabelingEscherichia coliwith positron-emitting radioisotopes and quantifying transport with three-dimensional (3D) positron emission tomography (PET) imaging. Our results indicate that the highest bacterial attachment occurred at the interfaces between sand layers oriented orthogonal to the direction of flow. The predicted bacterial attachment from a 3D numerical model matched the experimental PET results, highlighting that the experimentally observed bacterial transport behavior can be accurately captured with a distribution of a first-order irreversible attachment model. This is the first demonstration of the direct measurement of attachment coefficient distributions from bacterial transport experiments in geologic media and provides a transformational approach to better understand bacterial transport mechanisms, improve model parametrization, and accurately predict how local geologic conditions can influence bacterial fate and transport in groundwater.

Pharmacist-Led Interventions to Reduce Drug-Related Problems in Prescribing for Pediatric Outpatients in a Developing Country: A Randomized Controlled Trial.

OBJECTIVE: To evaluate a pharmacist-led intervention's effectiveness in reducing drug-related problems (DRPs ( related to prescriptions for pediatric outpatients. METHODS: We conducted a randomized controlled trial. We recruited and randomly assigned 31 physicians to control or intervention groups. We collected 775 prescriptions (375 from the control group and 400 from the intervention group) at the start. For 3 weeks, intervention physicians received additional information and meetings with pharmacists in addition to the usual practices of the hospital. We then collected prescriptions at the end of the study. We classified DRPs, based on reliable references (Supplemental Table S1) at baseline and endpoint (a week after the intervention). The primary outcome was the proportion of prescriptions with DRPs, and secondary outcomes were the proportions of prescriptions with specific DRP types. RESULTS: The influence of the intervention on general DRPs and specific DRPs was the study's main finding. The pharmacist-led intervention helped reduce the prescriptions with DRPs proportion in the intervention group to 41.0%, compared with 49.3% in the control group (p < 0.05). The DRPs proportion related to the timing of administration relative to meals, unlike the other DRP types, increased in the control group (from 31.7% to 34.9%) and decreased in the intervention group (from 31.3% to 25.3%), with a significant difference between the 2 groups at endpoint (p < 0.01). Patients aged >2 to ≤6 years (OR, 1.871; 95% CI, 1.340-2.613) and receiving ≥5 drugs (OR, 5.037; 95% CI, 2.472-10.261) were at greater risk of experiencing DRPs related to prescribing. CONCLUSIONS: A pharmacist-led intervention improved DRP occurrence related to physicians' prescribing. Pharmacists could be involved in in-depth research with physicians in the prescribing process to provide tailored interventions.

The histidine phosphotransfer AHP4 plays a negative role in Arabidopsis plant response to drought.

Cytokinin plays an important role in plant stress responses via a multistep signaling pathway, involving the histidine phosphotransfer proteins (HPs). In Arabidopsis thaliana, the AHP2, AHP3 and AHP5 proteins are known to affect drought responses; however, the role of AHP4 in drought adaptation remains undetermined. In the present study, using a loss-of-function approach we showed that AHP4 possesses an important role in the response of Arabidopsis to drought. This is evidenced by the higher survival rates of ahp4 than wild-type (WT) plants under drought conditions, which is accompanied by the downregulated AHP4 expression in WT during periods of dehydration. Comparative transcriptome analysis of ahp4 and WT plants revealed AHP4-mediated expression of several dehydration- and/or abscisic acid-responsive genes involved in modulation of various physiological and biochemical processes important for plant drought acclimation. In comparison with WT, ahp4 plants showed increased wax crystal accumulation in stems, thicker cuticles in leaves, greater sensitivity to exogenous abscisic acid at germination, narrow stomatal apertures, heightened leaf temperatures during dehydration, and longer root length under osmotic stress. In addition, ahp4 plants showed greater photosynthetic efficiency, lower levels of reactive oxygen species, reduced electrolyte leakage and lipid peroxidation, and increased anthocyanin contents under drought, when compared with WT. These differences displayed in ahp4 plants are likely due to upregulation of genes that encode enzymes involved in reactive oxygen species scavenging and non-enzymatic antioxidant metabolism. Overall, our findings suggest that AHP4 plays a crucial role in plant drought adaptation.

Safety and immunogenicity of Nanocovax, a SARS-CoV-2 recombinant spike protein vaccine: Interim results of a double-blind, randomised controlled phase 1 and 2 trial.

Background: Nanocovax is a recombinant severe acute respiratory syndrome coronavirus 2 subunit vaccine composed of full-length prefusion stabilized recombinant SARS-CoV-2 spike glycoproteins (S-2P) and aluminium hydroxide adjuvant. Methods: We conducted a dose-escalation, open label trial (phase 1) and a randomized, double-blind, placebo-controlled trial (phase 2) to evaluate the safety and immunogenicity of the Nanocovax vaccine (in 25 mcg, 50 mcg, and 75 mcg doses, aluminium hydroxide adjuvanted (0·5 mg/dose) in 2-dose regime, 28 days apart (ClinicalTrials.gov number, NCT04683484). In phase 1, 60 participants received two intramuscular injection of the vaccine following dose-escalation procedure. The primary outcomes were reactogenicity and laboratory tests to evaluate the vaccine safety. In phase 2, 560 healthy adults received either vaccine doses similar in phase 1 (25 or 50 or 75 mcg S antigen in 0·5 mg aluminium per dose) or adjuvant (0·5 mg aluminium) in a ratio of 2:2:2:1. One primary outcome was the vaccine safety, including solicited adverse events for 7 day and unsolicited adverse events for 28 days after each injection as well as serious adverse event or adverse events of special interest throughout the study period. Another primary outcome was anti-S IgG antibody response (Index unit/ml). Secondary outcomes were surrogate virus neutralisation (inhibition percentage), wild-type SARS-CoV-2 neutralisation (dilution fold), and T-cell responses by intracellular staining for interferon gamma (IFNg). Anti-S IgG and neutralising antibody levels were compared with convalescent serum samples from symptomatic Covid-19 patients. Findings: For phase 1 study, no serious adverse events were observed for all 60 participants. Most adverse events were grade 1 and disappeared shortly after injection. For phase 2 study, after randomisation, 480 participants were assigned to receive the vaccine with adjuvant, and 80 participants were assigned to receive the placebo (adjuvant only). Reactogenicity was absent or mild in the majority of participants and of short duration (mean ≤3 days). Unsolicited adverse events were mild in most participants. There were no serious adverse events related to Nanocovax. Regarding the immunogenicity, Nanocovax induced robust anti-S antibody responses. In general, there humoral responses were similar among vaccine groups which reached their peaks at day 42 and declined afterward. At day 42, IgG levels of vaccine groups were 60·48 [CI95%: 51·12-71·55], 49·11 [41·26-58·46], 57·18 [48·4-67·5] compared to 7·10 [6·32-13·92] of convalescent samples. IgG levels reported here can be converted to WHO international standard binding antibody unit (BAU/ml) by multiplying them to a conversion factor of 21·8. Neutralising antibody titre of vaccine groups at day 42 were 89·2 [52·2-152·3], 80·0 [50·8-125.9] and 95·1 [63·1-143·6], compared to 55·1 [33·4-91·0] of the convalescent group. Interpretation: Up to day 90, Nanocovax was found to be safe, well tolerated, and induced robust immune responses. Funding: This work was funded by the Coalition for Epidemic Preparedness Innovations (CEPI), the Ministry of Science and Technology of Vietnam, and Nanogen Pharmaceutical Biotechnology JSC.

Effect of Pharmacist-Led Interventions on Physicians' Prescribing for Pediatric Outpatients.

Background: Children are at high risk of drug-related problems, increased risk of treatment failures, and high treatment costs. We aimed to evaluate the effect of pharmacist-led interventions on physicians' prescribing for pediatric outpatients. Methods: A prospective study with pre- and post-intervention measurement assessment was conducted to collect pediatric outpatients' prescriptions during the pre-intervention period (January 2020) and post-intervention (August 2020) at a children's hospital in Vietnam. Drug-related problems were identified and categorized according to Pharmaceutical Care Network Europe (PCNE), version 9.1. The intervention program was developed based on the results of pre-intervention observations. After the intervention, prescriptions were evaluated. Statistical tests were used to compare the proportions of drug-related problems before and after the intervention and to identify factors related to drug-related problems. Results: There were 2788 out of 4218 (66.1%) prescriptions with at least one drug-related problem before the intervention. Of these drug-related problems, the most common was inappropriate timing of administration and incorrect dosage (36.1% and 35.6%, respectively). After the intervention, the percentage of prescriptions with at least one drug-related problem was 45.5% (p < 0.001). Most of the drug-related problem types decreased significantly (p < 0.05). The binary logistic regression analysis results showed that in addition to pharmacists' intervention, patients' gender, primary disease, comorbidity status, and the total number of drugs prescribed were also factors related to drug-related problems. Conclusions: Drug-related problems in pediatric outpatients were quite common. Pharmacists' intervention helped to improve the prevalence and types of drug-related problems.

The geography of sobriety checkpoints and alcohol-impaired driving.

BACKGROUND AND AIMS: Sobriety checkpoints are an effective strategy to reduce alcohol-impaired driving, motor vehicle crashes, injuries and fatalities. The aim of this study was to identify the geographic extent over which individual sobriety checkpoints affect alcohol-impaired driving. DESIGN, SETTING, PARTICIPANTS: Spatial ecological panel analysis using geolocated breath test data from the Queensland Police Service, Australia, for January 2012 to June 2018. Data were aggregated over 338 weeks within 528 Statistical Area level 2 (SA2) units (n = 178 464 SA2-weeks) and 84 Statistical Area level 3 (SA3) units (n = 28 392 SA3-weeks). SA2 units in Queensland contain a mean population of 8883.5 (SD = 55 018.3) and encompass 468.9 roadway kilometers (SD = 1490.0); SA3 units contain a mean population of 57 201.6 (SD = 29521.6) and encompass 2936.0 roadway kilometers (SD = 7025.0). MEASUREMENTS: Independent measures were the density of sobriety checkpoints conducted per 500 roadway kilometers within local and spatially adjacent space-time units. The dependent measure was the rate of tests that detected breath alcohol concentration (a proxy for blood alcohol concentration [BAC]) greater than the legal maximum value of 0.05% for fully licensed drivers in Queensland. Bayesian hierarchical spatial negative binomial models-related sobriety checkpoints to the rate of breath tests with BAC ≥ 0.05% within and between space-time units. FINDINGS: One additional sobriety checkpoint conducted per 500 roadway kilometers was associated with 2.5% reduction in the rate of breath tests with BAC ≥ 0.05% within local SA2 units (incidence rate ratio [IRR] = 0.975; 95% credibility interval (CrI): 0.973-0.978), and with 5.5% reduction in the rate of breath tests with BAC ≥ 0.05% within local SA3 units (IRR = 0.945; 95%CrI: 0.937-0.953). Associations were attenuated towards null in spatially adjacent units and in temporally lagged units (e.g. SA3-weeks; adjacent lagged 1 week: IRR = 0.969; 95%CrI: 0.937-1.003). CONCLUSIONS: Individual sobriety checkpoints appear to be associated with reductions in nearby alcohol-impaired driving. Relationships decay after approximately 1 week and beyond local areas containing approximately 60 000 residents and 3000 kilometers of roadway.

Drug-Related Problems in Prescribing for Pediatric Outpatients in Vietnam.

BACKGROUND: Our study was conducted to determine the prevalence of drug-related problems (DRPs) in outpatient prescriptions, the impact of DRPs on treatment efficacy, safety, and cost, and the determinants of DRPs in prescribing for pediatric outpatients in Vietnam. METHODS: A retrospective cross-sectional study was conducted on pediatric outpatients at a pediatric hospital in Can Tho, Vietnam. DRPs were classified according to the Pharmaceutical Care Network Europe classification (PCNE) of 2020. The study determined prevalence of DRPs and their impacts on efficacy, safety, and cost. Multivariate regression was used to identify the determinants of DRPs. RESULTS: The study included 4339 patients (mean age 4.3, 55.8% male), with a total of 3994 DRPs, averaging 0.92 DRP/prescription. The proportion of prescriptions with at least one DRP was 65.7%. DRPs included inappropriate drug selection (35.6%), wrong time of dosing relative to meals (35.6%), inappropriate dosage form (9.3%), inappropriate indication (7.1%), and drug-drug interactions (0.3%). The consensus of experts was average when evaluating each aspect of efficiency reduction, safety reduction, and treatment cost increase, with Fleiss' coefficients of 0.558, 0.511, and 0.541, respectively (p < 0.001). Regarding prescriptions, 50.1% were assessed as reducing safety. The figures for increased costs and decreased treatment effectiveness were 29.0% and 23.9%, respectively. Patients who were ≤2 years old were more likely to have DRPs than patients aged 2 to 6 years old (OR = 0.696; 95% CI = 0.599-0.809) and patients aged over 6 years old (OR = 0.801; 95% CI = 0.672-0.955). Patients who had respiratory system disease were more likely to have DRPs than patients suffering from other diseases (OR = 0.715; 95% CI = 0.607-0.843). Patients with comorbidities were less likely to have DRPs than patients with no comorbidities (OR = 1.421; 95% CI = 1.219-1.655). Patients prescribed ≥5 drugs were more likely to have DRPs than patients who took fewer drugs (OR = 3.677; 95% CI = 2.907-4.650). CONCLUSION: The proportion of prescriptions in at least one DRP was quite high. Further studies should evaluate clinical significance and appropriate interventions, such as providing drug information and consulting doctors about DRPs.

Retrospective analysis of a pilot pharmacist-led hospice deprescribing program initiative.

CONTEXT: Medication deprescribing in palliative care settings has been insufficiently studied. OBJECTIVE: To determine the feasibility of a deprescribing program in hospice patients with limited life expectancy. DESIGN: Pharmacist-led, single arm, single-centered, retrospective analysis of a pilot deprescribing program in an integrated healthcare delivery organization between 9/1/2018 to 1/31/2019. OUTCOME MEASURES: The primary outcome was the proportion of patients who achieved ≥50% reduction of the recommended medications to deprescribe. RESULTS: A total of 97 patients were included in the analysis. The average age was 77.5 ± 23.7 years, with 53.6% being women and 54.6% white. The most common primary diagnosis was cancer (58.8%), with cardiovascular disease the next most common (15.5%). The mean number of baseline comorbidities was 2.0 ± 1.6. Of 698 prescriptions at the start of hospice enrollment, 79.4% of patients achieved a ≥50% reduction in medications recommended for deprescribing. This success was seen mostly in cardiovascular and other nonspecific medications. We found that every 1-unit increase in the number of patient encounters with hospice pharmacists was associated with a 3.2-fold higher odds of achieving a ≥50% reduction in medications that were recommended for deprescribing. CONCLUSION: The findings from this pilot study revealed that a collaborative, pharmacist-led, collaborative medication deprescribing program initiative was associated with a 79% success in ≥50% medication reduction. More frequent patient encounters had higher odds of success. Future studies, utilizing a control group, should focus on determining the effectiveness of the program and the impact on quality of life.

The dynamics, processes, mechanisms, and functioning of personality: An overview of the field.

Personality psychology has long focused on structural trait models, but it can also offer a rich understanding of the dynamics, processes, mechanisms, and functioning of individual differences or entire persons. The field of personality dynamics, which works towards such an understanding, has experienced a renaissance in the last two decades. This review article seeks to act as a primer of that field. It covers its historical roots, summarizes current research strands - along with their theoretical backbones and methodologies - in an accessible way, and sketches some considerations for the future. In doing so, we introduce relevant concepts, give an overview of different topics and phenomena subsumed under the broad umbrella term 'dynamics', and highlight the interdisciplinarity as well as applied relevance of the field. We hope this article can serve as a useful overview for scholars within and outside of personality psychology who are interested in the dynamic nature of human behaviour and experience.

Alcohol-involved motor vehicle crashes and the size and duration of random breath testing checkpoints.

OBJECTIVE: Sobriety checkpoints have strong empirical and theoretical support as an intervention to reduce alcohol-involved motor vehicle crashes. The purpose of this study was to examine whether checkpoint size (the number of police officers) and checkpoint duration (the amount of time in operation) affect associations between individual checkpoints and subsequent alcohol-related crash incidence. METHOD: Queensland Police Service provided latitude-longitude coordinates and date and time data for all breath tests that occurred in Brisbane, Australia, from January 2012 to June 2018. We applied hierarchical cluster analysis to the latitude-longitude coordinates for breath tests, identifying checkpoints as clusters of ≥25 breath tests conducted by ≥3 breath testing devices over a duration of 3 to 8 hours. Generalized linear autoregressive moving average (GLARMA) models related counts of alcohol-involved motor vehicle crashes to the number of checkpoints conducted per week, as well as 1 week prior and 2 weeks prior. RESULTS: A total of 3420 alcohol-related crashes occurred and 2069 checkpoints were conducted in Brisbane over the 6.5-year (339-week) study period. On average, checkpoints included a mean of 266.0 breath tests (SD = 216.3), 16.4 devices (SD = 13.7), and were 286.3 minutes in duration (SD = 104.2). Each 10 additional checkpoints were associated with a 12% decrease in crash incidence at a lag of 1 week (IRR = 0.88; 95%CI: 0.80, 0.97). We detected no differential associations according to checkpoint size or duration. CONCLUSIONS: Sobriety checkpoints are associated with fewer alcohol-related motor vehicle crashes for around 1 week. Checkpoint size and duration do not appear to affect this relationship.

The situation during the COVID-19 pandemic: A snapshot in Germany.

During government-implemented restrictions in the wake of the COVID-19 pandemic, people's everyday lives changed profoundly. However, there is to date little research chronicling how people perceived their changed everyday lives and which consequences this had. In a two-wave study, we examined the psychological characteristics of people's situations and their correlates during shutdown in a large German sample (NT1 = 1,353; NT2 = 446). First, we compared characteristics during government-issued restrictions with retrospective accounts from before and with a follow-up assessment 6 to 7 months later when many restrictions had been lifted. We found that mean levels were lower and variances were higher for most characteristics during the shutdown. Second, the experience of certain situation characteristics was associated in meaningful and theoretically expected ways with people's traits, appraisals of the COVID-19 crisis, and subjective well-being. Lastly, situation characteristics often substantially explained the associations of traits with appraisals and well-being. Our findings highlight the importance of considering perceived situations as these contribute to people's functioning during crises.

Optical coherence tomography reveals light-dependent retinal responses in Alzheimer's disease.

Spectral-domain optical coherence tomography (SD-OCT) is an accessible clinical tool for measuring structural changes to the retina, and increasingly as a biomarker for brain-predominant neurodegenerative diseases like Alzheimer's. Information about retinal function can also be extracted from OCT images, but is under-studied, with literature examples often employing challenging protocols or requiring specialized hardware. The first goal of this study was to verify that functional retinal imaging was feasible with a commercially-available SD-OCT device and a clinically practical protocol. Inspired by methods from other functional imaging modalities, we acquired images while repeatedly cycling lights on and off, and spatially normalized retinas to facilitate intra- and inter-individual analyses. In eight healthy young adults, light-dependent increases in reflectivity were easily demonstrated at photoreceptor inner and outer segments, changing by ~7% in bright light and ~3% in dim light. Bright light elicited a subtle (~2%) but consistent light-dependent decrease in reflectivity through much of the rest of the retina, including the avascular outer nuclear layer (ONL). We speculated that some of these changes are influenced by glial function - as through water management - a topic of high interest in neurodegenerative diseases that may involve the glymphatic system. Functional abnormalities in patients with antibodies against aquaporin-4 (n â€‹= â€‹3) supported this interpretation. We next compared patients with early-onset Alzheimer's disease (n â€‹= â€‹14) to age-matched controls (n â€‹= â€‹14), revealing that patients had a relatively exaggerated light-induced change in ONL reflectivity (p â€‹< â€‹0.05). Because these measurements can be obtained within 30 â€‹min, regular use in research and limited clinical settings is feasible.

Situation-Based Contingencies Underlying Wisdom-Content Manifestations: Examining Intellectual Humility in Daily Life.

Objectives: Existing assessments of intellectual humility (IH)-a key component of wisdom-do not examine its manifestation in daily life while sufficiently focusing on the core idea of the construct: owning up to one's intellectual shortcomings. The present research sought to examine situational contingencies underlying daily manifestations of IH-relevant characteristics. Research Design and Methods: We developed a trait version of the State-Trait IH Scale in two studies and subsequently examined daily manifestations of IH-relevant characteristics utilizing a contextualized state version of the State-Trait IH Scale in a 21-day experience sampling study. Here, we tested how specific situational contingencies (associated with the context and the personality of the individual with whom participants engaged) influenced the manifestation of IH-relevant qualities. Results: We found strong evidence for the validity of both versions of the scale. Specifically, the state measure exhibited high within-person variability, and aggregated state assessments were strongly correlated with the trait measure. Additionally, morality positively predicted manifestation of IH, whereas disagreeableness negatively predicted manifestation of IH. Discussion and Implications: These results offer new directions for research on the expression of wisdom-related characteristics in daily life.

g-Ratio weighted imaging of the human spinal cord in vivo.

The fiber g-ratio is defined as the ratio of the inner to the outer diameter of the myelin sheath. This ratio provides a measure of the myelin thickness that complements axon morphology (diameter and density) for assessment of demyelination in diseases such as multiple sclerosis. Previous work has shown that an aggregate g-ratio map can be computed using a formula that combines axon and myelin density measured with quantitative MRI. In this work, we computed g-ratio weighted maps in the cervical spinal cord of nine healthy subjects. We utilized the 300mT/m gradients from the CONNECTOM scanner to estimate the fraction of restricted water (fr) with high accuracy, using the CHARMED model. Myelin density was estimated using the lipid and macromolecular tissue volume (MTV) method, derived from normalized proton density (PD) mapping. The variability across spinal level, laterality and subject were assessed using a three-way ANOVA. The average g-ratio value obtained in the white matter was 0.76+/-0.03, consistent with previous histology work. Coefficients of variation of fr and MTV were respectively 4.3% and 13.7%. fr and myelin density were significantly different across spinal tracts (p=3×10-7 and 0.004 respectively) and were positively correlated in the white matter (r=0.42), suggesting shared microstructural information. The aggregate g-ratio did not show significant differences across tracts (p=0.6). This study suggests that fr and myelin density can be measured in vivo with high precision and that they can be combined to produce a g-ratio-weighted map robust to free water pool contamination from cerebrospinal fluid or veins. Potential applications include the study of early demyelination in multiple sclerosis, and the quantitative assessment of remyelination drugs.

Stereoselective Total Synthesis of (-)-Renieramycin T.

A stereoselective total synthesis of (-)-Renieramycin T (1t) from a key tetrahydroisoquinoline intermediate previously utilized in our formal total synthesis of Ecteinascidin 743 is described. The synthesis features a concise approach for construction of the pentacyclic framework using a Pictet-Spengler cyclization of bromo-substituted carbinolamine 17, which obviates the regioselectivity problem of the Pictet-Spengler cyclization. The results of cytotoxicity studies are also presented.

Cytotoxic effects of ellagitannins isolated from walnuts in human cancer cells.

Walnuts contain many bioactive components that may slow cancer growth. A previous report showed that a diet supplemented with walnuts decreased the tumor size formed by MDA-MB-231 human cancer cells injected into nude mice. However, the mechanism of action was never determined. We characterized the effects of a methanol extract prepared from walnuts on human MDA-MB-231, MCF7, and HeLa cells. The extract was cytotoxic to all cancer cells. We identified compounds from the methanol extract that induced this cytotoxicity. The predominant compounds were Tellimagrandin I and Tellimagrandin II, members of the ellagitannin family. We also show a walnut extract decreases the intracellular pH, depolarizes the mitochondrial membrane with release of cytochrome c and phosphatidylserine flipping. The antimitogenic effects of walnut extract were associated with a twofold reduction of mitochondria respiration. These results suggest impairment of mitochondrial function and apoptosis as relevant mechanism of anticancer effects of the walnut extract.