DWELL: Design for WELLness. A pilot study of an online Facebook intervention to improve perceptions of knowledge, engagement, and self-efficacy in the creation of healthy home environments.

Background: Many factors in the environment influence healthy behaviors. Designing user-friendly environments, by changing the way choices are presented in the environment, may result in behavioral changes and promote the well-being. Objectives: To run a pilot study to evaluate the feasibility and acceptability of DWELL (Design for WELLness), which is an online Facebook intervention to improve perceptions of knowledge, engagement, and self-efficacy in the creation of healthy home environments. Methods: Both quantitative and qualitative methods were used to evaluate this 7.5-week pilot study. The intervention was conducted during the first wave of COVID-19 lockdown in Israel. Participants answered an online questionnaire at the beginning and end of the pilot. Afterwards, eleven semi-structured telephone interviews were conducted with some of the participants. Results: There were 36 mothers who participated in the study. The overall DWELL index increased by 15.43 points (p < 0.001) from the beginning of the pilot [Mean(SD) = 48.14(17.91)] to the end [Mean(SD) = 63.57(11.98]. There were significant increases in all 5 items of DWELL (p < 0.05). Positive feedback was obtained from interviewees about their experience with the program, including being interested with the posts and having a mutual learning experience with other members. The intervention was found to be beneficial to most families during COVID-19 lockdown time. Conclusions: DWELL was found to be a promising intervention for improving perceptions regarding designing home environments for wellness. These results justified the continuation of the program toward its next phase of the RCT.

Improving Knowledge, Engagement, and Self-Efficacy in the Creation of Healthy Home Environments for Mothers Using a Facebook Intervention (Design for Wellness): Randomized Controlled Trial.

BACKGROUND: Designing the home environment can promote well-being. Social networks provide learning opportunities to improve health. OBJECTIVE: This study aimed to develop and evaluate a Facebook intervention called Design for Wellness (DWELL). The program was created to improve knowledge, engagement, and self-efficacy in the creation of healthy home environments. METHODS: A randomized controlled trial was conducted to assess the effects of the intervention program DWELL. Content was uploaded to the Facebook group and gave the participants practical solutions for how to design their home environment for wellness. The intervention addressed multiple components of health behaviors, such as healthy eating, physical activity, tobacco-free environment, hygiene, family conversations regarding wellness issues, and stress reduction. The main outcome was the participants' overall score on the DWELL index, which we developed to assess the elements of our intervention: knowledge, awareness, engagement, and self-efficacy regarding home design for wellness. The intervention was conducted in Israel and lasted 6 weeks during the third wave of the COVID-19 pandemic. The primary analysis included a multivariable model to assess the DWELL score at the end of the study while controlling for baseline characteristics. The waitlist control group did not receive an intervention between the 2 administrations of the questionnaire. RESULTS: In total, 643 participants began the program: 322 (50.1%) in the intervention group and 321 (49.9%) in the control group. Of the 643 participants, 476 (74%) completed the study. At the end of the study, there was a statistically significant benefit of the intervention as assessed using a one-way analysis of covariance: there was a mean difference of 8.631 (SD 1.408) points in the DWELL score in favor of the intervention group (intervention: mean 61.92, SD 14.30; control: mean 53.29, SD 16.374; P<.001). Qualitative feedback from participants in the intervention group strengthened the positive results as most of them found the group beneficial. The Facebook group was very active. Being more engaged in the group correlated with having a higher DWELL score, but this relationship was weak (r=0.37; P<.001). The mean significant difference of 26.281 (SD 19.24) points between the overall DWELL score and the overall engagement score indicated that participants who were not active in the group still followed the posts and benefited. We found no improvements in the secondary outcome regarding participants' well-being. The COVID-19 lockdown may have prevented this. CONCLUSIONS: DWELL was found to be a beneficial intervention for improving perceptions of the design of home environments to foster wellness. Facebook was an effective platform to deliver this intervention. DWELL may become a prototype for other health promotion interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03736525; https://clinicaltrials.gov/study/NCT03736525?term=DWELL&rank=1.

Pasteurella sp. associated with fatal septicaemia in six African elephants.

The sudden mortality of African elephants (Loxodonta africana) in Botswana and Zimbabwe in 2020 provoked considerable public interest and speculation. Poaching and malicious poisoning were excluded early on in the investigation. Other potential causes included environmental intoxication, infectious diseases, and increased habitat stress due to ongoing drought. Here we show evidence of the mortalities in Zimbabwe as fatal septicaemia associated with Bisgaard taxon 45, an unnamed close relative of Pasteurella multocida. We analyse elephant carcasses and environmental samples, and fail to find evidence of cyanobacterial or other intoxication. Post-mortem and histological findings suggest a bacterial septicaemia similar to haemorrhagic septicaemia caused by P. multocida. Biochemical tests and 16S rDNA analysis of six samples and genomic analysis of one sample confirm the presence of Bisgaard taxon 45. The genome sequence contains many of the canonical P. multocida virulence factors associated with a range of human and animal diseases, including the pmHAS gene for hyaluronidase associated with bovine haemorrhagic septicaemia. Our results demonstrate that Bisgaard taxon 45 is associated with a generalised, lethal infection and that African elephants are susceptible to opportunistically pathogenic Pasteurella species. This represents an important conservation concern for elephants in the largest remaining metapopulation of this endangered species.

Neutralization, effector function and immune imprinting of Omicron variants.

Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain1 (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting.

Tobacco smoke incursion into private residences in Israel: a cross-sectional study examining public perceptions of private rights and support for governmental policies.

BACKGROUND: Tobacco smoke incursion (TSI) into private residences is a widespread problem in many countries. We sought to assess the prevalence of self-reported TSI and public attitudes about TSI in Israel, a country with a relatively high smoking prevalence and high population density. METHODS: We conducted a random digit dial survey among residents in Israel (N = 285) in 2017, which examined the frequency, source, correlates of, and attitudes towards TSI and potential regulatory options. The cooperation rate was 63.9%. RESULTS: Among respondents, 44.7% reported ever experiencing home TSI, with higher exposure among residents of multi-unit housing (MUH) (MUH versus private homes: aOR (Adjusted Odds Ratio): 3.60, CI (Confidence Interval): [1.96, 6.58], p < .001). Most respondents (69.8%), including nearly half of smokers, prioritized the right of individuals to breath smoke-free air in their apartments over the right of smokers to smoke in their apartments. Women and non-smokers were more likely to support the right to breathe smoke-free air (Women versus men: aOR: 2.77 CI: [1.48, 5.16], p = .001; Nonsmokers versus smokers: aOR: 3.21 CI [1.59, 6.48], p = .001). However, only about a quarter (24.8%) of respondents who ever experienced TSI raised the issue with the neighbor who smoked, the neighbor's landlord, or the building committee. The vast majority (85.2%) of all respondents, including three-quarters of smokers, supported smoke-free legislation for multi-unit housing (MUH), with those ever-exposed to TSI and non-smokers more likely to support legislation (ever-exposed versus never-exposed aOR = 2.99, CI [1.28, 6.97], p = 0.011; nonsmokers versus smokers aOR = 3.00, CI [1.28, 7.01], p = 0.011). CONCLUSIONS: Among study participants, tobacco smoke incursion was a common, yet unwelcome experience. Most respondents believed that the right to breathe smoke-free air in one's apartment superseded that of neighbors to smoke anywhere in their home, and most supported legislation to prevent TSI. Though further study is needed to understand better TSI and effective methods for its prevention, our findings suggest that policy interventions, including legal action at the level of the Supreme Court and/or the Knesset, are needed. Regulation, policy initiatives and campaigns to denormalize smoking in proximity to other people and private residences globally could reduce the scope of this widespread problem, protect individuals from home TSI, and improve population health.

Potent broadly neutralizing antibody VIR-3434 controls hepatitis B and D virus infection and reduces HBsAg in humanized mice.

BACKGROUND & AIMS: Chronic hepatitis B is a global public health problem, and coinfection with hepatitis delta virus (HDV) worsens disease outcome. Here, we describe a hepatitis B virus (HBV) surface antigen (HBsAg)-targeting monoclonal antibody (mAb) with the potential to treat chronic hepatitis B and chronic hepatitis D. METHODS: HBsAg-specific mAbs were isolated from memory B cells of HBV vaccinated individuals. In vitro neutralization was determined against HBV and HDV enveloped with HBsAg representing eight HBV genotypes. Human liver-chimeric mice were treated twice weekly with a candidate mAb starting 3 weeks post HBV inoculation (spreading phase) or during stable HBV or HBV/HDV coinfection (chronic phase). RESULTS: From a panel of human anti-HBs mAbs, VIR-3434 was selected and engineered for pre-clinical development. VIR-3434 targets a conserved, conformational epitope within the antigenic loop of HBsAg and neutralized HBV and HDV infection with higher potency than hepatitis B immunoglobulins in vitro. Neutralization was pan-genotypic against strains representative of HBV genotypes A-H. In the spreading phase of HBV infection in human liver-chimeric mice, a parental mAb of VIR-3434 (HBC34) prevented HBV dissemination and the increase in intrahepatic HBV RNA and covalently closed circular DNA. In the chronic phase of HBV infection or co-infection with HDV, HBC34 treatment decreased circulating HBsAg by >1 log and HDV RNA by >2 logs. CONCLUSIONS: The potently neutralizing anti-HBs mAb VIR-3434 reduces circulating HBsAg and HBV/HDV viremia in human liver-chimeric mice. VIR-3434 is currently in clinical development for treatment of patients with chronic hepatitis B or D. IMPACT AND IMPLICATIONS: Chronic infection with hepatitis B virus and co-infection with hepatitis D virus place approximately 290 million individuals worldwide at risk of severe liver disease and cancer. Available treatments result in low rates of functional cure or require lifelong therapy that does not eliminate the risk of liver disease. We isolated and characterized a potent human antibody that neutralizes hepatitis B and D viruses and reduces infection in a mouse model. This antibody could provide a new treatment for patients with chronic hepatitis B and D.

Identifying and Overcoming the Sampling Challenges in Relative Binding Free Energy Calculations of a Model Protein:Protein Complex.

Relative alchemical binding free energy calculations are routinely used in drug discovery projects to optimize the affinity of small molecules for their drug targets. Alchemical methods can also be used to estimate the impact of amino acid mutations on protein:protein binding affinities, but these calculations can involve sampling challenges due to the complex networks of protein and water interactions frequently present in protein:protein interfaces. We investigate these challenges by extending a graphics processing unit (GPU)-accelerated open-source relative free energy calculation package (Perses) to predict the impact of amino acid mutations on protein:protein binding. Using the well-characterized model system barnase:barstar, we describe analyses for identifying and characterizing sampling problems in protein:protein relative free energy calculations. We find that mutations with sampling problems often involve charge-changes, and inadequate sampling can be attributed to slow degrees of freedom that are mutation-specific. We also explore the accuracy and efficiency of current state-of-the-art approaches─alchemical replica exchange and alchemical replica exchange with solute tempering─for overcoming relevant sampling problems. By employing sufficiently long simulations, we achieve accurate predictions (RMSE 1.61, 95% CI: [1.12, 2.11] kcal/mol), with 86% of estimates within 1 kcal/mol of the experimentally determined relative binding free energies and 100% of predictions correctly classifying the sign of the changes in binding free energies. Ultimately, we provide a model workflow for applying protein mutation free energy calculations to protein:protein complexes, and importantly, catalog the sampling challenges associated with these types of alchemical transformations. Our free open-source package (Perses) is based on OpenMM and is available at https://github.com/choderalab/perses.

Development and validation of a new questionnaire to assess perceptions regarding DWELL: Design for WELLness.

Designing home environments for health and wellness is a crucial strategy for disease prevention and health promotion. Yet, there is not a tool to evaluate perceptions regarding home design for health and wellness. This study aimed to develop and validate a new instrument to measure people's perceptions regarding the concept of DWELL: Design for WELLness in the home environment. We developed a short 5-item online questionnaire to detect changes in knowledge, awareness, engagement and self-efficacy regarding DWELL. The instrument was validated in an online study. Of the 613 mothers who answered the questionnaire initially, 397 answered the questionnaire a second time. Factor analysis and Cronbach's alpha indicated that all five DWELL questions load into one single factor (the model explained 61.84% of total variance), and measure a reliable scale of the same construct, with high levels of internal consistency (Cronbach's α = 0.85) at both first and second administrations. Spearman correlations between DWELL first and second administrations of the questionnaire indicated moderate-to-high test-retest reliability (0.55-0.70, p < 0.001). DWELL was found to be a valid tool which fills a gap in the public health literature. This measure serves as a free and convenient online instrument to gain insights regarding the effect of modifying environments for disease prevention and health promotion. The tool may be used to assess perceptions in the conditions leading wellness promotion in the home.

A pan-influenza antibody inhibiting neuraminidase via receptor mimicry.

Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly to the highly variable head region of haemagglutinin and their effectiveness is limited by viral drift1 and suboptimal immune responses2. Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as Victoria/2/87-like, Yamagata/16/88-like and ancestral IBVs. FNI9 broadly neutralizes seasonal IAVs and IBVs, including the immune-evading H3N2 strains bearing an N-glycan at position 245, and shows synergistic activity when combined with anti-haemagglutinin stem-directed antibodies. Structural analysis reveals that D107 in the FNI9 heavy chain complementarity-determinant region 3 mimics the interaction of the sialic acid carboxyl group with the three highly conserved arginine residues (R118, R292 and R371) of the neuraminidase catalytic site. FNI9 demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. The unprecedented breadth and potency of the FNI9 monoclonal antibody supports its development for the prevention of influenza illness by seasonal and pandemic viruses.

The association between risk perceptions, anxiety, and self-reported changes in tobacco and nicotine product use due to COVID-19 in May-June 2020 in Israel.

BACKGROUND: Early in the COVID-19 pandemic, reports about a possible protective effect of nicotine on COVID-19 conflicted with messaging by public health organizations about increased risks of COVID-19 due to smoking. The ambiguous information the public received, combined with COVID-19-induced anxiety, may have led to changes in tobacco or other nicotine product use. This study examined changes in use of combustible cigarettes (CCs), nargila (hookah/waterpipe), e-cigarettes, and IQOS and home-smoking behaviors. We also assessed COVID-19 related anxiety and perceptions regarding changes in risk of COVID-19 severity due to smoking. METHODS: We used cross-sectional data from a population telephone survey that was conducted in Israel in the early phase of the COVID-19 pandemic (May-June 2020) and included 420 adult (age 18+) individuals who reported having ever used CCs (n = 391), nargila (n = 193), and/or electronic cigarettes (e-cigarettes)/heated tobacco products (e.g., IQOS) (n = 52). Respondents were asked about the effect that COVID-19 had on their nicotine product use (quit/reduced use, no change, increased use). We assessed changes in product use, risk perceptions, and anxiety using adjusted multinomial logistic regression analyses. RESULTS: Most respondents did not change their frequency of product use (CCs: 81.0%, nargila: 88.2%, e-cigarettes/IQOS: 96.8%). A small percentage either decreased use (CCs: 7.2%, nargila: 3.2%, e-cigarettes/IQOS:2.4%) or increased use (CCs:11.8%, nargila:8.6%, e-cigarettes/IQOS:+ 0.9%). 55.6% of respondents used a product in the home prior to COVID-19; but during the first lockdown COVID-19 period, a greater percentage increased (12.6%) than decreased (4.0%) their home use. Higher levels of anxiety due to COVID-19 were associated with increased home smoking (aOR = 1.59, 95% CI:1.04-2.42, p = 0.02). Many respondents believed that increased severity of COVID-19 illness was associated with CCs (62.0%) and e-cigarettes/vaping (45.3%), with uncertainty about the association being lower for CCs (20.5%) than for vaping (41.3%). CONCLUSIONS: While many respondents believed that nicotine product use (particularly CCs and e-cigarettes) was associated with increased risk of COVID-19 disease severity, the majority of users did not change their tobacco/nicotine use. The confusion about the relationship between tobacco use and COVID-19 calls for clear evidence-based messaging from governments. The association between home smoking and increased COVID-19-related stress suggests the need for campaigns and resources to prevent smoking in the home, particularly during times of stress.

Orexin 2 receptor-selective agonist danavorexton (TAK-925) promotes wakefulness in non-human primates and healthy individuals.

The orexin 2 receptor-selective agonist danavorexton (TAK-925) has been shown to produce wake-promoting effects in wild-type mice, narcolepsy-model mice, and individuals with narcolepsy type 1 and type 2. Here, we report wake-promoting effects of danavorexton in non-human primates and healthy men during their sleep phase. Electroencephalogram analyses revealed that subcutaneous administration of danavorexton significantly increased wakefulness in common marmosets (p < 0.05 at 0.1 mg kg-1 , and p < 0.001 at 1 mg kg-1 and 10 mg kg-1 ) and cynomolgus monkeys (p ≤ 0.05 at 1 mg kg-1 and 3 mg kg-1 ). In a phase 1b crossover, randomized, double-blind, placebo-controlled and active-controlled study in sleep-deprived healthy participants (ClinicalTrials.gov identifier: NCT03522506), modafinil 300 mg (used to demonstrate assay sensitivity) and continuous infusion of danavorexton 44 mg and danavorexton 112 mg showed statistically superior wake-promoting effects to placebo (n = 18). Measured using the Maintenance of Wakefulness Test, mean (standard deviation) sleep latencies during infusion of danavorexton 44 mg, danavorexton 112 mg and placebo were 21.4 (8.9), 31.8 (3.2) and 9.2 (6.4) min, respectively. Least-squares mean difference from placebo in average sleep latency was 16.8 min with danavorexton 44 mg and 30.2 min with danavorexton 112 mg (both p < 0.001). Karolinska Sleepiness Scale scores were statistically significantly lower (indicating decreased sleepiness) for participants receiving danavorexton than for those receiving placebo during infusion (danavorexton 44 mg, p = 0.010; danavorexton 112 mg, p < 0.001). Together, these results indicate that an orexin 2 receptor agonist increases wakefulness in non-human primates and healthy individuals during their sleep phase.

The D-amino acid oxidase inhibitor luvadaxistat improves mismatch negativity in patients with schizophrenia in a randomized trial.

Several attempts have been made to enhance N-methyl-D-aspartate (NMDA) receptor function in schizophrenia, but they have yielded mixed results. Luvadaxistat, a D-amino acid oxidase (DAAO) inhibitor that increases the glutamate co-agonist D-serine levels, is being developed for the treatment of cognitive impairment associated with schizophrenia. We conducted a biomarker study in patients, assessing several endpoints related to physiological outcomes of NMDA receptor modulation to determine whether luvadaxistat affects neural circuitry biomarkers relevant to NMDA receptor function and schizophrenia. This was a randomized, placebo-controlled, double-blind, two-period crossover phase 2a study assessing luvadaxistat 50 mg and 500 mg for 8 days in 31 patients with schizophrenia. There were no treatment effects of luvadaxistat at either dose in eyeblink conditioning, a cerebellar-dependent learning measure, compared with placebo. We observed a nominally significant improvement in mismatch negativity (MMN) and a statistical trend to improvement for auditory steady-state response at 40 Hz, in both cases with 50 mg, but not with 500 mg, compared with placebo. Although the data should be interpreted cautiously owing to the small sample size, they suggest that luvadaxistat can improve an illness-related circuitry biomarker at doses associated with partial DAAO inhibition. These results are consistent with 50 mg, but not higher doses, showing a signal of efficacy in cognitive endpoints in a larger phase 2, 12-week study conducted in parallel. Thus, MMN responses after a short treatment period may predict cognitive function improvement. MMN and ASSR should be considered as biomarkers in early trials addressing NMDA receptor hypofunction.

Identifying and overcoming the sampling challenges in relative binding free energy calculations of a model protein:protein complex.

Relative alchemical binding free energy calculations are routinely used in drug discovery projects to optimize the affinity of small molecules for their drug targets. Alchemical methods can also be used to estimate the impact of amino acid mutations on protein:protein binding affinities, but these calculations can involve sampling challenges due to the complex networks of protein and water interactions frequently present in protein:protein interfaces. We investigate these challenges by extending a GPU-accelerated open-source relative free energy calculation package (Perses) to predict the impact of amino acid mutations on protein:protein binding. Using the well-characterized model system barnase:barstar, we describe analyses for identifying and characterizing sampling problems in protein:protein relative free energy calculations. We find that mutations with sampling problems often involve charge-changes, and inadequate sampling can be attributed to slow degrees of freedom that are mutation-specific. We also explore the accuracy and efficiency of current state-of-the-art approaches-alchemical replica exchange and alchemical replica exchange with solute tempering-for overcoming relevant sampling problems. By employing sufficiently long simulations, we achieve accurate predictions (RMSE 1.61, 95% CI: [1.12, 2.11] kcal/mol), with 86% of estimates within 1 kcal/mol of the experimentally-determined relative binding free energies and 100% of predictions correctly classifying the sign of the changes in binding free energies. Ultimately, we provide a model workflow for applying protein mutation free energy calculations to protein:protein complexes, and importantly, catalog the sampling challenges associated with these types of alchemical transformations. Our free open-source package (Perses) is based on OpenMM and available at https://github.com/choderalab/perses .

Tobacco Smoke Exposure According to Location of Home Smoking in Israel: Findings from the Project Zero Exposure Study.

Young children are particularly vulnerable to harms from tobacco smoke exposure (TSE). This study aimed to compare TSE: (1) between children who live in smoking families and those who do not; and (2) among children who live in smoking households with varying smoking locations. The data came from two studies that were conducted concurrently in Israel (2016-2018). Study 1: a randomized controlled trial of smoking families (n = 159); Study 2: a cohort study of TSE among children in non-smoking families (n = 20). Hair samples were collected from one child in each household. Baseline hair nicotine data were analyzed for 141 children in Study 1 and 17 children in Study 2. Using a logistic regression analysis (exposed vs. not exposed as per laboratory determination) and a linear regression (log hair nicotine), we compared TSE between: (1) children in Study 1 vs. Study 2; (2) children in families with different smoking locations in Study 1: balcony; garden, yard, or other place outside of the home; or inside the home (designated smoking areas within the home (DSAs) or anywhere). A higher proportion of children living in smoking households were measurably exposed to tobacco smoke (68.8%) compared to children living in non-smoking households (35.3%, p = 0.006). Among children from smoking families, 75.0% of those whose parents smoked in the house were exposed, while 61.8% of children whose parents restricted smoking to the porch (n = 55) were exposed, and 71.4% of those whose parents smoked outside the home (including gardens and yards) (n = 42) were exposed. In univariable and multivariable models, smoking location was not significantly associated with exposure. The majority of children in smoking families were measurably exposed to TSE, even if smoking was restricted to designated areas in the home, balconies, orgarden/yard/other outdoor areas. Reducing population smoking rates, particularly among parents, restricting smoking to at least 10 meters from homes and children, and denormalizing smoking around others are recommended to reduce population-level child TSE and tobacco-attributable disease and death.

Children's Savings Programs as Public-Private Partnerships: A Tool to Advance Health Equity for Low-Income Families.

Higher education can lead to economic mobility, but cost is a barrier for low-income families. Children's savings account (CSA) programs for higher education increase educational aspirations. Early Bird, a novel health system-integrated CSA program being assessed through a randomized control trial could greatly influence families' outcomes. Three preliminary lessons have emerged.

Central nervous system effects of TAK-653, an investigational alpha-amino-3-hydroxy-5-methyl-4-isoxazole receptor (AMPAR) positive allosteric modulator in healthy volunteers.

TAK-653 is a novel AMPA receptor positive allosteric modulator in clinical development for the treatment of major depressive disorder (MDD). This study aimed to measure the functional pharmacodynamic central nervous system (CNS) effects of TAK-653. A randomised, double-blind, placebo-controlled, three-way crossover (placebo, TAK-653 0.5 mg and 6 mg) study with 24 healthy volunteers was performed. NeuroCart tests consisting of body sway (BS), saccadic peak velocity (SPV), smooth pursuit eye movements (SP), adaptive tracking (AT), Bowdle and Bond and Lader Visual Analogue Scales (B-VAS and BL-VAS) and Stroop test were performed pre-dose and 3.5 and 4 h post-dose. Data were analysed using a mixed model analysis of covariance with baseline as covariate. It was found that TAK-653 did not affect BS and subjective drug effects as measured by B-VAS and BL-VAS at either dose level. TAK-653 0.5 mg increased SPV (degrees/second) (19.49 [5.98, 32.99], P = 0.02) and affected Stroop difference in reaction time between correct congruent and correct incongruent answers and number of correct responses in incongruent trials (22.0 [4.0, 40.0], P = 0.05 and -0.3 [-0.5, -0.1], P = 0.02, respectively). TAK-653 6 mg improved AT (%) (1.68 [0.51, 2.84], P = 0.02) and increased SPV (degrees/s) (15.40 [1.91, 28.90], P = 0.06) and SP (%) (2.32 [0.37, 4.27], P = 0.05). Based on these findings it can be concluded that TAK-653 demonstrated a psychostimulant-like pharmacodynamic profile on the NeuroCart consistent with previously reported increase of cortical excitability following Transcranial Magnetic Stimulation (TMS) of the human motor cortex.

Association between objective measures and parent-reported measures of child tobacco smoke exposure: A secondary data analysis of four trials.

INTRODUCTION: Tobacco smoke exposure (TSE) harms children and adults. Studies of childhood TSE exposure often relies on parental reports, but may benefit from objective measures. The objective of our study was to study the relationship between reported and objective measures of TSE. METHODS: We analyzed data from four intervention trials, conducted in clinical or community settings, to identify objective measures most closely associated with parent-reported measures and the optimal set of parent-reported measures for predicting objective measures. We also assessed whether there was a learning curve in reported exposure over time, and the importance of replicate biomarker measures. RESULTS: Correlations between objective and parent-reported measures of child TSE were modest at best, ranging from zero to 0.41. Serum cotinine and urinary cotinine were most strongly associated with parental reports. Parental questions most closely related to biomarkers were number of cigarettes and home smoking rules; together these formed the best set of predictive questions. No trial included all objective measures and all questions, precluding definitive statements about relative advantages. Within-subject repeatability of biomarker measures varied across studies, suggesting that direct pilot data are needed to assess the benefit of replicate measurements. CONCLUSIONS: Improvements in objective and parent-reported child exposure measurements are needed to accurately monitor child TSE, evaluate efforts to reduce such exposure, and better protect child health.