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The process of ion cutting was used to integrate single crystalline Si layers on glass for potential active matrix flat panel display and other applications. It was found that p-Si wafers implanted at 100-150°C with H with a dose in the order of a few times 10[sup 16] cm[sup -2] could be readily bonded to glass substrates when both of the surfaces were properly treated and activated. The as-implanted Si wafer surface was converted from p type to n type. Upon bonding at room temperature, annealing (300°C) and exfoliation (450°C), the transferred Si layer on glass and the as-exfoliated surface of the implanted Si wafer remained n type. A highly defective region was observed near the top of the Si layer on glass, however the crystalline quality was nearly defect free in the deeper region of the layer. Annealing at sequentially higher temperatures led to the recovery of p type conductivity at ∼600-650°C. The type conversion and the subsequent annealing behavior observed on the samples were rationalized in terms of ion enhanced oxygen diffusion and the presence of H-related shallow donors in the Si. [ABSTRACT FROM AUTHOR]

Objectives We reported the findings of a randomized controlled trial (RCT) to examine the effects of an individualized functional enhancement program (FEP) on functional skills and mood symptoms in mild and moderate dementia. Subjects & Methods 74 Chinese older persons with dementia were recruited into a skills training program by occupational therapists (OT). Thirty seven subjects were trained with an individualized selection of daily activities (FEP Intervention, I); 37 were trained with general occupational therapy (Control, C). The FEP comprised of twice weekly group sessions of skills training and problem solving using cognitive behavioral approach. Results At 1 month after completion of program, both I and C subjects showed an improvement in process skills of the assessment of motor and process skills (AMPS)(paired t-tests, p < 0.05). At 4 months post-program, the I group showed a further reduction of cornell scale for depression in dementia (CSDD) scores (paired t-test, p = 0.02); Apathy improved at 1 month post-training (p = 0.04), but deteriorated at 4 months (p = 0.01). Group differences in changes of mood and functional scores were not significant (ANVOCA, p > 0.05). Conclusions The findings suggested a potential benefit for individualized occupational therapy. It should be tailor made with individual needs and continued for sustained effectiveness. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract A family of facilitative glucose transporters or GLUTs mediates glucose uptake by cells and tissues. The glucose transporter isoform GLUT4, which is the predominant isoform expressed in mature muscle and fat tissues, is primarily responsible for the increase in glucose uptake in response to insulin stimulation. Recent work in our laboratory suggests that there are two divergent responses initiated by insulin stimulation. The first response involves the recruitment of GLUT4 transporters from intracellular reserves and their subsequent insertion into the plasma membrane. The second pathway results in an increase in the intrinsic activity of the transporters. This review will discuss evidence supporting the divergence of the two pathways regulating glucose uptake and, in particular, evidence for the increased intrinsic activity of GLUT4 in response to insulin stimulation. Inhibitors of p38 mitogen-activated protein kinase (MAPK) affected only the arm leading to the insulin-stimulated activation of GLUT4. This implicates p38 MAPK involvement in the regulation of this pathway. There is further evidence that p38 MAPK is itself recruited to the plasma membrane. The role of the phosphorylation state of the glucose transporter in response to insulin stimulation has been studied and indicates that, contrary to what might be predicted, there is actually a decrease in its phosphorylation at the plasma membrane in response to insulin. The relationship of this change to glucose uptake remains to be established. Other possible mechanisms regulating GLUT4 activity include binding of (+) or (-) modulators of its function. [ABSTRACT FROM AUTHOR]

Objective: As the global village becomes a reality, there is an increasing need to conduct international collaborative studies in family practice. A workshop at the WONCA meeting in Hong Kong used international attendees to produce a set of guidelines for international research.Methods: At the workshop four completed international projects, each using a different strategy, were presented so that common themes might become apparent. The themes were then discussed and guidelines emerged from the process.Results: Seven guidelines emerged for consideration before embarking on an international collaborative research project in family medicine. The guidelines deal with the characteristics of the research question and the importance of communication. The need for simple, brief methods of data collection, funding and pilot testing were identified.Conclusion: The question must be relevant to all participants to maintain interest and measurement tools must be validated to understand the impact of cultural differences in understanding. [ABSTRACT FROM AUTHOR]

Objective: To evalute emotional response towards perceived loss of activities of daily living in Chinese elders with dementia. Patients and Methods: Eighty-one elderly people with a clinical diagnosis of dementia were recruited from residential homes and social cnetre for the elderly in Hong Kong. A purpose-designed questionnaire on subjective evaluation of ability and emotional reactions towards functional deterioration was derived. The association between the subjective evaluation of ability, emotional reactions, and acutal activities of daily living performance measured by the Chinese version of Disability Assessment for Dementia were evaluated. Resutls: There were no significant correlations between subjective evaluation of ability and the emotional reactions towards functional impairment. Subjects reported greater higher emotional distress over possible loss of basic activities of daily living than instrumental activities of daily living (t=3.04,p=0.003). Subjects with better basic activities of daily living abilities were likely to report greater distress if their instrumental activities of daily living were impaired (Spearman's rho=0.30,p=0.01). Conclusion: Although elderly people with dementia may have compromised congnitive abilities, attention to functional training is an important means of improving their emotional well-being. [ABSTRACT FROM AUTHOR]

Background: Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti-tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract., Methods: Phase 2a patients (n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients (n = 27) received one intravenous dose of 300 or 1800 mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid., Results: MTPS9579A did not meet the primary endpoint (hazard ratio = 0.90; 95% CI: 0.55-1.47; p = 0.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8-fold lower, and bronchial active and total tryptase levels were higher (119-fold and 30-fold, respectively). Pharmacokinetic/pharmacodynamic modeling predicted intravenous doses of 3800 mg every 4 weeks would be necessary to achieve 95% active tryptase inhibition from baseline., Conclusions: The MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy., (© 2024 Genentech and The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Purpose: In Southeastern Ontario, increased patient distance from the regional lung cancer diagnostic assessment program (LDAP) is associated with a lower likelihood of patient care via LDAP while receiving care via LDAP is associated with improved survival. We implemented an LDAP outreach clinic to provide specialist assessment for patients with suspected lung cancer at a regional community hospital and assessed the impact on timeliness and accessibility of care., Materials and Methods: The Kingston Health Sciences Centre LDAP team engaged with community hospital partners to develop and launch the LDAP outreach clinic. We performed a retrospective chart review of LDAP patients (N = 1,070) before (August-November 2021; n = 234) and after implementation of the outreach clinic (November 2021-October 2022; n = 836). Descriptive data are reported as No. (%). Unpaired t tests and statistical process control charts assess for significance. A cost analysis of out-of-pocket patient costs related to travel and parking is presented in 2022 Canadian dollars (CAD)., Results: Compared with a 3-month matched time period before (August-October 2021) and after outreach clinic (August-October 2022), the mean time from referral to assessment and time from referral to diagnosis decreased from 20.3 to 14.4 days ( P = .0019) and 40.0 to 28.9 days ( P = .0007), respectively. Over 12 months, the total patient travel was reduced by 8,856 km, which combined with parking cost-savings, resulted in patient out-of-pocket savings of CAD $5,755.60 (CAD $47.60/patient). Accounting for physician travel, the total travel saved was 5,688 km, corresponding to reduced CO 2 emissions by 1.9 tCO 2 ., Conclusion: Implementation of a lung cancer outreach clinic led to improved timeliness of care, patient cost-savings, and reduced carbon footprint while serving patients in their community.

Personalized dosing approaches play important roles in clinical practices to improve benefit: risk profiles. Whereas this is also important for drug development, especially in the context of drugs with narrow therapeutic windows, such approaches have not been fully evaluated during clinical development. Fazpilodemab (BFKB8488A) is an agonistic bispecific antibody which was being developed for the treatment of nonalcoholic steatohepatitis. The objective of this study was to characterize the exposure-response relationships of fazpilodemab with the purpose of guiding dose selection for a phase II study, as well as to evaluate various personalized dosing strategies to optimize the treatment benefit. Fazpilodemab exhibited clear exposure-response relationships for a pharmacodynamic (PD) biomarker and gastrointestinal adverse events (GIAEs), such as nausea and vomiting. Static exposure-response analysis, as well as longitudinal adverse event (AE) analysis using discrete-time Markov model, were performed to characterize the observations. Clinical trial simulations were performed based on the developed exposure-response models to evaluate probability of achieving target PD response and the frequency of GIAEs to inform phase II dose selection. Dynamic simulation of personalized dosing strategies demonstrated that the AE-based personalized dosing is the most effective approach for optimizing the benefit-risk profiles. The approach presented here can be a useful framework for quantifying the benefit of personalized dosing for drugs with narrow therapeutic windows., (© 2024 Genentech, Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

GPKPDviz is a Shiny application (app) dedicated to real-time simulation, visualization, and assessment of the pharmacokinetic/pharmacodynamic (PK/PD) models. Within the app, gPKPDviz is capable of generating virtual populations and complex dosing and sampling scenarios, which, together with the streamlined workflow, is designed to efficiently assess the impact of covariates and dosing regimens on PK/PD end points. The actual population data from clinical trials can be loaded into the app for simulation if desired. The app-generated dosing regimens include single or multiple dosing, and more complex regimens, such as loading doses or intermittent dosing. When necessary, the dosing regimens can be defined externally and loaded to the app for simulation. Using mrgsolve as the simulation engine, gPKPDviz is typically used for population simulation, however, with a slight modification of the mrgsolve model, gPKPDviz is capable of performing individual simulations with individual post hoc parameters, individual dosing logs, and individual sampling timepoints through an external dataset. A built-in text editor has a debugging feature for the mrgsolve model, providing the same error messages as model compilation in R. GPKPDviz has had stringent validation by comparing simulation results between the app and using mrgsolve in R. GPKPDviz is a member of the suite of Modeling and Simulation Shiny apps developed at Genentech to facilitate the typical modeling work in Clinical Pharmacology. For broader access to the Pharmacometric community, gPKPDviz has been published as an open-source application in GitHub under the terms of GNU General Public License., (© 2023 Genentech, Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Over two-thirds of pregnant women in the U.S. have insufficient 25(OH)D (Vitamin D) concentrations, which can adversely impact fetal health. Several pollutants have been associated with 25(OH)D, but have not been considered in the context of chemical co-exposures. We aimed to determine associations between a broad mixture of prenatal environmental chemical exposures and 25(OH)D concentrations in mid-pregnancy. Stored mid-pregnancy serum samples were assayed from 421 women delivering live births in Southern California in 2000-2003. 25(OH)D, six BFRs, eleven polychlorinated biphenyls (PCBs), six per- and polyfluoroalkyl substances, and two organochlorine pesticides were detected in ≥60% of specimens. Gestational exposures to airborne particulate matter ≤ 10 μm (PM 10 ) and ≤ 2.5 μm (PM 2.5 ), nitrogen monoxide (NO), nitrogen dioxide (NO 2 ), and ozone concentrations were derived from monitoring station data. Bayesian Hierarchical Modeling (BHM) and Bayesian Kernel Machine Regression (BKMR) analyses estimated overall mixture and individual chemical associations accounting for co-exposures and covariates with mean 25(OH)D levels, and BHM was used to estimate associations with insufficient (<75 nMol/L) 25(OH)D levels. Non-mixture associations for each chemical were estimated with linear and logistic models. PM 10 [BHM estimate: -0.133 nmol/l 95% Credible Interval (-0.240, -0.026)] was associated with lower 25(OH)D in BHM and BKMR. Higher quantiles of combined exposures were associated with lower 25(OH)D, though with wide credible intervals. In non-mixture models, PM 10 , PM 2.5 , NO, and NO 2 were associated with lower concentrations, while O 3 and PBDE153 were associated with higher 25(OH)D and/or lower insufficiency. While some chemicals were associated with increased and others with decreased 25(OH)D concentrations, the overall mixture was associated with lower concentrations. Mixture analyses differed from non-mixture regressions, highlighting the importance of mixtures approaches for estimating real-world associations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: To report the safety and efficacy of ipatasertib (AKT inhibitor) combined with rucaparib (PARP inhibitor) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with second-generation androgen receptor inhibitors., Patients and Methods: In this two-part phase Ib trial (NCT03840200), patients with advanced prostate, breast, or ovarian cancer received ipatasertib (300 or 400 mg daily) plus rucaparib (400 or 600 mg twice daily) to assess safety and identify a recommended phase II dose (RP2D). A part 1 dose-escalation phase was followed by a part 2 dose-expansion phase in which only patients with mCRPC received the RP2D. The primary efficacy endpoint was prostate-specific antigen (PSA) response (≥50% reduction) in patients with mCRPC. Patients were not selected on the basis of tumor mutational status., Results: Fifty-one patients were enrolled (part 1 = 21; part 2 = 30). Ipatasertib 400 mg daily plus rucaparib 400 mg twice daily was the selected RP2D, received by 37 patients with mCRPC. Grade 3/4 adverse events occurred in 46% (17/37) of patients, with one grade 4 adverse event (anemia, deemed related to rucaparib) and no deaths. Adverse events leading to treatment modification occurred in 70% (26/37). The PSA response rate was 26% (9/35), and the objective response rate per Response Criteria in Solid Tumors (RECIST) 1.1 was 10% (2/21). Median radiographic progression-free survival per Prostate Cancer Working Group 3 criteria was 5.8 months [95% confidence interval (CI), 4.0-8.1], and median overall survival was 13.3 months (95% CI, 10.9-not evaluable)., Conclusions: Ipatasertib plus rucaparib was manageable with dose modification but did not demonstrate synergistic or additive antitumor activity in previously treated patients with mCRPC., (©2023 American Association for Cancer Research.)

XmAb24306 is a lymphoproliferative interleukin (IL)-15/IL-15 receptor α (IL-15Rα) Fc-fusion protein currently under clinical investigation as an immunotherapeutic agent for cancer treatment. XmAb24306 contains mutations in IL-15 that attenuate its affinity to the heterodimeric IL-15 receptor βγ (IL-15R). We observe substantially prolonged pharmacokinetics (PK) (half-life ∼ 2.5 to 4.5 days) in single- and repeat-dose cynomolgus monkey (cyno) studies compared to wild-type IL-15 (half-life ∼ 1 hour), leading to increased exposure and enhanced and durable expansion of NK cells, CD8+ T cells and CD4-CD8- (double negative [DN]) T cells. Drug clearance varied with dose level and time post-dose, and PK exposure decreased upon repeated dosing, which we attribute to increased target-mediated drug disposition (TMDD) resulting from drug-induced lymphocyte expansion (i.e., pharmacodynamic (PD)-enhanced TMDD). We developed a quantitative systems pharmacology (QSP) model to quantify the complex PKPD behaviors due to the interactions of XmAb24306 with multiple cell types (CD8+, CD4+, DN T cells, and NK cells) in the peripheral blood (PB) and lymphoid tissues. The model, which includes nonspecific drug clearance, binding to and TMDD by IL15R differentially expressed on lymphocyte subsets, and resultant lymphocyte margination/migration out of PB, expansion in lymphoid tissues, and redistribution to the blood, successfully describes the systemic PK and lymphocyte kinetics observed in the cyno studies. Results suggest that after 3 doses of every-two-week (Q2W) doses up to 70 days, the relative contributions of each elimination pathway to XmAb24306 clearance are: DN T cells > NK cells > CD8+ T cells > nonspecific clearance > CD4+ T cells. Modeling suggests that observed cellular expansion in blood results from the influx of cells expanded by the drug in lymphoid tissues. The model is used to predict lymphoid tissue expansion and to simulate PK-PD for different dose regimens. Thus, the model provides insight into the mechanisms underlying the observed PK-PD behavior of an engineered cytokine and can serve as a framework for the rapid integration and analysis of data that emerges from ongoing clinical studies in cancer patients as single-agent or given in combination., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The pharmacokinetic (PK) characteristics of omalizumab and its pharmacodynamic (PD) effect in patients has yet to be fully characterized in chronic spontaneous urticaria, which could elucidate its pathogenesis and treatment response. This study has two objectives; (1) characterize the population PK of omalizumab and its PD effect on IgE, and (2) develop a drug effect model of omalizumab in urticaria (via change in weekly itch severity score). The target-mediated population of PK/PD model incorporating omalizumab-IgE binding and turnover adequately described PK and PD of omalizumab. The effect compartment model and linear drug effect and additive placebo response adequately described placebo and treatment effects of omalizumab. Several baseline covariates were identified for PK/PD and drug effect models. The developed model has the potential to aid in understanding variability in PK/PD as well as response to omalizumab treatment., (© 2023 Genentech, Inc and QuanTx Consulting. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Tryptase, a protease implicated in asthma pathology, is secreted from mast cells upon activation during an inflammatory allergic response. MTPS9579A is a novel monoclonal antibody that inhibits tryptase activity by irreversibly dissociating the active tetramer into inactive monomers. This study assessed the relationship between MTPS9579A concentrations in healthy subjects and tryptase levels in serum and nasal mucosal lining fluid from healthy subjects and patients with moderate-to-severe asthma. These data were used to develop a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model that quantitatively inter-relates MTPS9579A exposure and inhibition of active tryptase in the airway of patients with asthma. From initial estimates of airway tryptase levels and drug partitioning, the PK/PD model predicted almost complete neutralization of active tryptase in the airway of patients with asthma with MTPS9579A doses of 900 mg and greater, administered intravenously (i.v.) once every 4 weeks (q4w). Suppression of active tryptase during an asthma exacerbation event was also evaluated using the model by simulating the administration of MTPS9579A during a 100-fold increase in tryptase secretion in the local tissue. The PK/PD model predicted that 1800 mg MTPS9579A i.v. q4w results in 95.7% suppression of active tryptase at the steady-state trough concentration. Understanding how the exposure-response relationship of MTPS9579A in healthy subjects translates to patients with asthma is critical for future clinical studies assessing tryptase inhibition in the airway of patients with moderate-to-severe asthma., (© 2023 Genentech, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

COVID-19 has radically transformed urban travel behavior throughout the world. Agencies have had to provide adequate service while navigating a rapidly changing environment with reduced revenue. As COVID-19-related restrictions are lifted, transit agencies are concerned about their ability to adapt to changes in ridership behavior and public transit usage. To aid their becoming more adaptive to sudden or persistent shifts in ridership, we addressed three questions: To what degree has COVID-19 affected fixed-line public transit ridership and what is the relationship between reduced demand and -vehicle trips? How has COVID-19 changed ridership patterns and are they expected to persist after restrictions are lifted? Are there disparities in ridership changes across socioeconomic groups and mobility-impaired riders? Focusing on Nashville and Chattanooga, TN, ridership demand and vehicle trips were compared with anonymized mobile location data to study the relationship between mobility patterns and transit usage. Correlation analysis and multiple linear regression were used to investigate the relationship between socioeconomic indicators and changes in transit ridership, and an analysis of changes in paratransit demand before and during COVID-19. Ridership initially dropped by 66% and 65% over the first month of the pandemic for Nashville and Chattanooga, respectively. Cellular mobility patterns in Chattanooga indicated that foot traffic recovered to a greater degree than transit ridership between mid-April and the last week in June, 2020. Education-level had a statistically significant impact on changes in fixed-line bus transit, and the distribution of changes in demand for paratransit services were similar to those of fixed-line bus transit., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© National Academy of Sciences: Transportation Research Board 2023.)

A Cox proportional hazard (CoxPH) model is conventionally used to assess exposure-response (E-R), but its performance to uncover the ground truth when only one dose level of data is available has not been systematically evaluated. We established a simulation workflow to generate realistic E-R datasets to assess the performance of the CoxPH model in recovering the E-R ground truth in various scenarios, considering two potential reasons for the confounded E-R relationship. We found that at high doses, when the pharmacological effects are largely saturated, missing important confounders is the major reason for inferring false-positive E-R relationships. At low doses, when a positive E-R slope is the ground truth, either missing important confounders or mis-specifying the interactions can lead to inaccurate estimates of the E-R slope. This work constructed a simulation workflow generally applicable to clinical datasets to generate clinically relevant simulations and provide an in-depth interpretation on the E-R relationships with confounders inferred by the conventional CoxPH model., (© 2022 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Black women have the highest incidence of preterm birth (PTB). Upstream factors, including neighborhood context, may be key drivers of this increased risk. This study assessed the relationship between neighborhood quality, defined by the Healthy Places Index, and PTB among Black women who lived in Oakland, California, and gave birth between 2007 and 2011 (N = 5418 women, N = 107 census tracts). We found that, compared with those living in lower quality neighborhoods, women living in higher quality neighborhoods had 20-38% lower risk of PTB, independent of confounders. Findings have implications for place-based research and interventions to address racial inequities in PTB., (© 2022. The Author(s).)

SPINK6 was identified in human skin as a cellular inhibitor of serine proteases of the KLK family. Airway serine proteases are required to cleave hemagglutinin (HA) of influenza A viruses (IAVs) to initiate an infection in the human airway. We hypothesized that SPINK6 may inhibit common airway serine proteases and restrict IAV activation. We demonstrate that SPINK6 specifically suppresses the proteolytic activity of HAT and KLK5, HAT- and KLK5-mediated HA cleavage, and restricts virus maturation and replication. SPINK6 constrains the activation of progeny virions and impairs viral growth; and vice versa, blocking endogenous SPINK6 enhances HA cleavage and viral growth in physiological-relevant human airway organoids where SPINK6 is intrinsically expressed. In IAV-infected mice, SPINK6 significantly suppresses viral growth and improves mouse survival. Notably, individuals carrying the higher SPINK6 expression allele were protected from human H7N9 infection. Collectively, SPINK6 is a novel host inhibitor of serine proteases in the human airway and restricts IAV activation., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)

The notoriously destructive and invasive soft scale, Ceroplastes cirripediformis Comstock (Hemiptera: Coccomorpha: Coccidae), is recorded for the first time from India. The scale is redescribed to facilitate its identification and information on its host range, natural enemies and distribution is provided. An identification key to the Indian species in this genus is given. Management options in the event of an outbreak are discussed briefly. The establishment of this scale insect warrants special attention in India as it is a potentially damaging plant pest and has a broad host range across many plant families.

Competing Interests: The authors have no conflicts of interest to disclose.

Increasing vitamin D deficiency and evidence for vitamin D's role in brain and immune function have recently led to studies of neurodevelopment; however, few are specific to autism spectrum disorder (ASD) and vitamin D in pregnancy, a likely susceptibility period. We examined this in a case-control study of 2000-2003 Southern Californian births; ASD and intellectual disability (ID) were identified through the Department of Developmental Services and controls from birth certificates (N = 534, 181, and 421, respectively, in this analysis). Total 25-Hydroxyvitamin D (25(OH)D) was measured in mid-pregnancy serum, categorized as deficient (<50 nmol/L), insufficient (50-74 nmol/L), or sufficient (≥75 nmol/L, referent category), and examined continuously (per 25 nmol/L). Crude and adjusted odds ratios (AORs) and 95% confidence intervals (95% CI) were calculated. Non-linearity was examined with cubic splines. AORs (95% CI) for ASD were 0.79 (0.49-1.3) for maternal deficiency (9.5%), 0.93 (0.68-1.3) for insufficiency (25.6%), and 0.95 (0.86, 1.05) for linear continuous 25(OH)D. Results were similarly null for ASD with or without ID, and ID only. Interactions were observed; non-Hispanic whites (NHW) (AOR = 0.82, 95% CI = 0.69-0.98) and males (AOR = 0.89, 95% CI = 0.80-0.99) had protective associations for ASD with continuous 25(OH)D. A positive association with ASD was observed in females (AOR = 1.40, 95% CI = 1.06-1.85). With splines, a non-linear inverted j-shaped pattern was seen overall (P = 0.009 for non-linearity), with the peak around 100 nmol/L; a non-linear pattern was not observed among NHW, females, nor for ID. Our findings from a large study of ASD and prenatal vitamin D levels indicate that further research is needed to investigate non-linear patterns and potentially vulnerable sub-groups. LAY SUMMARY: We studied whether mothers' vitamin D levels during pregnancy were related to their children having autism (or low IQ) later. Low vitamin D levels were not related to greater risk of autism or low IQ in children overall. With higher levels of mothers' vitamin D, risk of autism went down in boys, but went up in girls. Risk of autism also went down in children of non-Hispanic white mothers with higher vitamin D levels, but we did not find a relation in other race/ethnic groups., (© 2020 International Society for Autism Research and Wiley Periodicals LLC.)

COVID-19 pandemic is the third zoonotic coronavirus (CoV) outbreak of the century after severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) since 2012. Treatment options for CoVs are largely lacking. Here, we show that clofazimine, an anti-leprosy drug with a favorable safety and pharmacokinetics profile, possesses pan-coronaviral inhibitory activity, and can antagonize SARS-CoV-2 replication in multiple in vitro systems, including the human embryonic stem cell-derived cardiomyocytes and ex vivo lung cultures. The FDA-approved molecule was found to inhibit multiple steps of viral replication, suggesting multiple underlying antiviral mechanisms. In a hamster model of SARS-CoV-2 pathogenesis, prophylactic or therapeutic administration of clofazimine significantly reduced viral load in the lung and fecal viral shedding, and also prevented cytokine storm associated with viral infection. Additionally, clofazimine exhibited synergy when administered with remdesivir. Since clofazimine is orally bioavailable and has a comparatively low manufacturing cost, it is an attractive clinical candidate for outpatient treatment and remdesivir-based combinatorial therapy for hospitalized COVID-19 patients, particularly in developing countries. Taken together, our data provide evidence that clofazimine may have a role in the control of the current pandemic SARS-CoV-2, endemic MERS-CoV in the Middle East, and, possibly most importantly, emerging CoVs of the future.

Objective: The benefits of aerobic exercise early after stroke are well known, but concerns about cardiovascular risk are a barrier to clinical implementation. Symptom-limited exercise testing with electrocardiography (ECG) is recommended but not always feasible. The purpose of this study was to determine the frequency of and corresponding exercise intensities at which ECG abnormalities occurred during submaximal exercise testing that would limit safe exercise prescription beyond those intensities., Methods: This study was a retrospective analysis of ECGs from 195 patients who completed submaximal exercise testing during stroke rehabilitation. A graded submaximal exercise test was conducted with a 5- or 12-lead ECG and was terminated on the basis of predetermined endpoint criteria (heart rate, perceived exertion, signs, or symptoms). ECGs were retrospectively reviewed for exercise-induced abnormalities and their associated heart rates., Results: The peak heart rate achieved was 65.4% (SD = 10.5%) of the predicted maximum heart rate or 29.1% (SD = 15.5%) of the heart rate reserve (adjusted for beta-blocker medications). The test was terminated more often because of perceived exertion (93/195) than because of heart rate limits (60/195). Four patients (2.1%) exhibited exercise-induced horizontal or downsloping ST segment depression of ≥1 mm. Except for 1 patient, the heart rate at test termination was comparable with the heart rate associated with the onset of the ECG abnormality., Conclusion: A graded submaximal exercise test without ECG but with symptom monitoring and conservative heart rate and perceived exertion endpoints may facilitate safe exercise intensities early after stroke. Symptom-limited exercise testing with ECG is still recommended when progressing to higher intensity exercise., Impact: Concerns about cardiovascular risk are a barrier to physical therapists implementing aerobic exercise in stroke rehabilitation. This study showed that, in the absence of access to exercise testing with ECG, submaximal testing with conservative heart rate and perceived exertion endpoints and symptom monitoring can support physical therapists in the safe prescription of aerobic exercise early after stroke., Lay Summary: It is recommended that people with stroke participate in aerobic exercise as early as possible during their rehabilitation. A submaximal exercise test with monitoring of heart rate, perceived exertion, blood pressure, and symptoms can support physical therapists in safely prescribing that exercise., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Vitamin D is essential for several physiological functions and biological processes. Increasing levels of maternal vitamin D are required throughout pregnancy as a unique source of vitamin D for the fetus, and consequently maternal vitamin D deficiency may result in several adverse outcomes in newborns. However, the genetic regulation of vitamin D in pregnancy and at birth is not yet well understood. We performed genome-wide association studies of maternal midgestational serum-derived and neonatal blood-spot-derived total 25-hydroxyvitamin D from a case-control study of autism spectrum disorder (ASD). We identified one fetal locus (rs4588) significantly associated with neonatal vitamin D levels in the GC gene, encoding the binding protein for the transport and function of vitamin D. We also found suggestive cross-associated loci for neonatal and maternal vitamin D near immune genes, such as CXCL6-IL8 and ACKR1 We found no interactions with ASD. However, when including a set of cases with intellectual disability but not ASD ( N = 179), we observed a suggestive interaction between decreased levels of neonatal vitamin D and a specific maternal genotype near the PKN2 gene. Our results suggest that genetic variation influences total vitamin D levels during pregnancy and at birth via proteins in the vitamin D pathway, but also potentially via distinct mechanisms involving loci with known roles in immune function that might be involved in vitamin D pathophysiology in pregnancy., (Copyright © 2020 by the Genetics Society of America.)

Objective : To determine the frequency of physiotherapist-administered aerobic exercise testing/training, the proportion of physiotherapists who administer this testing/training, and the barriers that currently exist across different practice environments. A secondary objective is to identify the learning needs of physiotherapists for the development of an education curriculum in aerobic exercise testing and training with electrocardiograph (ECG) administration and interpretation. Design : National, cross-sectional survey. Participants : Registered physiotherapists practicing in Canada. Results : Out of 137 participants, most (75%) physiotherapists prescribed aerobic exercise on a regular basis (weekly); however, 65% had never conducted an aerobic exercise test. There were no significant differences in frequency of aerobic exercise testing across different practice environments or across years of physiotherapy experience. Physiotherapists perceived the main barriers to aerobic exercise testing as being a lack of equipment/space (78%), time (65%), and knowledge (56%). Although most (82%) were uncomfortable administering 12-lead ECG-monitored aerobic exercise tests, 60% stated they would be interested in learning more about ECG interpretation. Conclusion : This study found that physiotherapists are regularly implementing aerobic exercise. This exercise was infrequently guided by formal aerobic exercise testing, which could increase access to safe and effective exercise within the optimal aerobic training zone. As well, this could facilitate training in patients with cardiovascular diagnoses that require additional testing for medical clearance. Increased ECG training and access to equipment for physiotherapists may augment pre-screening aerobic exercise testing. This training should include learning the key arrhythmias for aerobic exercise test termination as defined by the American College of Sports Medicine.

Vitamin D deficiency has been increasing concurrently with prevalence of autism spectrum disorders (ASD), and emerging evidence suggests vitamin D is involved in brain development. Most prior studies of ASD examined vitamin D levels in children already diagnosed, but a few examined levels during perinatal development, the more likely susceptibility period. Therefore, we examined newborn vitamin D levels in a case-control study conducted among births in 2000-2003 in southern California. Children with ASD (N = 563) or intellectual disability (ID) (N = 190) were identified from the Department of Developmental Services and compared to population controls (N = 436) identified from birth certificates. 25-hydroxyvitamin D (25(OH)D) was measured in archived newborn dried blood spots by a sensitive assay and corrected to sera equivalents. We categorized 25(OH) D levels as deficient (<50 nmol/L), insufficient (50-74 nmol/L), and sufficient (≥75 nmol/L), and also examined continuous levels, using logistic regression. The adjusted odds ratios (AOR) and 95% confidence intervals for ASD were 0.96 (0.64-1.4) for 25(OH)D deficiency (14% of newborns) and 1.2 (0.86-1.6) for insufficiency (26% of newborns). The AORs for continuous 25(OH)D (per 25 nmol/L) were 1.0 (0.91-1.09) for ASD and 1.14 (1.0-1.30) for ID. Thus, in this relatively large study of measured newborn vitamin D levels, our results do not support the hypothesis of lower 25(OH)D being associated with higher risk of ASD (or ID), although we observed suggestion of interactions with sex and race/ethnicity. 25(OH)D levels were relatively high (median 84 nmol/L in controls), so results may differ in populations with higher prevalence of low vitamin D levels. Autism Res 2019, 12: 989-998. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We studied whether vitamin D levels measured at birth were related to whether a child later developed autism (or low IQ). Our results did not show that children with autism, or low IQ, overall had lower vitamin D levels at birth than children without autism. Vitamin D levels were fairly high, on average, in these children born in Southern California., (© 2019 International Society for Autism Research, Wiley Periodicals, Inc.)

The CXCL12 gene produces a series of transcript variants through alternative splicing at the 3' end of its pre-mRNA. This study explores the biological activities of these alternative transcripts and the mechanisms involved in the regulation of CXCL12 transcription and RNA splicing. We identified a "GA" insertion mutation in the region of CXCL12α DNA encoding the conserved 3'UTR. This variant transcript was named CXCL12-3'GA+. The mutation occurred at a frequency of 13.2% in healthy Chinese individuals. However, its frequency in healthy Caucasians was 22.6%, significantly higher than what was observed in the Chinese. Genomic analysis indicated that the GA+ mutation likely encodes a G-quadruplex structure in close proximity to a cluster of important AU-rich elements (AREs) that are well-established regulators of mRNA stability at the 3'UTR. Experiments using molecular constructs encoding the 3'UTR of CXCL12 revealed that the GA+ allele can significantly increase gene expression compared to the WT allele. Further studies uncovered that the WT allele was associated with the production of a 225-bp minor transcript isoform (MTI) through alternative splicing resulting in the deletion of exon 2. ARMS-PCR using samples collected from cultured PBMCs of WT/GA+ genotype carriers indicated that the GA+ allele was preferentially transcribed compared to the WT allele. In summary, the study demonstrates that a GA insertion in the region encoding the 3'UTR of CXCL12α may affect gene expression through alternative mRNA splicing. This finding provides a basis for understanding how multiple elements in the sequence encoding the 3'UTR of the CXCL12 gene regulates its transcription and may lead to insights about diseases involving abnormal CXCL12α expression., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Neighbourhood opportunity, measured by poverty, income and deprivation, has been associated with preterm birth, however little is known about the contribution of early-life and life-course neighbourhood opportunity to preterm birth risk and racial-ethnic disparities. We examined maternal early-life and adult neighbourhood opportunity in relation to risk of preterm birth and racial-ethnic disparities in a population-based cohort of women under age 30., Methods: We linked census tract poverty data to 2 generations of California births from 1982-2011 for 403 315 white, black, or Latina mothers-infant pairs. We estimated the risk of preterm birth, and risk difference (RD) comparing low opportunity (≥20% poverty) in early life or adulthood to high opportunity using targeted maximum likelihood estimation., Results: At each time point, low opportunity was related to increased preterm birth risk compared to higher opportunity neighbourhoods for white, black and Latina mothers (RDs 0.3-0.7%). Compared to high opportunity at both time points, risk differences were generally highest for sustained low opportunity (RD 1.5, 1.3, and 0.7% for white, black and Latina mothers, respectively); risk was elevated with downward mobility (RD 0.7, 1.3, and 0.4% for white, black and Latina mothers, respectively), and with upward mobility only among black mothers (RD 1.2%). The black-white preterm birth disparity was reduced by 22% under high life-course opportunity., Conclusions: Early-life and sustained exposure to residential poverty is related to increased PTB risk, particularly among black women, and may partially explain persistent black-white disparities., (© 2018 John Wiley & Sons Ltd.)

We evaluated whether low-grade albuminuria or black race modulates ambulatory blood pressure (BP) or nocturnal BP response to the DASH diet. Among 202 adults enrolled in the DASH multicenter trial who were fed the DASH or control diet for 8 weeks, reductions in 24-hour daytime and nighttime SBP and DBP were significantly larger for DASH compared to control. Median changes in nocturnal BP dipping were not significant. Compared to urine albumin excretion of <7 mg/d, ≥7 mg/d was associated with larger significant median reductions in 24-hour SBP (-7.3 vs -3.1 mm Hg), all measures of DBP (24-hour: -5.9 vs -1.8 mm Hg; daytime: -9.9 vs -4.0 mm Hg; nighttime -9.0 vs -2.0 mm Hg), and with increased nocturnal SBP dipping (2.3% vs -0.5%). Black race was associated with larger median reduction in 24-hour SBP only (-5.5 vs -2.4 mm Hg). This analysis suggests greater effect of DASH on ambulatory BP in the presence of low-grade albuminuria., (©2018 Wiley Periodicals, Inc.)

Gamma-butyrolactones (GBLs) are signalling molecules that control antibiotic production in Streptomyces bacteria. The genetically engineered strain S. coelicolor M1152 was found to overproduce GBLs SCB1-3 as well as five novel GBLs named SCB4-8. Incorporation experiments using isotopically-labelled precursors confirmed the chemical structures of SCB1-3 and established those of SCB4-8.

People with stroke do not achieve adequate levels of physical exercise following discharge from rehabilitation. We developed a group exercise and self-management program (PROPEL), delivered during stroke rehabilitation, to promote uptake of physical activity after discharge. This study aimed to establish the feasibility of a larger study to evaluate the effect of this program on participation in self-directed physical activity. Participants with subacute stroke were recruited at discharge from one of three rehabilitation hospitals; one hospital offered the PROPEL program whereas the other two did not (comparison group; COMP). A high proportion (11/16) of eligible PROPEL program participants consented to the study. Fifteen COMP participants were also recruited. Compliance with wearing an accelerometer for 6 weeks continuously and completing physical activity questionnaires was high (>80%), whereas only 34% of daily heart rate data were available. Individuals who completed the PROPEL program seemed to have higher outcome expectations for exercise, fewer barriers to physical activity, and higher participation in physical activity than COMP participants (Hedge's g ≥ 0.5). The PROPEL program delivered during stroke rehabilitation shows promise for reducing barriers to exercise and increasing participation in physical activity after discharge. This study supports feasibility of a larger randomized trial to evaluate this program.

Medication non-adherence is one of the major obstacles to recovery in first-episode psychosis (FEP). This study aimed to identify the predictors and rates of medication non-adherence in the first and second year after the start of treatment (baseline) in urban Chinese FEP patients. Relevant information on medication non-adherence and potential baseline predictors, including demographic variables, clinical measures, violence/suicide attempts, stressful life experiences, intervention received, and follow-up attendance, were collected from case records of 1400 FEP patients in Hong Kong. The non-adherence rate was 16.2% in year 1 and 15.4% in year 2. Regression analyses revealed the predictors for non-adherence in year 1 were no hospitalization at baseline, non-schizophrenia diagnosis, and more years of education. Predictors of non-adherence in year 2 included acute/subacute onset and older age of onset. Predictors common in both years were defaulting from psychiatric follow-up during baseline, standard psychiatric care (no early intervention), and lower positive symptoms severity at baseline. In assessing non-adherence risk and for planning phase-specific early interventions for FEP, particularly in a Chinese context, healthcare professionals should consider the common and specific predictors for non-adherence identified in the first and second years of treatment and should not overlook patients with less clinically severe symptoms., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

To discern virulent from innocuous microbes, the innate immune system senses events associated with bacterial access to immunoprivileged sites such as the host cell cytosol. One such pathway is triggered by the cytosolic delivery of flagellin, the major subunit of the flagellum, by bacterial secretion systems. This leads to inflammasome activation and subsequent proinflammatory cell death (pyroptosis) of the infected phagocyte. In this study, we demonstrate that the causative agent of typhoid fever, Salmonella enterica serovar Typhi, can partially subvert this critical innate immune recognition event. The transcriptional regulator TviA, which is absent from Salmonella serovars associated with human gastroenteritis, repressed the expression of flagellin during infection of human macrophage-like (THP-1) cells. This mechanism allowed S. Typhi to dampen inflammasome activation, leading to reduced interleukin-1β (IL-1β) secretion and diminished cell death. Likewise, the introduction of the tviA gene in nontyphoidal Salmonella enterica serovar Typhimurium reduced flagellin-induced pyroptosis. These data suggest that gene regulation of virulence factors enables S. Typhi to evade innate immune recognition by concealing a pathogen-induced process from being sensed by the inflammasome., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Delivery of microbial products into the mammalian cell cytosol by bacterial secretion systems is a strong stimulus for triggering pro-inflammatory host responses. Here we show that Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, tightly regulates expression of the invasion-associated type III secretion system (T3SS-1) and thus fails to activate these innate immune signaling pathways. The S. Typhi regulatory protein TviA rapidly repressed T3SS-1 expression, thereby preventing RAC1-dependent, RIP2-dependent activation of NF-κB in epithelial cells. Heterologous expression of TviA in S. enterica serovar Typhimurium (S. Typhimurium) suppressed T3SS-1-dependent inflammatory responses generated early after infection in animal models of gastroenteritis. These results suggest that S. Typhi reduces intestinal inflammation by limiting the induction of pathogen-induced processes through regulation of virulence gene expression.

Objective: To determine whether attending an aerobic fitness program during inpatient stroke rehabilitation is associated with increased participation in physical activity after discharge., Design: This was a prospective cohort study. Patients who received inpatient stroke rehabilitation and were discharged into the community (n = 61; mean age, 65 years) were recruited. Thirty-five participants attended a standardized aerobic fitness program during inpatient rehabilitation, whereas 26 did not. The Physical Activity Scale for Individuals with Physical Disabilities (PASIPD) and adherence to the American College of Sports Medicine (ACSM) guidelines were assessed up to 6 months after discharge., Results: Participants in the fitness group had PASIPD scores and adherence to ACSM guidelines similar to those of participants in the nonfitness group up to 6 months after discharge. There was no significant correlation between volume of exercise performed during the inpatient program and amount of physical activity after discharge., Conclusion: Participation in an inpatient fitness program did not increase participation in physical activity after discharge in individuals with stroke. A new model of care that encourages patients to pursue physical activity after discharge and reduces the potential barriers to participation should be developed.

Technology-based assessment tools with semi-automated processing, such as pressure-sensitive mats used for gait assessment, may be considered to be objective; therefore it may be assumed that rater reliability is not a concern. However, user input is often required and rater reliability must be determined. The purpose of this study was to assess the inter- and intra-rater reliability of spatial and temporal characteristics of gait in stroke patients using the GAITRite system. Forty-six individuals with stroke attending in-patient rehabilitation walked across the pressure-sensitive mat 2-4 times at preferred walking speeds, with or without a gait aid. Five raters independently processed gait data. Three raters re-processed the data after a delay of at least one month. The intraclass correlation coefficients (ICC) and 95% confidence intervals of the ICC were determined for velocity, step time, step length, and step width. Inter-rater reliability for velocity, step time, and step length were high (ICC>0.90). Intra-rater reliability was generally greater than inter-rater reliability (from 0.81 to >0.99 for inter-rater versus 0.77 to >0.99 for intra-rater reliability). Overall, this study suggests that GAITRite is a reliable assessment tool; however, there still remains subjectivity in processing the data, resulting in no patients with perfect agreement between raters. Additional logic checking within the processing software or standardization of training could help to reduce potential errors in processing., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Circadian and ultradian variations of basal glucocorticoid secretion and transient elevations during stress are essential for homeostasis. Using intronic qRT-PCR to measure changes in primary transcript (hnRNA) we have shown that secretory events induced by stress or ACTH injection are followed by episodic increases in transcription of rate limiting steroidogenic proteins, such as steroidogenic acute regulatory protein (StAR), cytochrome P450 side chain cleavage and melanocortin receptor associated protein. These transcriptional episodes imply rapid turnover of steroidogenic proteins and the need of de novo synthesis following each secretory event. In addition to episodic ACTH secretion, it is likely that intracellular feedback mechanisms at the adrenal fasciculata level contribute to the generation of episodes of transcription. The time relationship between activation and translocation of the CREB co-activator, transducer of regulated CREB activity (TORC) to the nucleus preceding transcriptional episodes suggest the involvement of TORC in the transcriptional activation of StAR and other steroidogenic proteins., (Published by Elsevier Ireland Ltd.)

Our innate immune system distinguishes microbes from self by detecting conserved pathogen-associated molecular patterns. However, these are produced by all microbes, regardless of their pathogenic potential. To distinguish virulent microbes from those with lower disease-causing potential the innate immune system detects conserved pathogen-induced processes, such as the presence of microbial products in the host cytosol, by mechanisms that are not fully resolved. Here we show that NOD1 senses cytosolic microbial products by monitoring the activation state of small Rho GTPases. Activation of RAC1 and CDC42 by bacterial delivery or ectopic expression of SopE, a virulence factor of the enteric pathogen Salmonella, triggered the NOD1 signalling pathway, with consequent RIP2 (also known as RIPK2)-mediated induction of NF-κB-dependent inflammatory responses. Similarly, activation of the NOD1 signalling pathway by peptidoglycan required RAC1 activity. Furthermore, constitutively active forms of RAC1, CDC42 and RHOA activated the NOD1 signalling pathway. Our data identify the activation of small Rho GTPases as a pathogen-induced process sensed through the NOD1 signalling pathway.