Interactions between Gepotidacin and Escherichia coli Gyrase and Topoisomerase IV: Genetic and Biochemical Evidence for Well-Balanced Dual-Targeting.

Antimicrobial resistance is a global threat to human health. Therefore, efforts have been made to develop new antibacterial agents that address this critical medical issue. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibacterial in clinical development. Recently, phase III clinical trials for gepotidacin treatment of uncomplicated urinary tract infections caused by uropathogens, including Escherichia coli, were stopped for demonstrated efficacy. Because of the clinical promise of gepotidacin, it is important to understand how the compound interacts with its cellular targets, gyrase and topoisomerase IV, from E. coli. Consequently, we determined how gyrase and topoisomerase IV mutations in amino acid residues that are involved in gepotidacin interactions affect the susceptibility of E. coli cells to the compound and characterized the effects of gepotidacin on the activities of purified wild-type and mutant gyrase and topoisomerase IV. Gepotidacin displayed well-balanced dual-targeting of gyrase and topoisomerase IV in E. coli cells, which was reflected in a similar inhibition of the catalytic activities of these enzymes by the compound. Gepotidacin induced gyrase/topoisomerase IV-mediated single-stranded, but not double-stranded, DNA breaks. Mutations in GyrA and ParC amino acid residues that interact with gepotidacin altered the activity of the compound against the enzymes and, when present in both gyrase and topoisomerase IV, reduced the antibacterial activity of gepotidacin against this mutant strain. Our studies provide insights regarding the well-balanced dual-targeting of gyrase and topoisomerase IV by gepotidacin in E. coli.

Betanin dye extracted from ayrampo (Opuntia soehrensii) seeds to develop dye-sensitized solar cells.

Pigments extracted from ayrampo seeds of the Peruvian-native prickly pear (Opuntia soehrensii) were used in dye-sensitized solar cells with promising efficiencies. The performance of the solar cells was then improved via the addition of citric acid to stabilise the photosensitive dye, and an efficiency of 1.41% was achieved with current output remaining stable after 7 days. Upon testing in low-light conditions, the solar conversion efficiency of devices increased to 4%. This paper not only highlights the potential of natural sensitizers in DSSCs but also shows that simple extraction and gentle handling methods can contribute to the device performance.

Predicting personal PAH exposure using high dimensional questionnaire and wristband data.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are a class of pervasive environmental pollutants with a variety of known health effects. While significant work has been completed to estimate personal exposure to PAHs, less has been done to identify sources of these exposures. Comprehensive characterization of reported sources of personal PAH exposure is a critical step to more easily identify individuals at risk of high levels of exposure and for developing targeted interventions based on source of exposure. OBJECTIVE: In this study, we leverage data from a New York (NY)-based birth cohort to identify personal characteristics or behaviors associated with personal PAH exposure and develop models for the prediction of PAH exposure. METHODS: We quantified 61 PAHs measured using silicone wristband samplers in association with 75 questionnaire variables from 177 pregnant individuals. We evaluated univariate associations between each compound and questionnaire variable, conducted regression tree analysis for each PAH compound and completed a principal component analysis of for each participant's entire PAH exposure profile to determine the predictors of PAH levels. RESULTS: Regression tree analyses of individual compounds and exposure mixture identified income, time spent outdoors, maternal age, country of birth, transportation type, and season as the variables most frequently predictive of exposure.

Post transition metal substituted Keggin-type POMs as thin film chemiresistive sensors for H2O and CO2 detection.

Chemiresitive sensing allows the affordable and facile detection of small molecules such as H2O and CO2. Herein, we report a novel class of Earth-abundant post transition metal substituted Keggin polyoxometalates (POMs) for chemiresistive sensing applications, with conductivities up to 0.01 S cm-1 under 100% CO2 and 65% Relative Humidity (RH).

Improving the Conductivity of Amide-Based Small Molecules through Enhanced Molecular Packing and Their Application as Hole Transport Mediators in Perovskite Solar Cells.

Organic-inorganic hybrid halide perovskite solar cells (PSCs) have attracted substantial attention from the photovoltaic research community, with the power conversion efficiency (PCE) already exceeding 26%. Current state-of-the-art devices rely on Spiro-OMeTAD as the hole-transporting material (HTM); however, Spiro-OMeTAD is costly due to its complicated synthesis and expensive product purification, while its low conductivity ultimately limits the achievable device efficiency. In this work, we build upon our recently introduced family of low-cost amide-based small molecules and introduce a molecule (termed TPABT) that results in high conductivity values (∼10-5 S cm-1 upon addition of standard ionic additives), outperforming our previous amide-based material (EDOT-Amide-TPA, ∼10-6 S cm-1) while only costing an estimated $5/g. We ascribe the increased optoelectronic properties to favorable molecular packing, as shown by single-crystal X-ray diffraction, which results in close spacing between the triphenylamine blocks. This, in turn, results in a short hole-hopping distance between molecules and therefore good mobility and conductivity. In addition, TPABT exhibits a higher bandgap and is as a result more transparent in the visible range of the solar spectrum, leading to lower parasitic absorption losses than Spiro-OMeTAD, and has increased moisture stability. We applied the molecule in perovskite solar cells and obtained good efficiency values in the ∼15% range. Our approach shows that engineering better molecular packing may be the key to developing high-efficiency, low-cost HTMs for perovskite solar cells.

Menstrual cycle length variation by demographic characteristics from the Apple Women's Health Study.

Menstrual characteristics are important signs of women's health. Here we examine the variation of menstrual cycle length by age, ethnicity, and body weight using 165,668 cycles from 12,608 participants in the US using mobile menstrual tracking apps. After adjusting for all covariates, mean menstrual cycle length is shorter with older age across all age groups until age 50 and then became longer for those age 50 and older. Menstrual cycles are on average 1.6 (95%CI: 1.2, 2.0) days longer for Asian and 0.7 (95%CI: 0.4, 1.0) days longer for Hispanic participants compared to white non-Hispanic participants. Participants with BMI ≥ 40 kg/m2 have 1.5 (95%CI: 1.2, 1.8) days longer cycles compared to those with BMI between 18.5 and 25 kg/m2. Cycle variability is the lowest among participants aged 35-39 but are considerably higher by 46% (95%CI: 43%, 48%) and 45% (95%CI: 41%, 49%) among those aged under 20 and between 45-49. Cycle variability increase by 200% (95%CI: 191%, 210%) among those aged above 50 compared to those in the 35-39 age group. Compared to white participants, those who are Asian and Hispanic have larger cycle variability. Participants with obesity also have higher cycle variability. Here we confirm previous observations of changes in menstrual cycle pattern with age across reproductive life span and report new evidence on the differences of menstrual variation by ethnicity and obesity status. Future studies should explore the underlying determinants of the variation in menstrual characteristics.

Nondrug interventions for reducing SARS-CoV-2 transmission are frequently incompletely reported.

OBJECTIVES: To investigate the completeness of reporting of behavioral, environmental, social and system interventions (BESSI) for reducing the transmission of SARS-CoV-2 evaluated in randomized trials, to obtain missing intervention details and to document the interventions assessed. STUDY DESIGN AND SETTING: We assessed completeness of reporting in randomized trials of BESSI using the Template for Intervention Description and Replication (TIDieR) checklist. Investigators were contacted to provide missing intervention details and if provided, intervention descriptions were reassessed and documented according to the TIDieR items. RESULTS: Forty-five trials (planned or complete) describing 21 educational interventions, 15 protective measures, and nine social distancing interventions were included. In 30 trials with a protocol or study report, 30% (9/30) of interventions were completely described; this increased to 53% (16/30) after contacting 24 trial investigators (11 responded). Across all interventions, intervention provider training (35%) was the most frequently incompletely described checklist item, followed by the 'when and how much' intervention item. CONCLUSION: Incomplete reporting of BESSI is a substantial problem with essential information necessary for implementation of interventions and for building on existing knowledge frequently missing and unable to be obtained. Such reporting is an avoidable source of research waste.

Pentafluorosulfanyl-functionalised BODIPY push-pull dyes for p-type dye-sensitized solar cells.

We report a push-pull BODIPY-based dye functionalised with an electronegative SF5 group at the meso position for applications in photocathodes in tandem dye-sensitized solar cells (DSSCs). The push-pull character enhances charge-transfer from the mesoporous NiO cathode surface towards the redox mediator. A Knoevenagel condensation reaction was used to introduce the carboxylic acid to anchor the dye to the oxide surface, via a styryl linker which increases the conjugation in the molecule and shifts the absorption to the red. The room-temperature synthesis and high yields, make the dye promising for manufacture on a large scale. The dye was applied in p-DSSCs giving a power conversion efficiency (0.066%), a short circuit photocurrent (J SC) of 3.84 mA cm-2, open circuit voltage (V OC) of 58 mV and fill factor of 30%.

Principal Component Pursuit for Pattern Identification in Environmental Mixtures.

BACKGROUND: Environmental health researchers often aim to identify sources or behaviors that give rise to potentially harmful environmental exposures. OBJECTIVE: We adapted principal component pursuit (PCP)-a robust and well-established technique for dimensionality reduction in computer vision and signal processing-to identify patterns in environmental mixtures. PCP decomposes the exposure mixture into a low-rank matrix containing consistent patterns of exposure across pollutants and a sparse matrix isolating unique or extreme exposure events. METHODS: We adapted PCP to accommodate nonnegative data, missing data, and values below a given limit of detection (LOD). We simulated data to represent environmental mixtures of two sizes with increasing proportions

Covid-19 vaccination and menstrual cycle length in the Apple Women's Health Study.

COVID-19 vaccination may be associated with change in menstrual cycle length following vaccination. We estimated covariate-adjusted differences in mean cycle length (MCL), measured in days, between pre-vaccination cycles, vaccination cycles, and post-vaccination cycles within vaccinated participants who met eligibility criteria in the Apple Women's Health Study, a longitudinal mobile-application-based cohort of people in the U.S. with manually logged menstrual cycles. A total of 9652 participants (8486 vaccinated; 1166 unvaccinated) contributed 128,094 cycles (median = 10 cycles per participant; inter-quartile range: 4-22). Fifty-five percent of vaccinated participants received Pfizer-BioNTech's mRNA vaccine, 37% received Moderna's mRNA vaccine, and 8% received the Johnson & Johnson/Janssen (J&J) vaccine. COVID-19 vaccination was associated with a small increase in MCL for cycles in which participants received the first dose (0.50 days, 95% CI: 0.22, 0.78) and cycles in which participants received the second dose (0.39 days, 95% CI: 0.11, 0.67) of mRNA vaccines compared with pre-vaccination cycles. Cycles in which the single dose of J&J was administered were, on average, 1.26 days longer (95% CI: 0.45, 2.07) than pre-vaccination cycles. Post-vaccination cycles returned to average pre-vaccination length. Estimated follicular phase vaccination was associated with increased MCL in cycles in which participants received the first dose (0.97 days, 95% CI: 0.53, 1.42) or the second dose (1.43 days, 95% CI: 1.06, 1.80) of mRNA vaccines or the J&J dose (2.27 days, 95% CI: 1.04, 3.50), compared with pre-vaccination cycles. Menstrual cycle change following COVID-19 vaccination appears small and temporary and should not discourage individuals from becoming vaccinated.

Long-term Traffic-related Air Pollutant Exposure and Amyotrophic Lateral Sclerosis Diagnosis in Denmark: A Bayesian Hierarchical Analysis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Limited evidence suggests ALS diagnosis may be associated with air pollution exposure and specifically traffic-related pollutants. METHODS: In this population-based case-control study, we used 3,937 ALS cases from the Danish National Patient Register diagnosed during 1989-2013 and matched on age, sex, year of birth, and vital status to 19,333 population-based controls free of ALS at index date. We used validated predictions of elemental carbon (EC), nitrogen oxides (NO x ), carbon monoxide (CO), and fine particles (PM 2.5 ) to assign 1-, 5-, and 10-year average exposures pre-ALS diagnosis at study participants' present and historical residential addresses. We used an adjusted Bayesian hierarchical conditional logistic model to estimate individual pollutant associations and joint and average associations for traffic-related pollutants (EC, NO x , CO). RESULTS: For a standard deviation (SD) increase in 5-year average concentrations, EC (SD = 0.42 µg/m 3 ) had a high probability of individual association with increased odds of ALS (11.5%; 95% credible interval [CrI] = -1.0%, 25.6%; 96.3% posterior probability of positive association), with negative associations for NO x (SD = 20 µg/m 3 ) (-4.6%; 95% CrI = 18.1%, 8.9%; 27.8% posterior probability of positive association), CO (SD = 106 µg/m 3 ) (-3.2%; 95% CrI = 14.4%, 10.0%; 26.7% posterior probability of positive association), and a null association for nonelemental carbon fine particles (non-EC PM 2.5 ) (SD = 2.37 µg/m 3 ) (0.7%; 95% CrI = 9.2%, 12.4%). We found no association between ALS and joint or average traffic pollution concentrations. CONCLUSIONS: This study found high probability of a positive association between ALS diagnosis and EC concentration. Further work is needed to understand the role of traffic-related air pollution in ALS pathogenesis.

Covid-19 vaccination and menstrual cycle length in the Apple Women's Health Study.

Background: COVID-19 vaccination may be associated with change in menstrual cycle length following vaccination. Methods: We conducted a longitudinal analysis within a subgroup of 14,915 participants in the Apple Women's Health Study (AWHS) who enrolled between November 2019 and December 2021 and met the following eligibility criteria: were living in the U.S., met minimum age requirements for consent, were English speaking, actively tracked their menstrual cycles, and responded to the COVID-19 Vaccine Update survey. In the main analysis, we included tracked cycles recorded when premenopausal participants were not pregnant, lactating, or using hormonal contraceptives. We used conditional linear regression and multivariable linear mixed-effects models with random intercepts to estimate the covariate-adjusted difference in mean cycle length, measured in days, between pre-vaccination cycles, cycles in which a vaccine was administered, and post-vaccination cycles within vaccinated participants, and between vaccinated and unvaccinated participants. We further compared associations between vaccination and menstrual cycle length by the timing of vaccine dose within a menstrual cycle (i.e., in follicular or luteal phase). We present Bonferroni-adjusted 95% confidence intervals to account for multiple comparisons. Results: A total of 128,094 cycles (median = 10 cycles per participant; interquartile range: 4-22) from 9,652 participants (8,486 vaccinated; 1,166 unvaccinated) were included. The average within-individual standard deviation in cycle length was 4.2 days. Fifty-five percent of vaccinated participants received Pfizer-BioNTech's mRNA vaccine, 37% received Moderna's mRNA vaccine, and 7% received the Johnson & Johnson/Janssen vaccine (J&J). We found no evidence of a difference between mean menstrual cycle length in the unvaccinated and vaccinated participants prior to vaccination (0.24 days, 95% CI: -0.34, 0.82).Among vaccinated participants, COVID-19 vaccination was associated with a small increase in mean cycle length (MCL) for cycles in which participants received the first dose (0.50 days, 95% CI: 0.22, 0.78) and cycles in which participants received the second dose (0.39 days, 95% CI: 0.11, 0.67) of mRNA vaccines compared with pre-vaccination cycles. Cycles in which the single dose of J&J was administered were, on average, 1.26 days longer (95% CI: 0.45, 2.07) than pre-vaccination cycles. Post-vaccination cycles returned to average pre-vaccination length. Estimates for pre vs post cycle lengths were 0.14 days (95% CI: -0.13, 0.40) in the first cycle following vaccination, 0.13 days (95% CI: -0.14, 0.40) in the second, -0.17 days (95% CI: -0.43, 0.10) in the third, and -0.25 days (95% CI: -0.52, 0.01) in the fourth cycle post-vaccination. Follicular phase vaccination was associated with an increase in MCL in cycles in which participants received the first dose (0.97 days, 95% CI: 0.53, 1.42) or the second dose (1.43 days, 95% CI: 1.06, 1.80) of mRNA vaccines or the J&J dose (2.27 days, 95% CI: 1.04, 3.50), compared with pre-vaccination cycles. Conclusions: COVID-19 vaccination was associated with an immediate short-term increase in menstrual cycle length overall, which appeared to be driven by doses received in the follicular phase. However, the magnitude of this increase was small and diminished in each cycle following vaccination. No association with cycle length persisted over time. The magnitude of change associated with vaccination was well within the natural variability in the study population. Menstrual cycle change following COVID-19 vaccination appears small and temporary and should not discourage individuals from becoming vaccinated.

Evaluating predictive relationships between wristbands and urine for assessment of personal PAH exposure.

During events like the COVID-19 pandemic or a disaster, researchers may need to switch from collecting biological samples to personal exposure samplers that are easy and safe to transport and wear, such as silicone wristbands. Previous studies have demonstrated significant correlations between urine biomarker concentrations and chemical levels in wristbands. We build upon those studies and use a novel combination of descriptive statistics and supervised statistical learning to evaluate the relationship between polycyclic aromatic hydrocarbon (PAH) concentrations in silicone wristbands and hydroxy-PAH (OH-PAH) concentrations in urine. In New York City, 109 participants in a longitudinal birth cohort wore one wristband for 48 h and provided a spot urine sample at the end of the 48-hour period during their third trimester of pregnancy. We compared four PAHs with the corresponding seven OH-PAHs using descriptive statistics, a linear regression model, and a linear discriminant analysis model. Five of the seven PAH and OH-PAH pairs had significant correlations (Pearson's r = 0.35-0.64, p ≤ 0.003) and significant chi-square tests of independence for exposure categories (p ≤ 0.009). For these five comparisons, the observed PAH or OH-PAH concentration could predict the other concentration within a factor of 1.47 for 50-80% of the measurements (depending on the pair). Prediction accuracies for high exposure categories were at least 1.5 times higher compared to accuracies based on random chance. These results demonstrate that wristbands and urine provide similar PAH exposure assessment information, which is critical for environmental health researchers looking for the flexibility to switch between biological sample and wristband collection.

Occupational therapy for cognitive impairment in stroke patients.

BACKGROUND: Cognitive impairment is a frequent consequence of stroke and can impact on a person's ability to perform everyday activities. Occupational therapists use a range of interventions when working with people who have cognitive impairment poststroke. This is an update of a Cochrane Review published in 2010. OBJECTIVES: To assess the impact of occupational therapy on activities of daily living (ADL), both basic and instrumental, global cognitive function, and specific cognitive abilities in people who have cognitive impairment following a stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE, Embase, four other databases (all last searched September 2020), trial registries, and reference lists. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials that evaluated an intervention for adults with clinically defined stroke and confirmed cognitive impairment. The intervention needed either to be provided by an occupational therapist or considered within the scope of occupational therapy practice as defined in the review. We excluded studies focusing on apraxia or perceptual impairments or virtual reality interventions as these are covered by other Cochrane Reviews. The primary outcome was basic activities of daily living (BADL) such as dressing, feeding, and bathing. Secondary outcomes were instrumental ADL (IADL) (e.g. shopping and meal preparation), community integration and participation, global cognitive function and specific cognitive abilities (including attention, memory, executive function, or a combination of these), and subdomains of these abilities. We included both observed and self-reported outcome measures. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies that met the inclusion criteria, extracted data, and assessed the certainty of the evidence. A third review author moderated disagreements if consensus was not reached. We contacted trial authors for additional information and data, where available. We assessed the certainty of key outcomes using GRADE.  MAIN RESULTS: We included 24 trials from 11 countries involving 1142 (analysed) participants (two weeks to eight years since stroke onset). This update includes 23 new trials in addition to the one study included in the previous version. Most were parallel randomised controlled trials except for one cross-over trial and one with a two-by-two factorial design. Most studies had sample sizes under 50 participants. Twenty studies involved a remediation approach to cognitive rehabilitation, particularly using computer-based interventions. The other four involved a compensatory and adaptive approach. The length of interventions ranged from 10 days to 18 weeks, with a mean total length of 19 hours. Control groups mostly received usual rehabilitation or occupational therapy care, with a few receiving an attention control that was comparable to usual care; two had no intervention (i.e. a waiting list). Apart from high risk of performance bias for all but one of the studies, the risk of bias for other aspects was mostly low or unclear.  For the primary outcome of BADL, meta-analysis found a small effect on completion of the intervention with a mean difference (MD) of 2.26 on the Functional Independence Measure (FIM) (95% confidence interval (CI) 0.17 to 4.22; P = 0.03, I2 = 0%; 6 studies, 336 participants; low-certainty evidence). Therefore, on average, BADL improved by 2.26 points on the FIM that ranges from 18 (total assist) to 126 (complete independence). On follow-up, there was insufficient evidence of an effect at three months (MD 10.00, 95% CI -0.54 to 20.55; P = 0.06, I2 = 53%; 2 studies, 73 participants; low-certainty evidence), but evidence of an effect at six months (MD 11.38, 95% CI 1.62 to 21.14, I2 = 12%; 2 studies, 73 participants; low-certainty evidence). These differences are below 22 points which is the established minimal clinically important difference (MCID) for the FIM for people with stroke. For IADL, the evidence is very uncertain about an effect (standardised mean difference (SMD) 0.94, 95% CI 0.41 to 1.47; P = 0.0005, I2 = 98%; 2 studies, 88 participants). For community integration, we found insufficient evidence of an effect (SMD 0.09, 95% CI -0.35 to 0.54; P = 0.68, I2 = 0%; 2 studies, 78 participants). There was an improvement of clinical importance in global cognitive functional performance after the intervention (SMD 0.35, 95% CI 0.16 to 0.54; P = 0.0004, I2 = 0%; 9 studies, 432 participants; low-certainty evidence), equating to 1.63 points on the Montreal Cognitive Assessment (MoCA) (95% CI 0.75 to 2.52), which exceeds the anchor-based MCID of the MoCA for stroke rehabilitation patients of 1.22. We found some effect for attention overall (SMD -0.31, 95% CI -0.47 to -0.15; P = 0.0002, I2 = 20%; 13 studies, 620 participants; low-certainty evidence), equating to a difference of 17.31 seconds (95% CI 8.38 to 26.24), and for executive functional performance overall (SMD 0.49, 95% CI 0.31 to 0.66; P < 0.00001, I2 = 74%; 11 studies, 550 participants; very low-certainty evidence), equating to 1.41 points on the Frontal Assessment Battery (range: 0-18). Of the cognitive subdomains, we found evidence of effect of possible clinical importance, immediately after intervention, for sustained visual attention (moderate certainty) equating to 15.63 seconds, for working memory (low certainty) equating to 59.9 seconds, and thinking flexibly (low certainty), compared to control. AUTHORS' CONCLUSIONS: The effectiveness of occupational therapy for cognitive impairment poststroke remains unclear. Occupational therapy may result in little to no clinical difference in BADL immediately after intervention and at three and six months' follow-up. Occupational therapy may slightly improve global cognitive performance of a clinically important difference immediately after intervention, likely improves sustained visual attention slightly, and may slightly increase working memory and flexible thinking after intervention. There is evidence of low or very low certainty or insufficient evidence for effect on other cognitive domains, IADL, and community integration and participation.  Given the low certainty of much of the evidence in our review, more research is needed to support or refute the effectiveness of occupational therapy for cognitive impairment after stroke. Future trials need improved methodology to address issues including risk of bias and to better report the outcome measures and interventions used.

Mixed metals exposure and cognitive function in Bangladeshi adolescents.

BACKGROUND: Over 57 million people in Bangladesh have been chronically exposed to arsenic-contaminated drinking water. They also face environmental exposure to elevated levels of cadmium (Cd), manganese (Mn), and lead (Pb), all of which have been previously observed in environmental and biological samples for this population. These metals have been linked to adverse neurocognitive outcomes in adults and children, though their effects on adolescents are not yet fully characterized. Additionally, previous studies have linked selenium (Se) to protective effects against the toxicity of these other metals. OBJECTIVES: To examine the associations between mixed metals exposure and cognitive function in Bangladeshi adolescents. METHODS: The Metals, Arsenic, & Nutrition in Adolescents study (MANAs) is a cross-sectional study of 572 Bangladeshi adolescents aged 14-16 years, whose parents were enrolled in the Health Effects of Arsenic Longitudinal Study (HEALS). Biosamples were collected from these adolescents for measurement of whole blood metalloid/metal levels of As, Cd, Mn, Pb, and Se. Participants also completed an abbreviated version of The Cambridge Neuropsychological Test Automated Battery (CANTAB), a cognitive function test designed to measure performance across several aspects of executive function. Linear regression was used to examine associations for each metal while controlling for the other metals. Bayesian Kernel Machine Regression (BKMR) assessed the overall mixture effect in addition to confirming the effects of individual metal components observed via linear regression. RESULTS: Linear regression revealed negative associations for Spatial Working Memory and both As and Mn (As B=-2.40, Mn B=-5.31, p < 0.05). We also observed negative associations between Cd and Spatial Recognition Memory (B=-2.77, p < 0.05), and Pb and Delayed Match to Sample, a measure of visual recognition and memory (B=-3.67, p < 0.05). Finally, we saw a positive association for Se and Spatial Span Length (B=0.92, p < 0.05). BKMR results were largely consistent with the regression analysis, showing meaningful associations for individual metals and CANTAB subtests, but no overall mixture effect. Via BKMR, we observed negative associations between Pb and Delayed Match to Sample, and Cd and Spatial Recognition Memory; this analysis also showed positive associations for Se and the Planning, Reaction Time, and Spatial Span subtests. BKMR posterior inclusion probability consistently reported that Se, the only component of the mixture to show a positive association with cognition, was the most important member of the mixture. CONCLUSIONS: Overall, we found Se to be positively associated with cognition, while Mn and As were linked to poorer working memory, and Cd and Pb were associated with poorer visual recognition and memory. Our observations are consistent with previous reports on the effects of these metal exposures in adults and children. Our findings also suggest agreement between linear regression and BKMR methods for analyzing metal mixture exposures. Additional studies are needed to evaluate the impact of mixed metals exposure on adverse health and poorer cognition later in life for those exposed during adolescence. Findings also suggest that metal exposure mitigation efforts aimed at adolescents might influence lifelong cognitive outcomes in regions where environmental exposure to metals is endemic.

Dye-sensitized solar cells strike back.

Dye-sensitized solar cells (DSCs) are celebrating their 30th birthday and they are attracting a wealth of research efforts aimed at unleashing their full potential. In recent years, DSCs and dye-sensitized photoelectrochemical cells (DSPECs) have experienced a renaissance as the best technology for several niche applications that take advantage of DSCs' unique combination of properties: at low cost, they are composed of non-toxic materials, are colorful, transparent, and very efficient in low light conditions. This review summarizes the advancements in the field over the last decade, encompassing all aspects of the DSC technology: theoretical studies, characterization techniques, materials, applications as solar cells and as drivers for the synthesis of solar fuels, and commercialization efforts from various companies.

Population pharmacokinetic analysis of crizotinib in children with progressive/recurrent high-grade and diffuse intrinsic pontine gliomas.

PURPOSE: Crizotinib, a potent oral tyrosine kinase inhibitor, was evaluated in combination with dasatinib in a phase 1 trial (NCT01644773) in children with progressive or recurrent high-grade and diffuse intrinsic pontine gliomas (HGG and DIPG). This study aimed to characterize the pharmacokinetics of crizotinib in this population and identify significant covariates. METHODS: Patients (N = 36, age range 2.9-21.3 years) were treated orally once or twice-daily with 100-215 mg/m2 crizotinib and 50-65 mg/m2 dasatinib. Pharmacokinetic studies were performed for crizotinib alone after the first dose and at steady state, and for the drug combination at steady state. Crizotinib plasma concentrations were measured using a validated LC-MS/MS method. Population modeling was performed (Monolix) and the impact of factors including patient demographics and co-medications were investigated on crizotinib pharmacokinetics. RESULTS: Crizotinib concentrations were described with a linear two-compartment model and absorption lag time. Concomitant dasatinib and overweight/obese status significantly influenced crizotinib pharmacokinetics, resulting in clinically relevant impact (> 20%) on drug exposure. Crizotinib mean apparent clearance (CL/F) was 66.7 L/h/m2 after single-dose and decreased to 26.5 L/h/m2 at steady state when given alone, but not when combined with dasatinib (mean 60.8 L/h/m2). Overweight/obese patients exhibited lower crizotinib CL/F and apparent volume V1/F (mean 46.2 L/h/m2 and 73.3 L/m2) compared to other patients (mean 75.5 L/h/m2 and 119.3 L/m2, p < 0.001). CONCLUSION: A potential pharmacokinetic interaction was observed between crizotinib and dasatinib in children with HGG and DIPG. Further, crizotinib exposure was significantly higher in overweight/obese patients, who may require a dosing adjustment.

Emicizumab initiation and bleeding outcomes in people with hemophilia A with and without inhibitors: A single-center report.

BACKGROUND: Emicizumab, a bispecific antibody factor VIII mimetic, is approved for prophylaxis in hemophilia, and has different risks and side effects compared to factor VIII products. OBJECTIVE: To better understand the early impact of emicizumab on our patients at the University of Colorado Hemophilia and Thrombosis Center (UCHTC), we evaluated adverse reactions, factor prophylaxis overlap, and bleeding rates after starting emicizumab through a quality improvement project. PATIENTS/METHODS: A retrospective chart review and structured phone interview were conducted from June to September 2019 for all patients who had started emicizumab at the UCHTC. Data about emicizumab dosing, reactions, bleeding events, and bleeding treatment were collected in 68 children and adults (aged 0.55-79.8 years, on emicizumab a median 213 days; range, 51-1229 days) with hemophilia A (35.3% with past or current inhibitor). RESULTS: Adverse reactions were primarily skin reactions, with no anaphylactic reactions or thrombosis. Bleeding events, defined as pain or swelling treated with factor or supportive measures, demonstrated wide variability, with 25 of 68 experiencing zero bleeds and 5 of 68 experiencing >8 bleeds per year. The most prevalent bleed type was traumatic musculoskeletal bleeding. Bleeding events occurred more often in the first 10 weeks after starting emicizumab, but no time period was without bleeding events. The majority of patients were prescribed every-week or every-2-week dosing, but some had alternative dosing frequency. CONCLUSIONS: Real-world emicizumab use in our center was characterized by variations in prescribing practices and bleeding outcomes and lack of severe adverse reactions.

A soft x-ray probe of a titania photoelectrode sensitized with a triphenylamine dye.

We present a thorough soft x-ray photoelectron spectroscopy (XPS) study of a mesoporous titanium dioxide electrode sensitized with the dye 4-(diphenylamino)phenylcyanoacrylic acid, referred to as "L0." Supported by calculations, the suite of XPS, x-ray absorption spectroscopy, and resonant photoelectron spectroscopy allows us to examine bonding interactions between the dye and the surface and the frontier electronic structure at the molecule-oxide interface. While placing these measurements in the context of existing literature, this paper is intended as a useful reference for further studies of more complex triphenylamine based sensitizers.