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Toothpaste tablets are claimed as a sustainable oral care solution because of their plastic-free concept and ability to deliver the same health benefits as toothpaste cream without harming the environment. Various studies on the environmental impacts related to toothpaste packaging have been conducted; however, far too little attention has been paid to toothpaste ingredients. Life cycle assessment was employed to evaluate the impacts between cleaning teeth with toothpaste cream and tablets. The functional unit of brushing teeth for 2 min twice a day for 6 months was compared within a cradle-to-grave system boundary. The study was conducted in the context of toothpaste manufacturing and domestic consumption in Thailand. Results show that using toothpaste tablets remarkably contributes to a higher score than applying toothpaste cream, accounting for 188 and 163 millipoints, respectively. About 65% of the total impact is from the use phase, and 20% is from ingredient production. The damage to human health is the biggest concern (10.358 × 10−6 DALY). Sugar alcohols, magnesium stearate, and polyvidone are inactive ingredients in the tablets that cause serious human health problems. Toothpaste manufacturers should reconsider ingredient substitution and redesign an appropriate amount and form of the tablet to mitigate the abovementioned impacts.

Background Diabetes mellitus (DM) has detrimental effects on the function of microvascular beds, resulting in blood–brain barrier (BBB) dysfunction. The objective of the study was to investigate whether DM affects the brain physiology through composition of cerebrospinal fluid (CSF) and compare gas tension and electrolyte levels in CSF between the diabetic and nondiabetic populations. Methods Patients aged between 20 and 70 years scheduled for elective orthopedic or urologic surgery requiring spinal anesthesia were enrolled. They were assigned to either of the two groups (control or type 2 DM). Gas tension and electrolytes in the CSF and whole blood samples were measured in both groups. Results All 49 enrolled patients (24 in the control and 25 in the DM group) completed the study. The concentrations of Na+ and Mg2+ in the blood were significantly lower in the DM group than those in the control. The levels of pCO2 and HCO 3 − {\text{HCO}}_{3}^{-} in the CSF were lower in the DM group than in the control group. In addition, there was a marked increase in the glucose level in both the blood and CSF in the DM group. Conclusion The results show that there were some homeostatic changes in blood and CSF in patients with DM.

Musculoskeletal soft connective tissues are commonly injured due to repetitive use, but the evolution of mechanical damage to the tissue structure during repeated loading is poorly understood. We investigated the strain-rate dependence of mechanical denaturation of collagen as a form of structural microdamage accumulation during creep fatigue loading of rat tail tendon fascicles. We cycled tendons at three strain rates to the same maximum stress relative to their rate-dependent tensile strength. Collagen denaturation at distinct points during the fatigue process was measured by fluorescence quantification of collagen hybridizing peptide binding. The amount of collagen denaturation was significantly correlated with fascicle creep strain, independent of the cyclic strain rate, supporting our hypothesis that tissue level creep is caused by collagen triple-helix unfolding. Samples that were loaded faster experienced more creep strain and denaturation as a function of the number of loading cycles relative to failure. Although this increased damage capacity at faster rates may serve as a protective measure during high-rate loading events, it may also predispose these tissues to subsequent injury and indicate a mechanism of overuse injury development. These results build on evidence that molecular-level collagen denaturation is the fundamental mechanism of structural damage to tendons during tensile loading. STATEMENT OF SIGNIFICANCE: This study is the first to investigate the accumulation of denatured collagen in tendons throughout fatigue loading when the maximum stress is scaled with the applied strain rate. The amount of denatured collagen was correlated with creep strain, independent of strain rate, but samples that were cycled faster withstood greater amounts of denaturation before failure. Differential accumulation of collagen damage between fast and slow repetitive loading has relevance toward understanding the prevalence of overuse musculoskeletal injuries following sudden changes in activity level. Since collagen is a ubiquitous biological structural component, the basic patterns and mechanisms of loading-induced collagen damage in connective tissues are relevant for understanding injury and disease in other tissues, including those from the cardiovascular and pulmonary systems.

Background Doxorubicin (Dox) is a widely used chemotherapy, but its effectiveness is limited by dose-dependent side effects. Although lower Dox doses reduce this risk, studies have reported higher recurrence of local disease with no improvement in survival rate in patients receiving low doses of Dox. To effectively mitigate this, a better understanding of the adverse effects of suboptimal Dox doses is needed. Methods Effects of sublethal dose of Dox on phenotypic changes were assessed with light and confocal microscopy. Migratory and invasive behavior were assessed by wound healing and transwell migration assays. MTT and LDH release assays were used to analyze cell growth and cytotoxicity. Flow cytometry was employed to detect cell surface markers of cancer stem cell population. Expression and activity of matrix metalloproteinases were probed with qRT-PCR and zymogen assay. To identify pathways affected by sublethal dose of Dox, exploratory RNAseq was performed and results were verified by qRT-PCR in multiple cell lines (MCF7, ZR75-1 and U-2OS). Regulation of Src Family kinases (SFK) by key players in DNA damage response was assessed by siRNA knockdown along with western blot and qRT-PCR. Dasatinib and siRNA for Fyn and Yes was employed to inhibit SFKs and verify their role in increased migration and invasion in MCF7 cells treated with sublethal doses of Dox. Results The results show that sublethal Dox treatment leads to increased migration and invasion in otherwise non-invasive MCF7 breast cancer cells. Mechanistically, these effects were independent of the epithelial mesenchymal transition, were not due to increased cancer stem cell population, and were not observed with other chemotherapies. Instead, sublethal Dox induces expression of multiple SFK—including Fyn, Yes, and Src—partly in a p53 and ATR-dependent manner. These effects were validated in multiple cell lines. Functionally, inhibiting SFKs with Dasatinib and specific downregulation of Fyn suppressed Dox-induced migration and invasion of MCF7 cells. Conclusions Overall, this study demonstrates that sublethal doses of Dox activate a pro-invasive, pro-migration program in cancer cells. Furthermore, by identifying SFKs as key mediators of these effects, our results define a potential therapeutic strategy to mitigate local invasion through co-treatment with Dasatinib.

Time spent in residences substantially contributes to human exposure to volatile organic compounds (VOCs). Such exposures have been difficult to study deeply, in part because VOC concentrations and indoor occupancy vary rapidly. Using a fast-response online mass spectrometer, we report time-resolved exposures from multi-season sampling of more than 200 VOCs in two California residences. Chemical-specific source apportionment revealed that time-averaged exposures for most VOCs were mainly attributable to continuous indoor emissions from buildings and their static contents. Also contributing to exposures were occupant-related activities, such as cooking, and outdoor-to-indoor transport. Health risk assessments are possible for a subset of observed VOCs. Acrolein, acetaldehyde, and acrylic acid concentrations were above chronic advisory health guidelines, whereas exposures for other assessable species were typically well below the guideline levels. Studied residences were built in the mid-20th century, indicating that VOC emissions even from older buildings and their contents can substantially contribute to occupant exposures.

Squalene can react with indoor ozone to generate a series of volatile and semi-volatile organic compounds, some of which may be skin or respiratory irritants, causing adverse health effects. Better understanding of the ozone/squalene reaction and product transport characteristics is thus important. In this study, we developed a physical-chemical coupling model to describe the behavior of ozone/squalene reaction products, that is, 6-methyl-5-hepten-2-one (6-MHO) and 4-oxopentanal (4-OPA) in the gas phase and skin, by considering the chemical reaction and physical transport processes (external convection, internal diffusion, and surface uptake). Experiments without intervention were performed in a single-family house in California utilizing time- and space-resolved measurements. The key parameters in the model were extracted from 5 day data and then used to predict the behaviors in some other days. Predictions from the present model can reproduce the concentration profiles of the three compounds (ozone, 6-MHO, and 4-OPA) well (R2 = 0.82-0.89), indicating high accuracy of the model. Exposure analysis shows that the total amount of 6-MHO and 4-OPA entering the blood capillaries in 4 days can reach 14.6 and 30.1 μg, respectively. The contribution of different sinks to ozone removal in the tested realistic indoor environment was also analyzed.

Tendons are collagenous soft tissues that transmit loads between muscles and bones. Depending on their anatomical function, tendons are classified as positional or energy-storing with differing biomechanical and biochemical properties. We recently demonstrated that during monotonic stretch of positional tendons, permanent denatured collagen begins accumulating upon departing the linear region of the stress-strain curve. However, it is unknown if this observation is true during mechanical overload of other types of tendons. Therefore, the purpose of this study was to investigate the onset of collagen denaturation relative to applied strain, and whether it differs between the two tendon types. Rat tail tendon (RTT) fascicles and rat flexor digitorum longus (FDL) tendons represented positional and energy-storing tendons, respectively. The samples were stretched to incremental levels of strain, then stained with fluorescently labeled collagen hybridizing peptides (CHPs); the CHP fluorescence was measured to quantify denatured collagen. Denatured collagen in both positional and energy-storing tendons begins to increase at the yield strain, upon leaving the linear region of the stress-strain curve as the sample begins to permanently deform. Despite significant differences between the two tendon types, it appears that collagen denaturation is initiated at tissue yield during monotonic stretch, and the fundamental mechanism of failure is the same. At tissue failure, positional tendons had double the percentage of denatured collagen compared to energy-storing tendons, with no difference between 0% control groups. These results have implications in understanding both acute and chronic tendon injuries, which will hopefully lead to improved treatment outcomes.

Measurements by semivolatile thermal desorption aerosol gas chromatography (SV-TAG) were used to investigate how semivolatile organic compounds (SVOCs) partition among indoor reservoirs in (1) a manufactured test house under controlled conditions (HOMEChem campaign) and (2) a single-family residence when vacant (H2 campaign). Data for phthalate diesters and siloxanes suggest that volatility-dependent partitioning processes modulate airborne SVOC concentrations through interactions with surface-laden condensed-phase reservoirs. Airborne concentrations of SVOCs with vapor pressures in the range of C13 to C23 alkanes were observed to be correlated with indoor air temperature. Observed temperature dependencies were quantitatively similar to theoretical predictions that assumed a surface-air boundary layer with equilibrium partitioning maintained at the air-surface interface. Airborne concentrations of SVOCs with vapor pressures corresponding to C25 to C31 alkanes correlated with airborne particle mass concentration. For SVOCs with higher vapor pressures, which are expected to be predominantly gaseous, correlations with particle mass concentration were weak or nonexistent. During primary particle emission events, enhanced gas-phase emissions from condensed-phase reservoirs partitioned to airborne particles, contributing substantially to organic particulate matter. An emission event related to oven-usage was inferred to deposit siloxanes in condensed-phase reservoirs throughout the house, leading to the possibility of reemission during subsequent periods with high particle loading.

The otoliths (ear stones) of fishes are commonly used to describe the age and growth of marine and freshwater fishes. These non-skeletal structures are fortuitous in their utility by being composed of mostly inorganic carbonate that is inert through the life of the fish. This conserved record functions like an environmental chronometer and bomb-produced radiocarbon (14C)—a 14C signal created by atmospheric testing of thermonuclear devices—can be used as a time-specific marker in validating fish age. However, complications from the hydrogeology of nearshore marine environments can complicate 14C levels, as was the case with gray snapper (Lutjanus griseus) along the Gulf of Mexico coast of Florida. Radiocarbon of these nearshore waters is influenced by freshwater input from the karst topography of the Upper Floridan Aquifer—estuarine waters that are 14C-depleted from surface and groundwater inputs. Some gray snapper likely recruited to this kind of environment where 14C levels were depleted in the earliest otolith growth, although age was validated for individuals that were not exposed to 14C-depleted waters to an age of at least 25 years with support for a 30-year lifespan.

Phthalate esters, commonly used as plasticizers, can be found indoors in the gas phase, in airborne particulate matter, in dust, and on surfaces. The dynamic behavior of phthalates indoors is not fully understood. In this study, time-resolved measurements of airborne phthalate concentrations and associated gas-particle partitioning data were acquired in a normally occupied residence. The vapor pressure and associated gas-particle partitioning of measured phthalates influenced their airborne dynamic behavior. Concentrations of higher vapor pressure phthalates correlated well with indoor temperature, with little discernable influence from direct occupant activity. Conversely, occupant-related behaviors substantially influenced the concentrations and dynamic behavior of a lower vapor pressure compound, diethyl hexyl phthalate (DEHP), mainly through production of particulate matter during cooking events. The proportion of airborne DEHP in the particle phase was experimentally observed to increase under high particle mass concentrations and lower indoor temperatures in correspondence with theory. Experimental observations indicate that indoor surfaces of the residence are large reservoirs of phthalates. The results also indicate that two key factors influenced by human behavior - temperature and particle mass concentration - cause short-term changes in airborne phthalate concentrations.

Loss-of-function mutations in progranulin (GRN), most of which cause progranulin haploinsufficiency, are a major autosomal dominant cause of frontotemporal dementia (FTD). Individuals with loss-of-function mutations on both GRN alleles develop neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder. Progranulin is a secreted glycoprotein expressed by a variety of cell types throughout the body, including neurons and microglia in the brain. Understanding the relative importance of neuronal and microglial progranulin insufficiency in FTD pathogenesis may guide development of therapies. In this study, we used mouse models to investigate the role of neuronal and microglial progranulin insufficiency in the development of FTD-like pathology and behavioral deficits. Grn(–/–) mice model aspects of FTD and NCL, developing lipofuscinosis and gliosis throughout the brain, as well as deficits in social behavior. We have previously shown that selective depletion of neuronal progranulin disrupts social behavior, but does not produce lipofuscinosis or gliosis. We hypothesized that reduction of microglial progranulin would induce lipofuscinosis and gliosis, and exacerbate behavioral deficits, in neuronal progranulin-deficient mice. To test this hypothesis, we crossed Grn(fl/fl) mice with mice expressing Cre transgenes targeting neurons (CaMKII-Cre) and myeloid cells/microglia (LysM-Cre). CaMKII-Cre, which is expressed in forebrain excitatory neurons, reduced cortical progranulin protein levels by around 50%. LysM-Cre strongly reduced progranulin immunolabeling in many microglia, but did not reduce total brain progranulin levels, suggesting that, at least under resting conditions, microglia contribute less than neurons to overall brain progranulin levels. Mice with depletion of both neuronal and microglial progranulin failed to develop lipofuscinosis or gliosis, suggesting that progranulin from extracellular sources prevented pathology in cells targeted by the Cre transgenes. Reduction of microglial progranulin also did not exacerbate the social deficits of neuronal progranulin-insufficient mice. These results do not support the hypothesis of synergistic effects between progranulin-deficient neurons and microglia. Nearly complete progranulin deficiency appears to be required to induce lipofuscinosis and gliosis in mice, while partial progranulin insufficiency is sufficient to produce behavioral deficits.

The purpose of this study was to develop a microplate assay for quantifying denatured collagen by measuring the fluorescence of carboxyfluorescein bound collagen hybridizing peptides (F-CHP). We have shown that F-CHP binds selectively with denatured collagen, and that mechanical overload of tendon fascicles causes collagen denaturation. Proteinase K was used to homogenize tissue samples after F-CHP staining, allowing fluorescence measurement using a microplate reader. We compared our new assay to our previous image analysis method and the trypsin-hydroxyproline assay, which is the only other available method to directly quantify denatured collagen. Relative quantification of denatured collagen was performed in rat tail tendon fascicles subjected to incremental tensile overload, and normal and ostoeoarthritic guinea pig cartilage. In addition, the absolute amount of denatured collagen was determined in rat tail tendon by correlating F-CHP fluorescence with percent denatured collagen as determined by the trypsin-hydroxyproline assay. Rat tail tendon fascicles stretched to low strains (

Introduction Falls are the leading cause of injury-related death among older adults according to the Centers for Disease Control and Prevention (CDC). The Falls Efficacy Scale (FES) and Vulnerable Elder Survey (VES-13) are validated screening tools used to assess concern of falling, health deterioration and functional decline. We set out to determine if the FES or VES-13 could serve as a predictor of falls among older adults in the Emergency Department (ED) setting. Methods This prospective pilot cohort study was conducted at a Level 1 Trauma Center. ED patients aged ≥65 were eligible for the study if they had a mechanical fall risk defined by CDC criteria. After consent and enrollment, FES and the VES surveys were completed. Participants were followed by phone quarterly, and results of the one-year follow-up self-report of fall history described. Results There were 200 subjects enrolled and after excluding those that were withdrawn, deceased, or lost to follow-up, 184 were available for analysis of their follow-up visit at 12 months. A greater proportion of the participants were women (108 (58.7%) vs 76 (41.3%); P=0.88). The average age of the study participants was 74.2±7.3 years. There was no significant difference in age between men and women (median: 73 vs 73; p=0.47). At the follow-up visit, 33 (17.9%) had a reported fall. The mean age did not significantly differ when comparing those with versus without a fall (75.6 vs 73.9; p=0.24). There was no significant difference in the proportion with a VES-13 ≥ 3 when comparing those with and without a reported fall (45.5% vs 37.8%; p = 0.41). The median FES score did not differ among those with as compared to without a fall (11 vs 10; p=0.12). Conclusions Subjects who had a VES-13 score of ≥3 were statistically no more likely to have fallen than those with a score of

Background: The roots of Codonopsis pilosula (Franch.) Nannf. have been used in traditional Chinese medicine for treating cardiovascular disease. In the current study, we aimed to discover herbal extracts from C. pilosula that are capable of improving cardiac function of infarcted hearts to develop a potential therapeutic approach. Methods: A mouse embryonic stem (ES) cell-based model with an enhanced green fluorescent protein (eGFP) reporter driven by a cardiomyocyte-specific promoter, the α-myosin heavy chain, was constructed to evaluate the cardiogenic activity of herbal extracts. Then, herbal extracts from C. pilosula with cardiogenic activity based on an increase in eGFP expression during ES cell differentiation were further tested in a rat myocardial infarction model with left anterior descending artery (LAD) ligation. Cardiac function assessments were performed using echocardiography, 1, 3, and 6 weeks post LAD ligation. Results: The herbal extract 417W from C. pilosula was capable of enhancing cardiogenic differentiation in mouse ES cells in vitro. Echocardiography results in the LAD-ligated rat model revealed significant improvements in the infarcted hearts at least 6 weeks after 417W treatment that were determined based on left ventricle fractional shortening (FS), fractional area contraction (FAC), and ejection fraction (EF). Conclusions: The herbal extract 417W can enhance the cardiogenic differentiation of ES cells and improve the cardiac function of infarcted hearts.

Oceanic whitetip sharks Carcharhinus longimanus are a cosmopolitan epipelagic species that was once prolific throughout the tropics and subtropics but was recently listed as Critically Endangered by the International Union for the Conservation of Nature and as Threatened under the United States Endangered Species Act. Although historically conspicuous in oceanic fisheries catches, relatively little is known about their habitat use, movement, and life history during migration. Given the paucity of data on migratory patterns and lack of age estimate validation available for this species, we evaluated vertebral growth bands for bomb radiocarbon (14C) patterns to derive additional information on these metrics. Individual growth bands (n = 62) were milled from vertebrae of eight individuals caught in the northwestern Atlantic Ocean. Age estimates based on vertebral growth bands ranged 1–13 years, with capture dates spanning 1978–2004. Plots of vertebral Δ14C relative to regional coral, shark, and fish otolith reference curves suggest age estimates based on presumed annual growth bands were accurate, although specimens were not old enough to capture the most informative portion of the bomb radiocarbon reference period. The magnitude of Δ14C varied among individuals, and individual chronologies demonstrated semi-cyclic patterns of Δ14C depletion and subsequent enrichment, which may be indicative of changes to diet as a function of annual migratory patterns and is supported by recently published telemetry, diet, and stable isotope studies. Although these data are preliminary in nature, they provide some evidence that Δ14C patterns in vertebrae can serve as a multi-purpose tool for life history studies of oceanic sharks.

Denatured collagen accumulates during cyclic fatigue loading and explains the micro-damage hypothesis of overuse tissue injury., Overuse injuries to dense collagenous tissues are common, but their etiology is poorly understood. The predominant hypothesis that micro-damage accumulation exceeds the rate of biological repair is missing a mechanistic explanation. Here, we used collagen hybridizing peptides to measure collagen molecular damage during tendon cyclic fatigue loading and computational simulations to identify potential explanations for our findings. Our results revealed that triple-helical collagen denaturation accumulates with increasing cycles of fatigue loading, and damage is correlated with creep strain independent of the cyclic strain rate. Finite-element simulations demonstrated that biphasic fluid flow is a possible fascicle-level mechanism to explain the rate dependence of the number of cycles and time to failure. Molecular dynamics simulations demonstrated that triple-helical unfolding is rate dependent, revealing rate-dependent mechanisms at multiple length scales in the tissue. The accumulation of collagen molecular denaturation during cyclic loading provides a long-sought “micro-damage” mechanism for the development of overuse injuries.

Objective Diazepam buccal film (DBF) is in development for treatment of patients experiencing bouts of increased seizure activity. We assessed safety, tolerability, and usability of self‐ or caregiver‐administered DBF in the outpatient setting. Methods Patients aged 2‐65 years needing treatment with a rescue benzodiazepine at least once monthly were eligible for the study. DBF (5‐17.5 mg) was dispensed based on age and body weight. Patients/caregivers administered DBF for up to five seizure episodes per month. Adverse events (AEs) and usability assessments were recorded after the first dose, then every 3 months. Results Onehundred eighteen patients who used ≥1 DBF dose (adults, n = 82; adolescents, n = 19; children, n = 17) were enrolled. Eleven treatment‐related AEs (10 being mild or moderate in severity) occurred in nine (7.6%) patients over a mean of 243 days of follow‐up. No patient discontinued participation because of AEs. Mild local buccal discomfort, buccal swelling, and cheek skin sensitivity were reported by one patient each. Twenty‐two serious AEs were reported; one was treatment‐related. The three deaths reported, all unrelated to DBF, resulted from seizures or seizure with brain malignancy. Self‐administration by adults was attempted on 23.6% (188/795) of use occasions. Administration of DBF occurred under ictal or peri‐ictal conditions on 49.5% (538/1087) of use occasions, and DBF was successfully administered on a first or second attempt on 96.6% (1050/1087) of use occasions. Overall, patients received their dose of DBF on 99.2% (1078/1087) of use occasions. A second DBF dose was required within 24 hours after the first dose on 8.5% (92/1087) of use occasions. Significance In this observational study of chronic intermittent use, DBF was easy to administer, safe, and well tolerated in adult, adolescent, and pediatric patients with epilepsy experiencing seizure emergencies. DBF can be readily self‐administered by adults with epilepsy, as well as successfully administered by a caregiver in seizure emergencies.

It is important to improve our understanding of exposure to particulate matter (PM) in residences because of associated health risks. The HOMEChem campaign was conducted to investigate indoor chemistry in a manufactured test house during prescribed everyday activities, such as cooking, cleaning, and opening doors and windows. This paper focuses on measured size distributions of PM (0.001-20 μm), along with estimated exposures and respiratory-tract deposition. Number concentrations were highest for sub-10 nm particles during cooking using a propane-fueled stovetop. During some cooking activities, calculated PM2.5 mass concentrations (assuming a density of 1 g cm-3) exceeded 250 μg m-3, and exposure during the postcooking decay phase exceeded that of the cooking period itself. The modeled PM respiratory deposition for an adult residing in the test house kitchen for 12 h varied from 7 μg on a day with no indoor activities to 68 μg during a simulated day (including breakfast, lunch, and dinner preparation interspersed by cleaning activities) and rose to 149 μg during a simulated Thanksgiving day.

Identifying the contributions of chemistry and transport to observed ozone pollution using regional-to-global models relies on accurate representation of ozone dry deposition. We use a recently developed configuration of the NOAA GFDL chemistry-climate model - in which the atmosphere and land are coupled through dry deposition-to investigate the influence of ozone dry deposition on ozone pollution over northern midlatitudes. In our model, deposition pathways are tied to dynamic terrestrial processes, such as photosynthesis and water cycling through the canopy and soil. Small increases in winter deposition due to more process-based representation of snow and deposition to surfaces reduce hemispheric-scale ozone throughout the lower troposphere by 5-12 ppb, improving agreement with observations relative to a simulation with the standard configuration for ozone dry deposition. Declining snow cover by the end of the 21st-century tempers the previously identified influence of rising methane on winter ozone. Dynamic dry deposition changes summer surface ozone by -4 to +7 ppb. While previous studies emphasize the importance of uptake by plant stomata, new diagnostic tracking of depositional pathways reveals a widespread impact of nonstomatal deposition on ozone pollution. Daily variability in both stomatal and nonstomatal deposition contribute to daily variability in ozone pollution. Twenty-first century changes in summer deposition result from a balance among changes in individual pathways, reflecting differing responses to both high carbon dioxide (through plant physiology versus biomass accumulation) and water availability. Our findings highlight a need for constraints on the processes driving ozone dry deposition to test representation in regional-to-global models.

Objective Clobazam oral soluble film (COSF) is a novel dosage form under development for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. The present study was undertaken to assess the pharmacokinetics of clobazam administered as single doses of COSF 20 and 10 mg compared with clobazam tablets (CTAB) 20 and 10 mg in healthy adults. A secondary objective was to assess the safety and tolerability of single doses of COSF 20 and 10 mg. Methods A total of 51 adult volunteers were enrolled in a single-dose, open-label, randomized four-sequence, four-period, crossover study with treatments (A) COSF 20 mg, (B) CTAB 20 mg, (C) COSF 10 mg, and (D) CTAB 10 mg. Pharmacokinetic sampling for clobazam and N-desmethylclobazam was carried out until 21 days postdose with a 28-day washout. Subjects were monitored for adverse events (AEs) throughout the study. Visual inspections of the administration site were performed before and after COSF administration to monitor for mucosal irritation. Results COSF at single doses of 10 and 20 mg was bioequivalent to CTAB at equivalent doses for both clobazam and its active metabolite N-desmethylclobazam. The pharmacokinetics of both formulations was dose-proportional at doses of 10 and 20 mg. The number of AEs and the number of subjects experiencing AEs were dose-related across the treatment groups, with somnolence the most common event. None of these events was severe or serious, and most were mild. There was no evidence for local irritation at the administration site following COSF. Significance COSF is a novel clobazam dosage form that is bioequivalent to CTAB. Because of its ease of administration, COSF may be expected to improve adherence, reduce likelihood of dosing error, and provide more accurate dosing than formulations of clobazam that are currently available.

One of the least understood aspects in atmospheric chemistry is how urban emissions influence the formation of natural organic aerosols, which affect Earth’s energy budget. The Amazon rainforest, during its wet season, is one of the few remaining places on Earth where atmospheric chemistry transitions between preindustrial and urban-influenced conditions. Here, we integrate insights from several laboratory measurements and simulate the formation of secondary organic aerosols (SOA) in the Amazon using a high-resolution chemical transport model. Simulations show that emissions of nitrogen-oxides from Manaus, a city of ~2 million people, greatly enhance production of biogenic SOA by 60–200% on average with peak enhancements of 400%, through the increased oxidation of gas-phase organic carbon emitted by the forests. Simulated enhancements agree with aircraft measurements, and are much larger than those reported over other locations. The implication is that increasing anthropogenic emissions in the future might substantially enhance biogenic SOA in pristine locations like the Amazon., It remains unclear how urban emissions influence the formation of secondary organic aerosols (SOA), including in the Amazon forest. Here, the authors simulate the formation of SOAs in the Amazon using a high-resolution regional chemical transport model. They find that urban emissions of NOx from Manaus enhance the production of biogenic SOA by 60–200%.

Hadal trenches are isolated habitats that cover the greatest ocean depths (6,500–11,000 m) and are believed to host high levels of endemism across multiple taxa. A group of apparent hadal endemics is within the snailfishes (Liparidae), found in at least five geographically separated trenches. Little is known about their biology, let alone the reasons for their success at hadal depths around the world. This study investigated the life history of hadal liparids using sagittal otoliths of two species from the Kermadec (Notoliparis kermadecensis) and Mariana (Pseudoliparis swirei) trenches in comparison to successful abyssal macrourids found at the abyssal-hadal transition zone. Otoliths for each species revealed alternating opaque and translucent growth zones that could be quantified in medial sections. Assuming these annuli represent annual growth, ages were estimated for the two hadal liparid species to be from five to 16 years old. These estimates were compared to the shallower-living snailfish Careproctus melanurus, which were older than described in previous studies, expanding the potential maximum age for the liparid family to near 25 years. Age estimates for abyssal macrourids ranged from eight to 29 years for Coryphaenoides armatus and six to 16 years for C. yaquinae. In addition, 18O/16O ratios (δ18O) were measured across the otolith using secondary ion mass spectrometry (SIMS) to investigate the thermal history of the three liparids, and two macrourids. Changes in δ18O values were observed across the otoliths of C. melanurus, C. armatus, and both hadal liparids, the latter of which may represent a change of >5 °C in habitat temperature through ontogeny. The results would indicate there is a pelagic larval stage for the hadal liparids that rises to a depth above 1000 m, followed by a return to the hadal environment as these liparids grow. This result was unexpected for the hadal liparids given their isolated environment and large eggs, and the biological implications and plausibility of interpretations of these data are discussed. This study presents a first look at the life history of some of the deepest-living fishes through otolith analyses.

The longevity of blue marlin (Makaira nigricans) remains unresolved. The use of fin spines and sagittal otoliths for age reading has led to unconfirmed longevity estimates near 20–30 years. Age validation has been elusive because large individuals are uncommonly caught, and a technique that can be applied to structures that provide estimates of age was absent. The use of otolith chemical signatures has been limited by sagittal otoliths that are very small — whole otolith mass of adult blue marlin rarely exceeds 10 mg for the largest fish. Recent advances in the detection limits of radiocarbon (14C) with accelerator mass spectrometry — coupled with recently acquired knowledge of marine bomb 14C signals spanning the tropical Pacific Ocean — have led to an opportunity to age blue marlin from small amounts of otolith material. In this study, otoliths from a recently collected 1245 lb (565 kg) female blue marlin at a measured 146-inch (371 cm) lower jaw fork length were analyzed for 14C. Estimated longevity was either 12–21 or 32–44 years on the basis of bomb 14C dating. Using multiple lines of evidence, it was determined that the young age scenario was most likely, with evidence for an age close to 20 years using a series of deductions in the bomb 14C dating method.

Objective In addition to traditional surgical outcomes, perioperative quality of life is being scrutinized as a patient-centric metric. As part of a prospective study in a contemporary surgical cohort, subjective health states were examined in context of postoperative wound complications (WCs). We hypothesized that WCs negatively affect quality of life. Methods The EuroQol (EQ)-5D subjective health state data, comprising five domains with 1 (good) to 3 (poor) ordinal scoring, plus visual analog score, were collected at the day of surgery and at 2 and 4 weeks of follow-up in a study evaluating silver-eluting dressings in 500 patients at three centers. A preference-weighted index was calculated. Groups were defined by no complication (NC) or presence of one or more postoperative WCs. Results Patients (72% male) were a mean age of 67.6 years. Primary indications included critical limb ischemia (41.4%), claudication (31.6%), and abdominal aortic aneurysm (11.2%; open groin access for endovascular aneurysm repair). At least one WC occurred in 148 patients (29.6%). Baseline demographics were similar except mean age (NC group, 67.9 years; WC group, 65.7 years; P = .042) and body mass index (NC group, 27.0 kg/m 2 ; WC group, 28.2 kg/m 2 ). WCs were associated with use of conduit for reconstruction ( P = .002), below-knee incisions ( P = .002), and incision length ( P P = .001) but not at 4 weeks (mean change, +0.044; P = .065) postoperatively. Subgroup analysis showed quality-of-life change after WC was most significant in the claudication group ( P = .008). The EQ-5D visual analog scale score was lowest in groups with rest pain (57.0) and tissue loss (55.1) and highest in the abdominal aortic aneurysm cohort (71.8). Conclusions EQ-5D identified a significantly decreased quality-of-life score 2 weeks after WCs in a cohort undergoing elective infrainguinal arterial surgery. This effect was not present 4 weeks postoperatively.

Benzodiazepines, including diazepam and midazolam, are the mainstay of treatment for seizure emergencies, including acute repetitive seizures. Nonparenteral dosage forms are used when parenteral (intravenous or intramuscular) dosing is not feasible. Currently available nonparenteral dosage forms have limitations in terms of usability, patient and caregiver acceptance, speed of action, and portability. Diazepam buccal film (DBF) is a compact, easily administered diazepam formulation. When placed onto the buccal mucosa inside the cheek, DBF adheres firmly and then rapidly dissolves, delivering diazepam transbucally and via the gastric route. In fasted healthy male volunteers, plasma levels were achieved rapidly after DBF placement in a linear dose-proportional fashion. Bioavailability in adult patients with epilepsy was not significantly different when DBF was applied interictally or periictally (within 5 min of a seizure). Diazepam buccal film was successfully placed and generally used without difficulty, even without patient cooperation immediately after a seizure. In a crossover comparative study with diazepam rectal gel (Diastat®) in adult patients with epilepsy, DBF performed equivalently to the rectal gel, but peak exposures were less variable. Diazepam buccal film is a convenient alternative for out-of-hospital treatment of seizure exacerbations. Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures.

In California's Central Valley, tule fog frequency increased 85% from 1930 to 1970, then declined 76% in the last 36 winters. Throughout these changes, fog frequency exhibited a consistent north-south trend, with maxima in southern latitudes. We analyzed seven decades of meteorological data and five decades of air pollution data to determine the most likely drivers changing fog, including temperature, dew point depression, precipitation, wind speed, and NOx (oxides of nitrogen) concentration. Climate variables, most critically dew point depression, strongly influence the short-term (annual) variability in fog frequency; however, the frequency of optimal conditions for fog formation show no observable trend from 1980 to 2016. NOx concentration, which has a decreasing north-south concentration gradient, declined continuously over this period, consistent with the long-term temporal and spatial trends in fog. As development in the Central Valley increased direct particle and other pollutant emissions from 1930 to 1970, fog frequency increased. Following the Clean Air Act, particle emissions quickly declined, and NOx emissions declined steadily, reducing the cloud condensation nuclei (CCN) available for fog formation. As a precursor of ammonium nitrate aerosols, which are efficient CCN, we used NOx measurements and emission trends as a proxy for the CCN trend. We conclude that while the short-term fog variability is dominantly driven by climate fluctuations, the longer-term temporal and spatial changes in fog have been driven by changes in air pollution. For conditions close to the dew point, a decrease in fog of 5 days/year per 10 parts per billion NOx decrease occurred across the Central Valley. ©2019. American Geophysical Union. All Rights Reserved.

Background Exome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels. However, identification of copy number variants (CNVs) using ES data remains challenging. The purpose of this study is to understand the contribution of CNVs and copy neutral runs of homozygosity (ROH) in molecular diagnosis of patients referred for ES. Methods In a cohort of 11,020 consecutive ES patients, an Illumina SNP array analysis interrogating mostly coding SNPs was performed as a quality control (QC) measurement and for CNV/ROH detection. Among these patients, clinical chromosomal microarray analysis (CMA) was performed at Baylor Genetics (BG) on 3229 patients, either before, concurrently, or after ES. We retrospectively analyzed the findings from CMA and the QC array. Results The QC array can detect ~ 70% of pathogenic/likely pathogenic CNVs (PCNVs) detectable by CMA. Out of the 11,020 ES cases, the QC array identified PCNVs in 327 patients and uniparental disomy (UPD) disorder-related ROH in 10 patients. The overall PCNV/UPD detection rate was 5.9% in the 3229 ES patients who also had CMA at BG; PCNV/UPD detection rate was higher in concurrent ES and CMA than in ES with prior CMA (7.2% vs 4.6%). The PCNVs/UPD contributed to the molecular diagnoses in 17.4% (189/1089) of molecularly diagnosed ES cases with CMA and were estimated to contribute in 10.6% of all molecularly diagnosed ES cases. Dual diagnoses with both PCNVs and SNVs were detected in 38 patients. PCNVs affecting single recessive disorder genes in a compound heterozygous state with SNVs were detected in 4 patients, and homozygous deletions (mostly exonic deletions) were detected in 17 patients. A higher PCNV detection rate was observed for patients with syndromic phenotypes and/or cardiovascular abnormalities. Conclusions Our clinical genomics study demonstrates that detection of PCNV/UPD through the QC array or CMA increases ES diagnostic rate, provides more precise molecular diagnosis for dominant as well as recessive traits, and enables more complete genetic diagnoses in patients with dual or multiple molecular diagnoses. Concurrent ES and CMA using an array with exonic coverage for disease genes enables most effective detection of both CNVs and SNVs and therefore is recommended especially in time-sensitive clinical situations. Electronic supplementary material The online version of this article (10.1186/s13073-019-0639-5) contains supplementary material, which is available to authorized users.

We report a recurrent CNOT1 de novo missense mutation, GenBank: NM_016284.4; c.1603C>T (p.Arg535Cys), resulting in a syndrome of pancreatic agenesis and abnormal forebrain development in three individuals and a similar phenotype in mice. CNOT1 is a transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells in a pluripotent state. These findings suggest that CNOT1 plays a critical role in pancreatic and neurological development and describe a novel genetic syndrome of pancreatic agenesis and holoprosencephaly.

Little is known about long-term changes in coral reef fish communities. Here we present a new technique that leverages fish otoliths in reef sediments to reconstruct coral reef fish communities. We found over 5,400 otoliths in 169 modern and mid-Holocene bulk samples from Caribbean Panama and Dominican Republic mid-Holocene and modern reefs, demonstrating otoliths are abundant in reef sediments. With a specially-built reference collection, we were able to assign over 4,400 otoliths to one of 56 taxa (35 families) though mostly at genus and family level. Many otoliths were from juvenile fishes for which identification is challenging. Richness (by rarefaction) of otolith assemblages was slightly higher in modern than mid-Holocene reefs, but further analyses are required to elucidate the underlying causes. We compared the living fish communities, sampled using icthyocide, with the sediment otolith assemblages on four reefs finding the otolith assemblages faithfully capture the general composition of the living fish communities. Radiocarbon dating performed directly on the otoliths suggests that relatively little mixing of sediment layers particularly on actively accreting branching coral reefs. All otolith assemblages were strongly dominated by small, fast-turnover fish taxa and juvenile individuals, and our exploration on taxonomy, functional ecology and taphonomy lead us to the conclusion that intense predation is likely the most important process for otolith accumulation in reef sediments. We conclude that otolith assemblages in modern and fossil reef sediments can provide a powerful tool to explore ecological changes in reef fish communities over time and space.