Pulmonary fibrosis (PF) is a form of chronic lung disease characterized by pathologic epithelial remodeling and accumulation of extracellular matrix (ECM). To comprehensively define the cell types, ...mechanisms, and mediators driving fibrotic remodeling in lungs with PF, we performed single-cell RNA sequencing of single-cell suspensions from 10 nonfibrotic control and 20 PF lungs. Analysis of 114,396 cells identified 31 distinct cell subsets/states. We report that a remarkable shift in epithelial cell phenotypes occurs in the peripheral lung in PF and identify several previously unrecognized epithelial cell phenotypes, including a
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pathologic, ECM-producing epithelial cell population that was highly enriched in PF lungs. Multiple fibroblast subtypes were observed to contribute to ECM expansion in a spatially discrete manner. Together, these data provide high-resolution insights into the complexity and plasticity of the distal lung epithelium in human disease and indicate a diversity of epithelial and mesenchymal cells contribute to pathologic lung fibrosis.
To better characterize the transport of neonicotinoid insecticides to the world's largest freshwater ecosystem, monthly samples (October 2015–September 2016) were collected from 10 major tributaries ...to the Great Lakes, USA. For the monthly tributary samples, neonicotinoids were detected in every month sampled and five of the six target neonicotinoids were detected. At least one neonicotinoid was detected in 74% of the monthly samples with up to three neonicotinoids detected in an individual sample (10% of all samples). The most frequently detected neonicotinoid was imidacloprid (53%), followed by clothianidin (44%), thiamethoxam (22%), acetamiprid (2%), and dinotefuran (1%). Thiacloprid was not detected in any samples. The maximum concentration for an individual neonicotinoid was 230 ng L−1 and the maximum total neonicotinoids in an individual sample was 400 ng L−1. The median detected individual neonicotinoid concentrations ranged from non-detect to 10 ng L−1. The detections of clothianidin and thiamethoxam significantly increased as the percent of cultivated crops in the basins increased (ρ = 0.73, P = .01; ρ = 0.66, P = .04, respectively). In contrast, imidacloprid detections significantly increased as the percent of the urbanization in the basins increased (ρ = 0.66, P = .03). Neonicotinoid concentrations generally increased in spring through summer coinciding with the planting of neonicotinoid-treated seeds and broadcast applications of neonicotinoids. More spatially intensive samples were collected in an agriculturally dominated basin (8 sites along the Maumee River, Ohio) twice during the spring, 2016 planting season to provide further information on neonicotinoid inputs to the Great Lakes. Three neonicotinoids were ubiquitously detected (clothianidin, imidacloprid, thiamethoxam) in all water samples collected within this basin. Maximum individual neonicotinoid concentrations was 330 ng L−1 and maximum total neonicotinoid concentration was 670 ng L−1; median detected individual neonicotinoid concentrations were 7.0 to 39 ng L−1.
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•Neonicotinoids prevalent year-round in tributaries to the Great Lakes, USA.•Concentrations and frequency of neonicotinoids increased in late spring through summer.•Imidacloprid detections increased with percent urbanization.•Clothianidin and thiamethoxam detections increased with percent cultivated crops.
Neonicotinoid insecticides from both agricultural and urban sources were prevalent year-round in tributaries to the Great Lakes, USA.
The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) ...and negative for human epidermal growth factor receptor 2 (HER2).
In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10
.
The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10
for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval CI, 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively.
Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).
Abstract Optimism is associated with positive outcomes across many health domains, from cardiovascular disease to depression. However, we know little about cognitive processes underlying optimism in ...psychopathology. The present study tested whether the ability to vividly imagine positive events in one's future was associated with dispositional optimism in a sample of depressed adults. Cross-sectional and longitudinal analyses were conducted, using baseline (all participants, N =150) and follow-up data (participants in the control condition only, N =63) from a clinical trial ( Blackwell et al., 2015 ). Vividness of positive prospective imagery, assessed on a laboratory-administered task at baseline, was significantly associated with both current optimism levels at baseline and future (seven months later) optimism levels, including when controlling for potential confounds. Even when depressed, those individuals able to envision a brighter future were more optimistic, and regained optimism more quickly over time, than those less able to do so at baseline. Strategies to increase the vividness of positive prospective imagery may aid mental health intervention development to boost optimism.
Animal reactions to oncoming vehicles: a conceptual review Lima, Steven L.; Blackwell, Bradley F.; DeVault, Travis L. ...
Biological reviews of the Cambridge Philosophical Society,
February 2015, Letnik:
90, Številka:
1
Journal Article
Recenzirano
Odprti dostop
ABSTRACT
Animal–vehicle collisions (AVCs) are a substantial problem in a human‐dominated world, but little is known about what goes wrong, from the animal's perspective, when a collision occurs with ...an automobile, boat, or aircraft. Our goal is to provide insight into reactions of animals to oncoming vehicles when collisions might be imminent. Avoiding a collision requires successful vehicle detection, threat assessment, and evasive behaviour; failures can occur at any of these stages. Vehicle detection seems fairly straightforward in many cases, but depends critically on the sensory capabilities of a given species. Sensory mechanisms for detection of collisions (looming detectors) may be overwhelmed by vehicle speed. Distractions are a likely problem in vehicle detection, but have not been clearly demonstrated in any system beyond human pedestrians. Many animals likely perceive moving vehicles as non‐threatening, and may generally be habituated to their presence. Slow or minimal threat assessment is thus a likely failure point in many AVCs, but this is not uniformly evident. Animals generally initiate evasive behaviour when a collision appears imminent, usually employing some aspect of native antipredator behaviour. Across taxa, animals exhibit a variety of behaviours when confronted with oncoming vehicles. Among marine mammals, right whales Eubalaena spp., manatees Trichechus spp., and dugongs Dugong dugon are fairly unresponsive to approaching vehicles, suggesting a problem in threat assessment. Others, such as dolphins Delphinidae, assess vehicle approach at distance. Little work has been conducted on the behavioural aspects of AVCs involving large mammals and automobiles, despite their prevalence. Available observations suggest that birds do not usually treat flying aircraft as a major threat, often allowing close approach before taking evasive action, as they might in response to natural predators. Inappropriate antipredator behaviour (often involving immobility) is a major source of AVCs in amphibians and terrestrial reptiles. Much behavioural work on AVCs remains to be done across a wide variety of taxa. Such work should provide broad phylogenetic generalizations regarding AVCs and insights into managing AVCs.
Phase III EGF104900 data demonstrated that lapatinib plus trastuzumab significantly improved progression-free survival (PFS) and clinical benefit rate versus lapatinib monotherapy, offering a ...chemotherapy-free option for patients with heavily pretreated human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC). Final planned overall survival (OS) analysis from EGF104900 is reported here.
Patients with HER2-positive MBC whose disease progressed during prior trastuzumab-based therapies were randomly assigned to receive lapatinib monotherapy or lapatinib in combination with trastuzumab. OS and updated PFS data are presented using Kaplan-Meier curves and log-rank tests stratified for hormone receptor and visceral disease status. Subgroup analyses were conducted to identify characteristics of patients deriving the greatest clinical benefit.
In this updated final analysis of all patients randomly assigned with strata (n = 291), lapatinib plus trastuzumab continued to show superiority to lapatinib monotherapy in PFS (hazard ratio HR, 0.74; 95% CI, 0.58 to 0.94; P = .011) and offered significant OS benefit (HR, 0.74; 95% CI, 0.57 to 0.97; P = .026). Improvements in absolute OS rates were 10% at 6 months and 15% at 12 months in the combination arm compared with the monotherapy arm. Multiple baseline factors, including Eastern Cooperative Oncology Group performance status of 0, nonvisceral disease, < three metastatic sites, and less time from initial diagnosis until random assignment, were associated with improved OS. Incidence of adverse events was consistent with previously reported rates.
These data demonstrated a significant 4.5-month median OS advantage with the lapatinib and trastuzumab combination and support dual HER2 blockade in patients with heavily pretreated HER2-positive MBC.
This study (EGF10004) assessed the safety/tolerability, pharmacokinetics, and clinical activity of daily oral dosing with lapatinib (GW572016) in patients with ErbB1-expressing and/or ...ErbB2-overexpressing advanced-stage refractory solid tumors.
Heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers were randomly assigned to one of five dose cohorts of lapatinib administered once daily. Pharmacokinetic samples were obtained on days 1 and 20. Clinical response was assessed every 8 weeks.
Sixty-seven patients with metastatic solid tumors were treated with lapatinib. The most frequently reported drug-related adverse events were diarrhea (42%) and rash (31%). No grade 4 drug-related adverse events were reported. Five grade 3 drug-related toxicities (gastrointestinal events and rash) were experienced by four patients. Drug-related interstitial pneumonitis or cardiac dysfunction associated with other ErbB-targeted therapies was not reported. Four patients with trastuzumab-resistant metastatic breast cancer-two of whom were classified as having inflammatory breast cancer-had partial responses (PRs). Twenty-four patients with various other carcinomas experienced stable disease, of whom 10 received lapatinib for > or = 6 months. The relationships between lapatinib dose or serum concentration and clinical response could not be adequately characterized due to the limited response data. The incidence of diarrhea increased with increasing dose, whereas the incidence of rash was not related to dose.
Lapatinib was well tolerated at doses ranging from 500 to 1,600 mg once daily. Clinical activity was observed in heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers, including four PRs in patients with trastuzumab-resistant breast cancers and prolonged stable disease in 10 patients.
Anxiety and depression are highly prevalent during adolescence and characterized by negative interpretation biases. Cognitive bias modification of interpretations (CBM-I) may reduce such biases and ...improve emotional functioning. However, as findings have been mixed and the traditional scenario training is experienced as relatively boring, a picture-based type of training might be more engaging and effective.
The current study investigated short- and long-term effects (up to 6 months) and users' experience of two types of CBM-I procedure in adolescents with heightened symptoms of anxiety or depression (N = 119, aged 12-18 year). Participants were randomized to eight online sessions of text-based scenario training, picture-word imagery training, or neutral control training.
No significant group differences were observed on primary or secondary emotional outcomes. A decrease in anxiety and depressive symptoms, and improvements in emotional resilience were observed, irrespective of condition. Scenario training marginally reduced negative interpretation bias on a closely matched assessment task, while no such effects were found on a different task, nor for the picture-word or control group. Subjective evaluations of all training paradigms were relatively negative and the imagery component appeared particularly difficult for adolescents with higher symptom levels.
The current results question the preventive efficacy and feasibility of both CBM-I procedures as implemented here in adolescents.
Mangrove forests are one of the world's most threatened tropical ecosystems with global loss exceeding 35% (ref. 1). Juvenile coral reef fish often inhabit mangroves, but the importance of these ...nurseries to reef fish population dynamics has not been quantified. Indeed, mangroves might be expected to have negligible influence on reef fish communities: juvenile fish can inhabit alternative habitats and fish populations may be regulated by other limiting factors such as larval supply or fishing. Here we show that mangroves are unexpectedly important, serving as an intermediate nursery habitat that may increase the survivorship of young fish. Mangroves in the Caribbean strongly influence the community structure of fish on neighbouring coral reefs. In addition, the biomass of several commercially important species is more than doubled when adult habitat is connected to mangroves. The largest herbivorous fish in the Atlantic, Scarus guacamaia, has a functional dependency on mangroves and has suffered local extinction after mangrove removal. Current rates of mangrove deforestation are likely to have severe deleterious consequences for the ecosystem function, fisheries productivity and resilience of reefs. Conservation efforts should protect connected corridors of mangroves, seagrass beds and coral reefs.
Trauma is the leading cause of morbidity and mortality in the pediatric population. However, during the societal disruptions secondary to the coronavirus (COVID-19) stay-at-home regulations, there ...have been reported changes to the pattern and severity of pediatric trauma. We review our two-institution experience.
Pediatric trauma emergency department (ED) encounters from the National Trauma Registry for a large, tertiary, metropolitan level 1 pediatric trauma center and pediatric burn admission at the regional burn center were extracted for children less than 19 years from March 15th thru May 15th during the years 2015–2020. The primary outcome was the difference in encounters during the COVID-19 (2020) epoch versus the pre-COVID-19 epoch (2015–2019).
There were 392 pediatric trauma encounters during the COVID-19 epoch as compared to 451, 475, 520, 460, 432 (mean 467.6) during the pre-COVID-19 epoch. Overall trauma admissions and ED trauma encounters were significantly lower (p < 0.001) during COVID-19. Burn injury admissions (p < 0.001) and penetrating trauma encounters (p = 0.002) increased during the COVID-19 epoch while blunt trauma encounters decreased (p < 0.001). Trauma occurred among more white (p = 0.01) and privately insured (p < 0.001) children, but no difference in suspected abuse, injury severity, mortality, age, or gender were detected. Sub-analysis showed significant decreases in motor vehicle crashes (p < 0.001), pedestrians struck by automobile (p < 0.001), all-terrain vehicle (ATV)/motorcross/bicycle/skateboard involved injuries (p = 0.02), falls (p < 0.001), and sports related injuries (p < 0.001). Fewer injuries occurring in the playground or home play equipment such as trampolines neared significance (p = 0.05). Interpersonal violence (assault, NAT, self-harm) was lower during the COVID-19 era (p = 0.04). For burn admissions, there was a significant increase in flame burns (p < 0.001).
Stay-at-home regulations alter societal patterns, leading to decreased overall and blunt traumas. However, the proportion of penetrating and burn injuries increased. Owing to increased stressors and time spent at home, healthcare professionals should keep a high suspicion for abuse and neglect.
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