Understanding the relative importance of top-down and bottom-up regulation of ecosystem structure is a fundamental ecological question, with implications for fisheries and water-quality management. ...For the Laurentian Great Lakes, where, since the early 1970s, nutrient inputs have been reduced, whereas top-predator biomass has increased, we describe trends across multiple trophic levels and explore their underlying drivers. Our analyses revealed increasing water clarity and declines in phytoplankton, native invertebrates, and prey fish since 1998 in at least three of the five lakes. Evidence for bottom-up regulation was strongest in Lake Huron, although each lake provided support in at least one pair of trophic levels. Evidence for top-down regulation was rare. Although nonindigenous dreissenid mussels probably have large impacts on nutrient cycling and phytoplankton, their effects on higher trophic levels remain uncertain. We highlight gaps for which monitoring and knowledge should improve the understanding of food-web dynamics and facilitate the implementation of ecosystem-based management.
Background. Individuals infected with Mycobacterium tuberculosis (Mtb) may develop symptoms and signs of disease (tuberculosis disease) or may have no clinical evidence of disease (latent ...tuberculosis infection LTBI). Tuberculosis disease is a leading cause of infectious disease morbidity and mortality worldwide, yet many questions related to its diagnosis remain. Methods. A task force supported by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America searched, selected, and synthesized relevant evidence. The evidence was then used as the basis for recommendations about the diagnosis of tuberculosis disease and LTBI in adults and children. The recommendations were formulated, written, and graded using the Grading, Recommendations, Assessment, Development and Evaluation (GRADE) approach. Results. Twenty-three evidence-based recommendations about diagnostic testing for latent tuberculosis infection, pulmonary tuberculosis, and extrapulmonary tuberculosis are provided. Six of the recommendations are strong, whereas the remaining 17 are conditional. Conclusions. These guidelines are not intended to impose a standard of care. They provide the basis for rational decisions in the diagnosis of tuberculosis in the context of the existing evidence. No guidelines can take into account all of the often compelling unique individual clinical circumstances.
Midlife hypertension confers increased risk for cognitive impairment in late life. The sensitive period for risk exposure and extent that risk is mediated through amyloid or vascular-related ...mechanisms are poorly understood. We aimed to identify if, and when, blood pressure or change in blood pressure during adulthood were associated with late-life brain structure, pathology, and cognition.
Participants were from Insight 46, a neuroscience substudy of the ongoing longitudinal Medical Research Council National Survey of Health and Development, a birth cohort that initially comprised 5362 individuals born throughout mainland Britain in one week in 1946. Participants aged 69–71 years received T1 and FLAIR volumetric MRI, florbetapir amyloid-PET imaging, and cognitive assessment at University College London (London, UK); all participants were dementia-free. Blood pressure measurements had been collected at ages 36, 43, 53, 60–64, and 69 years. We also calculated blood pressure change variables between ages. Primary outcome measures were white matter hyperintensity volume (WMHV) quantified from multimodal MRI using an automated method, amyloid-β positivity or negativity using a standardised uptake value ratio approach, whole-brain and hippocampal volumes quantified from 3D-T1 MRI, and a composite cognitive score—the Preclinical Alzheimer Cognitive Composite (PACC). We investigated associations between blood pressure and blood pressure changes at and between 36, 43, 53, 60–64, and 69 years of age with WMHV using generalised linear models with a gamma distribution and log link function, amyloid-β status using logistic regression, whole-brain volume and hippocampal volumes using linear regression, and PACC score using linear regression, with adjustment for potential confounders.
Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. 465 participants (238 51% men; mean age 70·7 years SD 0·7; 83 18% amyloid-β-positive) were included in imaging analyses. Higher systolic blood pressure (SBP) and diastolic blood pressure (DBP) at age 53 years and greater increases in SBP and DBP between 43 and 53 years were positively associated with WMHV at 69–71 years of age (increase in mean WMHV per 10 mm Hg greater SBP 7%, 95% CI 1–14, p=0·024; increase in mean WMHV per 10 mm Hg greater DBP 15%, 4–27, p=0·0057; increase in mean WMHV per one SD change in SBP 15%, 3–29, p=0·012; increase in mean WMHV per 1 SD change in DBP 15%, 3–30, p=0·017). Higher DBP at 43 years of age was associated with smaller whole-brain volume at 69–71 years of age (−6·9 mL per 10 mm Hg greater DBP, −11·9 to −1·9, p=0·0068), as were greater increases in DBP between 36 and 43 years of age (−6·5 mL per 1 SD change, −11·1 to −1·9, p=0·0054). Greater increases in SBP between 36 and 43 years of age were associated with smaller hippocampal volumes at 69–71 years of age (−0·03 mL per 1 SD change, −0·06 to −0·001, p=0·043). Neither absolute blood pressure nor change in blood pressure predicted amyloid-β status or PACC score at 69–71 years of age.
High and increasing blood pressure from early adulthood into midlife seems to be associated with increased WMHV and smaller brain volumes at 69–71 years of age. We found no evidence that blood pressure affected cognition or cerebral amyloid-β load at this age. Blood pressure monitoring and interventions might need to start around 40 years of age to maximise late-life brain health.
Alzheimer's Research UK, Medical Research Council, Dementias Platform UK, Wellcome Trust, Brain Research UK, Wolfson Foundation, Weston Brain Institute, Avid Radiopharmaceuticals.
The use of the term platform has proliferated in management research. However, theoretical work on the concept has lagged behind. We present a systematic review of the platform literature, ...identifying four distinct streams: organizational platforms, product family platforms, market intermediary platforms, and platform ecosystems. Each of these streams is characterized by a distinctive, although usually implied, theoretical logic. We elaborate on the theoretical logics of leverage and architectural openness, both of which underpin all four streams of platform research. We further discuss three distinctive leverage rationales exhibited in different platform variants—production, innovation, and transaction—and illustrate how platform ecosystems combine aspects of all three. We explain the metalogic of architectural leverage to facilitate the purposive manipulation of platforms, providing a link between platform design features and sources of leverage. This provides a model that allows the different platform types to be placed into context with others. Finally, we outline how the concept of architectural leverage can be used to understand platform evolution.
Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) ...patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.
Individuals infected with Mycobacterium tuberculosis (Mtb) may develop symptoms and signs of disease (tuberculosis disease) or may have no clinical evidence of disease (latent tuberculosis infection ...LTBI). Tuberculosis disease is a leading cause of infectious disease morbidity and mortality worldwide, yet many questions related to its diagnosis remain.
A task force supported by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America searched, selected, and synthesized relevant evidence. The evidence was then used as the basis for recommendations about the diagnosis of tuberculosis disease and LTBI in adults and children. The recommendations were formulated, written, and graded using the Grading, Recommendations, Assessment, Development and Evaluation (GRADE) approach.
Twenty-three evidence-based recommendations about diagnostic testing for latent tuberculosis infection, pulmonary tuberculosis, and extrapulmonary tuberculosis are provided. Six of the recommendations are strong, whereas the remaining 17 are conditional.
These guidelines are not intended to impose a standard of care. They provide the basis for rational decisions in the diagnosis of tuberculosis in the context of the existing evidence. No guidelines can take into account all of the often compelling unique individual clinical circumstances.
Globalized infectious diseases are causing species declines worldwide, but their source often remains elusive. We used whole-genome sequencing to solve the spatiotemporal origins of the most ...devastating panzootic to date, caused by the fungus
, a proximate driver of global amphibian declines. We traced the source of
to the Korean peninsula, where one lineage,
ASIA-1, exhibits the genetic hallmarks of an ancestral population that seeded the panzootic. We date the emergence of this pathogen to the early 20th century, coinciding with the global expansion of commercial trade in amphibians, and we show that intercontinental transmission is ongoing. Our findings point to East Asia as a geographic hotspot for
biodiversity and the original source of these lineages that now parasitize amphibians worldwide.
The contribution of animal testing in drug development has been widely debated and challenged. An industry-wide nonclinical to clinical translational database was created to determine how safety ...assessments in animal models translate to First-In-Human clinical risk. The blinded database was composed of 182 molecules and contained animal toxicology data coupled with clinical observations from phase I human studies. Animal and clinical data were categorized by organ system and correlations determined. The 2×2 contingency table (true positive, false positive, true negative, false negative) was used for statistical analysis. Sensitivity was 48% with a 43% positive predictive value (PPV). The nonhuman primate had the strongest performance in predicting adverse effects, especially for gastrointestinal and nervous system categories. When the same target organ was identified in both the rodent and nonrodent, the PPV increased. Specificity was 84% with an 86% negative predictive value (NPV). The beagle dog had the strongest performance in predicting an absence of clinical adverse effects. If no target organ toxicity was observed in either test species, the NPV increased. While nonclinical studies can demonstrate great value in the PPV for certain species and organ categories, the NPV was the stronger predictive performance measure across test species and target organs indicating that an absence of toxicity in animal studies strongly predicts a similar outcome in the clinic. These results support the current regulatory paradigm of animal testing in supporting safe entry to clinical trials and provide context for emerging alternate models.
•Translational database created to determine animal to human safety concordance.•182 molecules with animal and clinical data; concordance parameters determined•Positive predictive value of 43%; Negative predictive value of 86%•Absence of toxicity in animal study strongly predicts similar outcome in the clinic.•Database supports animal testing to ensure human safety in the clinic.
Tau aggregation occurs in neurodegenerative diseases including Alzheimer’s disease and many other disorders collectively termed tauopathies. trans-cellular propagation of tau pathology, mediated by ...extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused three effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest that immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy.
•Anti-tau antibodies block intracellular tau aggregation induced by tau seeds•Anti-tau antibodies strongly reduce tau pathology in vivo•Anti-tau antibodies decrease tau seeding activity in vivo•Anti-tau antibodies improve cognition
Yanamandra et al. find that antibodies that block aggregated forms of the tau protein from entering cells and seeding further tau aggregation have beneficial effects in an animal model that is relevant for Alzheimer’s disease and related disorders.
In 2011, Lake Erie experienced the largest harmful algal bloom in its recorded history, with a peak intensity over three times greater than any previously observed bloom. Here we show that long-term ...trends in agricultural practices are consistent with increasing phosphorus loading to the western basin of the lake, and that these trends, coupled with meteorological conditions in spring 2011, produced record-breaking nutrient loads. An extended period of weak lake circulation then led to abnormally long residence times that incubated the bloom, and warm and quiescent conditions after bloom onset allowed algae to remain near the top of the water column and prevented flushing of nutrients from the system. We further find that all of these factors are consistent with expected future conditions. If a scientifically guided management plan to mitigate these impacts is not implemented, we can therefore expect this bloom to be a harbinger of future blooms in Lake Erie.
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