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Students and established scholars of intellectual property law often look for historical context when trying to understand the development and present-day contours of IP rules and systems. American Patent Law supplies this context, offering readers a comprehensive account of the evolution of the US patent system and patent doctrine beginning in 1790. From the technologies for harvesting wood and shoemaking in the earliest periods to computer software and biotechnology of the present, each chapter of the book covers the characteristic technologies of each historical era. The book also describes how businesspeople in each era acquired and enforced patents and used patents as the foundation of various business arrangements. This book is a landmark in the history of technologies, the US patent system, and the way private actors have deployed patents across American history.
Aging is a subject of concern to everyone, but is widely misunderstood. If we view it as inevitable, we miss the fact that not everyone is able to grow to an old age. Realization of this reality helps us to understand that aging presents a wonderful opportunity - an opportunity to make choices about how we live which can enhance the aging process and offer a chance to live to our potential. This book clearly presents the four, multiple reserve, factors (cognitive, physical, psychological and social) which impact our ability to have healthy responses to the stresses of aging. By giving the biological basis for the advice given, you will learn the steps to take in your activities, diet and mental outlook to grasp the opportunity that aging offers. Everyone must know that what we do makes a difference.
United Kingdom Health Security Agency (UKHSA) guidance related to mask use for health care workers in a non-aerosol generating procedure (AGP) setting has remained as Level 2 water repellent paper mask (surgical mask) only. Energetic respiratory events, such as coughing, can generate vast numbers of droplets and aerosols. Coughing, considered to be a non-AGP event, frequently occurs in the relatively small, confined space of an ambulance (∼25 m3). The report seeks to explore whether existing research can provide an indication of the risk to ambulance staff, via aerosol transmission, of an acute respiratory infection (ARI) during a coughing event within the clinical setting of an ambulance.
International bibliographic databases were searched (CINAHL Plus, SCOPUS, PubMed, and CENTRAL) using appropriate search strings and a combination of relevant medical subject headings with appropriate truncation. Methodological filters were not applied. Papers without an English language abstract were excluded from the review. Grey literature was sought by searching specialist databases OpenGrey and GreyNet, as well as key organizations’ websites. The initial search identified 2,405 articles. Following screening, along with forward and backward citation of key papers identified within the literature search, 36 papers were deemed eligible for the scoping review.
Attempts to replicate a clinical environment to investigate the risk of transmission of airborne viruses to health care workers during a coughing event provided evidence for the generation of respirable aerosol particles and thus potential transmission of pathogens. In cases of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), potential to infect versus true airborne transmission is a debate that continues, but there is general consensus that a large variation of cough characteristics and aerosol generation amongst individuals exists. Studies widely endorsed face masks as a source control device, but there were conflicting views about the impact of mask leakage.
Further research is required to provide clarity of the risk to health care workers when caring for a coughing patient in the confined clinical ambulance setting and to provide an evidence base to assist in the determination of appropriate respiratory protective equipment (RPE).
A field experiment was conducted in 2019 and 2020 including a total of six site-years and four locations in Arkansas to determine the optimal sequence and timing of dicamba and glufosinate applications when applied alone, sequentially, or in combination to control Palmer amaranth by size: labeled (<10-cm height) and non-labeled (13- to 25-cm height). Single applications of dicamba, glufosinate, and dicamba plus glufosinate (not labeled) resulted in less than 80% Palmer amaranth control, regardless of weed size. The mixture of dicamba plus glufosinate was antagonistic for Palmer amaranth control and percent mortality. Sequential applications, averaged over all time intervals and herbicides, improved the percentage of Palmer amaranth control 11 to 17 percentage points over a single application, regardless of weed size at application 28 d after final application (DAFA). Palmer amaranth control with glufosinate followed by (fb) glufosinate and dicamba fb dicamba, pending weed size, were optimized at 7-, and 14- to 21-day intervals, respectively. Since single site of action (SOA) postemergence systems increase the likelihood of resistant biotypes and are not a best management practice (BMP) in that regard, sequential applications involving both dicamba and glufosinate were more effective. Further the sequence of application mattered with a preference for applying dicamba first. Dicamba fb glufosinate at a 14-day interval was profit-maximizing and the only herbicide treatment that resulted in 100% weed control when size was <10-cm. For larger weed sizes, economic analysis revealed dicamba fb dicamba to perform better than dicamba fb glufosinate when no penalty was assigned for using a single SOA. This resulted in greater yield loss risk and soil weed seed bank in comparison to timelier weed control with the smaller weed size. Hence timely weed control and two SOA to control Palmer amaranth are recommended as BMPs that reduce producer risk.
The mid-Maastrichtian carbon isotope event (MME), dated at ∼69 Ma, reflects a perturbation of the global carbon cycle that, in part, correlates with the enigmatic global extinction of ‘true’ (i.e., non-tegulated) inoceramid bivalves. The mechanisms of this extinction event are still debated.
While both the inoceramid extirpation and MME have been recorded in a variety of deep-sea sites, little is known about their expression in epicontinental chalk seas. In order to study the shallow-marine signature of the MME in this epicontinental shelf sea, we have generated quantitative foraminiferal assemblage data for two quarries (Hallembaye, NE Belgium; ENCI, SE Netherlands) in the Maastrichtian type area, complemented by a species-specific benthic δ13C record. In contrast to deep-sea records, no significant changes in benthic foraminiferal assemblages and benthic foraminiferal accumulation rates are observed across the MME in the type-Maastrichtian area. At the Hallembaye quarry, the otherwise rare endobenthic species Cuneus trigona reaches a transient peak abundance of 33.3% at the onset of the MME, likely caused by a local transient change in organic matter flux to the seafloor. Nevertheless, high and near-constant species evenness shows that neither oxygen nor organic matter flux was limited across the extinction level or during the MME. Benthic foraminiferal data from the uppermost part of the studied section, above the MME, indicate a significant increase in food supply to the seafloor. Decreased amounts of terrigenous elements across this interval document a lesser riverine or aeolian influx, which means that the increased benthic productivity is linked to a different origin. Potentially, the continuous precipitation of chalk under nutrient-poor conditions in the Late Cretaceous chalk sea was enabled by efficient nutrient recycling in the water column. In shallower depositional settings, nutrient recycling took place closer to the seafloor, which allowed more organic matter to reach the bottom. These results provide insights in the importance of nutrient cycling for biological productivity in the NW-European chalk sea.
Background: Eye movements reveal neurodegenerative disease processes due to overlap between oculomotor circuitry and disease-affected areas. Characterizing oculomotor behaviour in context of cognitive function may enhance disease diagnosis and monitoring. We therefore aimed to quantify cognitive impairment in neurodegenerative disease using saccade behaviour and neuropsychology. Methods: The Ontario Neurodegenerative Disease Research Initiative recruited individuals with neurodegenerative disease: one of Alzheimer’s disease, mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, or cerebrovascular disease. Patients (n=450, age 40-87) and healthy controls (n=149, age 42-87) completed a randomly interleaved pro- and anti-saccade task (IPAST) while their eyes were tracked. We explored the relationships of saccade parameters (e.g. task errors, reaction times) to one another and to cognitive domain-specific neuropsychological test scores (e.g. executive function, memory). Results: Task performance worsened with cognitive impairment across multiple diseases. Subsets of saccade parameters were interrelated and also differentially related to neuropsychology-based cognitive domain scores (e.g. antisaccade errors and reaction time associated with executive function). Conclusions: IPAST detects global cognitive impairment across neurodegenerative diseases. Subsets of parameters associate with one another, suggesting disparate underlying circuitry, and with different cognitive domains. This may have implications for use of IPAST as a cognitive screening tool in neurodegenerative disease.
The transition from military service to civilian life is a high-risk period for suicide attempts (SAs). Although stressful life events (SLEs) faced by transitioning soldiers are thought to be implicated, systematic prospective evidence is lacking.
Participants in the Army Study to Assess Risk and Resilience in Servicemembers (STARRS) completed baseline self-report surveys while on active duty in 2011–2014. Two self-report follow-up Longitudinal Surveys (LS1: 2016–2018; LS2: 2018–2019) were subsequently administered to probability subsamples of these baseline respondents. As detailed in a previous report, a SA risk index based on survey, administrative, and geospatial data collected before separation/deactivation identified 15% of the LS respondents who had separated/deactivated as being high-risk for self-reported post-separation/deactivation SAs. The current report presents an investigation of the extent to which self-reported SLEs occurring in the 12 months before each LS survey might have mediated/modified the association between this SA risk index and post-separation/deactivation SAs.
The 15% of respondents identified as high-risk had a significantly elevated prevalence of some post-separation/deactivation SLEs. In addition, the associations of some SLEs with SAs were significantly stronger among predicted high-risk than lower-risk respondents. Demographic rate decomposition showed that 59.5% (s.e. = 10.2) of the overall association between the predicted high-risk index and subsequent SAs was linked to these SLEs.
It might be possible to prevent a substantial proportion of post-separation/deactivation SAs by providing high-risk soldiers with targeted preventive interventions for exposure/vulnerability to commonly occurring SLEs.
The impact of secondary fluorescence on the material compositions measured by X-ray analysis for layered semiconductor thin films is assessed using simulations performed by the DTSA-II and CalcZAF software tools. Three technologically important examples are investigated: AlxGa1−xN layers on either GaN or AlN substrates, InxAl1−xN on GaN, and Si-doped (SnxGa1−x)2O3 on Si. Trends in the differences caused by secondary fluorescence are explained in terms of the propensity of different elements to reabsorb either characteristic or bremsstrahlung X-rays and then to re-emit the characteristic X-rays used to determine composition of the layer under investigation. Under typical beam conditions (7–12 keV), the quantification of dopants/trace elements is found to be susceptible to secondary fluorescence and care must be taken to prevent erroneous results. The overall impact on major constituents is shown to be very small with a change of approximately 0.07 molar cation percent for Al0.3Ga0.7N/AlN layers and a maximum change of 0.08 at% in the Si content of (SnxGa1−x)2O3/Si layers. This provides confidence that previously reported wavelength-dispersive X-ray compositions are not compromised by secondary fluorescence.
Previous research has suggested that statistical power is suboptimal in many biomedical disciplines, but it is unclear whether power is better in trials for particular interventions, disorders, or outcome types. We therefore performed a detailed examination of power in trials of psychotherapy, pharmacotherapy, and complementary and alternative medicine (CAM) for mood, anxiety, and psychotic disorders.
We extracted data from the Cochrane Database of Systematic Reviews (Mental Health). We focused on continuous efficacy outcomes and estimated power to detect predetermined effect sizes (standardized mean difference [SMD] = 0.20–0.80, primary SMD = 0.40) and meta-analytic effect sizes (ESMA). We performed meta-regression to estimate the influence of including underpowered studies in meta-analyses.
We included 256 reviews with 10 686 meta-analyses and 47 384 studies. Statistical power for continuous efficacy outcomes was very low across intervention and disorder types (overall median [IQR] power for SMD = 0.40: 0.32 [0.19–0.54]; for ESMA: 0.23 [0.09–0.58]), only reaching conventionally acceptable levels (80%) for SMD = 0.80. Median power to detect the ESMA was higher in treatment-as-usual (TAU)/waitlist-controlled (0.49–0.63) or placebo-controlled (0.12–0.38) trials than in trials comparing active treatments (0.07–0.13). Adequately-powered studies produced smaller effect sizes than underpowered studies (B = −0.06, p ⩽ 0.001).
Power to detect both predetermined and meta-analytic effect sizes in psychiatric trials was low across all interventions and disorders examined. Consistent with the presence of reporting bias, underpowered studies produced larger effect sizes than adequately-powered studies. These results emphasize the need to increase sample sizes and to reduce reporting bias against studies reporting null results to improve the reliability of the published literature.
This chapter aims to synthesize key findings from the SURE-Farm project. We first discuss possible amendments to the framework to assess the resilience of farming systems. We then review why many of Europe’s farming systems face a formidable and structural resilience crisis. While emphasizing the diversity of resilience capacities, challenges and needs, we formulate cornerstones for possible resilience-enhancing strategies. The chapter concludes with critical reflections and suggestions for resilience-enhancing strategies that comprise the levels of farms, farming systems and enabling environments. We identify limitations of the research and suggest avenues for future research on the resilience of farming systems.
Risk and risk management are essential elements of farming. We show that strategies to cope with risk often go beyond the level of the individual farm. Cooperation, learning and sharing of risks play a vital role in European agriculture. An enabling environment should support cooperative approaches, enable a diversity of risk management solutions and harness novel technological opportunities.
The importance of studying the radiocarbon content of dissolved inorganic carbon (DI14C) in the oceans has been recognized for decades. Starting with the GEOSECS program in the 1970s, 14C sampling has been a part of most global survey programs. Early results were used to study air-sea gas exchange while the more recent results are critical for helping calibrate ocean general circulation models used to study the effects of climate change. Here we summarize the major programs and discuss some of the important insights the results are starting to provide.
A variety of information sources are used in the best-evidence diagnostic procedure in child and adolescent mental healthcare, including evaluation by referrers and structured assessment questionnaires for parents. However, the incremental value of these information sources is still poorly examined.
To quantify the added and unique predictive value of referral letters, screening, multi-informant assessment and clinicians’ remote evaluations in predicting mental health disorders.
Routine medical record data on 1259 referred children and adolescents were retrospectively extracted. Their referral letters, responses to the Strengths and Difficulties Questionnaire (SDQ), results on closed-ended questions from the Development and Well-Being Assessment (DAWBA) and its clinician-rated version were linked to classifications made after face-to-face intake in psychiatry. Following multiple imputations of missing data, logistic regression analyses were performed with the above four nodes of assessment as predictors and the five childhood disorders common in mental healthcare (anxiety, depression, autism spectrum disorders, attention-deficit hyperactivity disorder, behavioural disorders) as outcomes. Likelihood ratio tests and diagnostic odds ratios were computed.
Each assessment tool significantly predicted the classified outcome. Successive addition of the assessment instruments improved the prediction models, with the exception of behavioural disorder prediction by the clinician-rated DAWBA. With the exception of the SDQ for depressive and behavioural disorders, all instruments showed unique predictive value.
Structured acquisition and integrated use of diverse sources of information supports evidence-based diagnosis in clinical practice. The clinical value of structured assessment at the primary–secondary care interface should now be quantified in prospective studies.
OBJECTIVES/GOALS: The goal of this study was to understand the impact of a high sodium diet on gene networks in the kidney that correlate with blood pressure in female primates, and translating findings to women. METHODS/STUDY POPULATION: Sodium-naÃ¯ve female baboons (n=7) were fed a low-sodium (LS) diet for 6 weeks followed by a high sodium (HS) diet for 6 weeks. Sodium intake, serum 17 beta-estradiol, and ultrasound-guided kidney biopsies for RNA-Seq were collected at the end of each diet. Blood pressure was continuously measured for 64-hour periods throughout the study by implantable telemetry devices. Weighted gene coexpression network analysis was performed on RNA-Seq data to identify transcripts correlated with blood pressure on each diet. Network analysis was performed on transcripts highly correlated with BP, and in silico findings were validated by immunohistochemistry of kidney tissues. RESULTS/ANTICIPATED RESULTS: On the LS diet, Na+ intake and serum 17 beta-estradiol concentration correlated with BP. Cell type composition of renal biopsies was consistent among all animals for both diets. Kidney transcriptomes differed by diet; analysis by unbiased weighted gene co-expression network analysis revealed modules of genes correlated with BP on the HS diet. Network analysis of module genes showed causal networks linking hormone receptors, proliferation and differentiation, methylation, hypoxia, insulin and lipid regulation, and inflammation as regulators underlying variation in BP on the HS diet. Our results show variation in BP correlated with novel kidney gene networks with master regulators PPARG and MYC in female baboons on a HS diet. DISCUSSION/SIGNIFICANCE: Previous studies in primates to identify molecular networks dysregulated by HS diet focused on males. Current clinical guidelines do not offer sex-specific treatment plans for sodium sensitive hypertension. This study leveraged variation in BP as a first step to identify correlated kidney regulatory gene networks in female primates after a HS diet.
In the December 2021 issue of Cardiology in the Young, Hubrechts and colleagues, from Brussels and Leuven in Belgium, describe their experience in which the pulmonary veins were normally connected to the morphologically left atrium. By virtue of the presence of a shelf dividing the morphologically left atrium, however, the venous return was to the morphologically right atrium, with no evidence of formation of the superior interatrial fold, meaning that there was no obstruction of flow into the systemic venous circulation. The question posed by the Belgian authors is whether the shelf dividing the morphologically left atrium is a deviated primary atrial septum, as the arrangement has previously been interpreted. As they discuss, it is currently impossible to arbitrate this conundrum. In our commentary, we discuss the background to the dilemma. We point out that, as yet, it is not possible to code accurately this congenital cardiac malformation within The International Paediatric and Congenital Cardiac Code (IPCCC), nor within the newly produced 11th Revision of the International Classification of Diseases (ICD-11).
OBJECTIVES/GOALS: A functional precision medicine platform to identify therapeutic targets for a glioblastoma patient with Li Fraumeni syndrome was performed. Comparative transcriptomics identified druggable targets and patient derived organoids and a 3D-PREDICT drug screening assay was used to validate the pipeline and identify further therapeutic targets. METHODS/STUDY POPULATION: A comparative transcriptomics pipeline was used to identify druggable genes that are uniquely overexpressed in our patient of interest relative to a cancer compendium of 12,747 tumor RNA sequencing datasets including 200 GBMs. Mini-ring patient derived organoid-based drug viability assays were performed to validate the comparative transcriptomics data. Additionally, a spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. RESULTS/ANTICIPATED RESULTS: Using comparative transcriptomics STAT1 and STAT2 were found to be significantly overexpressed in our patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitor, as a potential therapy. Druggable pathways predicted using comparative transcriptomics corresponded with ruxolitinib sensitivity in a panel of patient derived organoids screened with this compound. Cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. Additionally, 3D-PREDICT screening identified the mTOR inhibitor everolimus as a potential candidate. These two targeted therapies were selected for our patient and resulted in radiographic disease stability. DISCUSSION/SIGNIFICANCE: This research illustrates the use of comparative transcriptomics to identify druggable pathways irrespective of actionable DNA mutations present. Our results are promising and serve to highlight the importance of functional precision medicine in tailoring treatment regimes to specific patients.
OBJECTIVES/GOALS: Low statistical power is a problem is many fields. We performed a systematic review to determine the median statistical power of studies of epilepsy surgery outcomes. METHODS/STUDY POPULATION: We performed a PubMed search for studies reporting epilepsy surgery outcomes for the years 1980-2000, focusing on studies using stereo-electroencephalography (SEEG). We extracted patient count data for comparisons of surgical outcome between groups, based on a prognostic factor. We defined a clinically meaningful difference the surgical outcome for MRI positive (66.9%) compared to MRI negative (45.5%) in the largest study in the series. The statistical power of a Chi-square test was computed as the percentage of simulated runs (10,000 repetitions) assuming this difference with a p-value less than 0.05. RESULTS/ANTICIPATED RESULTS: Based on 69 studies, the median sample size was 38 patients, and the median statistical power was 24%. This implies at least a 17% (0.5/[0.24+0.05)) chance a study with a significant result in false, assuming 1:1 pre-test odds. A 'typical’ SEEG study with 33 patients and 2:1 allocation had a median significant odds ratio of 6.5, which over-estimates the true odds ratio of 2.4. DISCUSSION/SIGNIFICANCE: Studies of epilepsy surgery outcomes using SEEG are statistically underpowered. This means true effects will be missed, the chance a study with a significant result is false will be inflated, and significant effects found will be over-estimated. Studies of surgery outcome need better statistical rigor if they are to reliably guide treatment.
OBJECTIVES/GOALS: Recent research has attempted to identify diagnostic, prognostic, and predictive biomarkers, however, currently, no biomarkers can accurately diagnose GBC and predict patients prognosis. Using machine learning, we can utilize high-throughput RNA sequencing with clinicopathologic data to develop a predictive tool for GBC prognosis. METHODS/STUDY POPULATION: Current predictive models for GBC outcomes often utilize clinical data only. We aim to build a superior algorithm to predict overall survival in GBC patients with advanced disease, using machine learning approaches to prioritize biomarkers for GBC prognosis. We have identified over 80 fresh frozen GBC tissue samples from Rochester, Minnesota, Daegu, Korea, Vilnius, Lithuania, and Calgary, Canada. We will perform next-generation RNA sequencing on these tissue samples. The patients clinical, pathologic and survival data will be abstracted from the medical record. Random forests, support vector machines, and gradient boosting machines will be applied to train the data. Standard 5-fold cross validation will be used to assess performance of each ML algorithm. RESULTS/ANTICIPATED RESULTS: Our preliminary analysis of next generation RNA sequencing from 18 GBC tissue samples identified recurrent mutations in genes enriched in pathways in cytoskeletal signaling, cell organization, cell movement, extracellular matrix interaction, growth, and proliferation. The top three most significantly altered pathways, actin cytoskeleton signaling, hepatic fibrosis/hepatic stellate cell activation, and epithelial adherens junction signaling, emphasized a molecular metastatic and invasive fingerprint in our patient cohort. This molecular fingerprint is consistent with the previous knowledge of the highly metastatic nature of gallbladder tumors and is also manifested physiologically in the patient cohort. DISCUSSION/SIGNIFICANCE: Integrative analysis of molecular and clinical characterization of GBC has not been fully established, and minimal improvement has been made to the survival of these patients. If overall survival can be better predicted, we can gain a greater understanding of key biomarkers driving the tumor phenotype.