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Can multicellular life be distinguished from single cellular life on an exoplanet? We hypothesize that abundant upright photosynthetic multicellular life (trees) will cast shadows at high sun angles that will distinguish them from single cellular life and test this using Earth as an exoplanet. We first test the concept using unmanned aerial vehicles at a replica moon-landing site near Flagstaff, Arizona and show trees have both a distinctive reflectance signature (red edge) and geometric signature (shadows at high sun angles) that can distinguish them from replica moon craters. Next, we calculate reflectance signatures for Earth at several phase angles with POLDER (Polarization and Directionality of Earth's reflectance) satellite directional reflectance measurements and then reduce Earth to a single pixel. We compare Earth to other planetary bodies (Mars, the Moon, Venus and Uranus) and hypothesize that Earth's directional reflectance will be between strongly backscattering rocky bodies with no weathering (like Mars and the Moon) and cloudy bodies with more isotropic scattering (like Venus and Uranus). Our modelling results put Earth in line with strongly backscattering Mars, while our empirical results put Earth in line with more isotropic scattering Venus. We identify potential weaknesses in both the modelled and empirical results and suggest additional steps to determine whether this technique could distinguish upright multicellular life on exoplanets.
Chordoma is a rare bone cancer for which there are no approved drugs. Surgery is the principle treatment but complete resection can be challenging due to the location of the tumours in the spine and therefore finding an effective drug treatment is a pressing unmet clinical need. A major recent study identified the transcription factor Brachyury as the primary vulnerability and drug target in chordoma. Previously, all-trans retinoic acid (ATRA) has been shown to negatively influence expression of the Brachyury gene, TBXT. Here we extend this finding and demonstrate that ATRA lowers Brachyury protein levels in chordoma cells and reduces proliferation of the chordoma cell line U-CH1 as well as causing loss of distinctive chordoma cell morphology. ATRA is available as a generic drug and is the first line treatment for acute promyelocytic leukaemia (APL). This study implies ATRA could have therapeutic value if repurposed for chordoma.
This study consisted of six field experiments was conducted in 2018 and 2019 to evaluate the tolerance of four corn hybrids (P9998AM, P9840AM, DKC42-60RIB and DKC43-47RIB) to the tankmix of tolpyralate + atrazine with a commercial glyphosate formulation. At 1 WAA, two corn hybrids (P9998AM and P9840AM) exhibited more injury from tolpyralate + atrazine (2X rate) applied alone and in combination with glyphosate than DKC42-60RIB and DKC43-47RIB; but all corn hybrids responded similarly with respect to visible injury 2, 4 and 8 WAA, stand loss and yield. Application of tolpyralate + atrazine or glyphosate + tolpyralate + atrazine at the 2X rate caused greater corn injury (up to 27%) than tolpyralate + atrazine or glyphosate + tolpyralate + atrazine at the 1X rate (up to 8%) at 1 WAA. The addition of commercial glyphosate with tolpyralate + atrazine did not enhance injury symptoms. Results of this study show that there is a wide margin of corn safety with tolpyralate + atrazine applied alone and in combination with a commercial formulation of glyphosate.
Tolpyralate is a new 4-hydroxyphenyl-pyruvate dioxygenase (HPPD)-inhibiting herbicide for weed control in corn. Previous research has reported efficacy of tolpyralate + atrazine on several annual grass and broadleaf weed species; however, no studies have evaluated weed control of tolpyralate + atrazine depending on time-of-day (TOD) of application. Six field experiments were conducted over a two-year period (2018, 2019) near Ridgetown, ON to determine if there is an effect of TOD of application on tolpyralate + atrazine efficacy on common annual grass and broadleaf weeds. An application was made at three-hour intervals beginning at 06:00 h and the last application at 24:00 h. There was a slight TOD effect on velvetleaf, pigweed species and common ragweed control with tolpyralate + atrazine; however, the magnitude of change throughout the day was ≤3% at 2, 4 or 8 WAA. There was no effect of TOD of tolpyralate + atrazine on the control of lambsquarters, barnyardgrass and green foxtail. All weed species were controlled ≥88% 8 WAA. There was no effect of TOD of tolpyralate + atrazine application on corn yield. Results of this study show no evidence of a TOD effect on weed control efficacy with tolpyralate + atrazine.
The current study aimed to investigate availability and placement of healthy and discretionary (less healthy) food in supermarkets in Victoria, Australia, and examine variation by supermarket chain and area-level socio-economic disadvantage.
Cross-sectional supermarket audit. Measures included: (i) proportion of shelf space (in square metres) allocated to selected healthy and discretionary food and beverages; (ii) proportion of end-of-aisle, checkout and island bin displays containing discretionary food and beverages and (iii) proportion of space within end-of-aisle, checkout and island bin displays devoted to discretionary food and beverages.
Metropolitan areas of Melbourne and Geelong, Australia. Assessment: June–July 2019.
Random sample of 104 stores, with equal numbers from each supermarket group (Coles, Woolworths, Aldi and Independent stores) within strata of area-level socio-economic position.
Proportion of shelf space devoted to selected discretionary foods was greater for Independent stores (72·7 %) compared with Woolworths (65·7 %), Coles (64·8 %) and Aldi (63·2 %) (all P < 0·001). Proportion of shelf space devoted to selected discretionary food for all Coles, Woolworths and Aldi stores was 9·7 % higher in the most compared with the least disadvantaged areas (P = 0·002). Across all stores, 90 % of staff-assisted checkout displays and 50 % of end-of-aisle displays included discretionary food. Aldi was less likely to feature discretionary food in end-of-aisle and checkout displays compared with other supermarket groups.
Extensive marketing of discretionary food in all Australian supermarket chains was observed, which is likely to strongly influence purchasing patterns and population diets. Findings should be used to inform private and public sector policies to reduce marketing of discretionary food in supermarkets.
Addiction is characterized by excessive desire for a particular substance or behavioral incentive at the expense of other life rewards. Addictive desire can develop even in absence of any associated increase in pleasure, and also in absence of withdrawal. Here we review evidence that the brain mechanisms underlying desire or ‘wanting’ can operate independently from those mediating pleasure, or "liking." That is, "wanting" and "liking" are mediated by two anatomically and neurochemically distinct brain mechanisms that normally interact together to influence motivation, but can become dissociated in the transition to addiction. Pleasure "liking" is the hedonic impact of a pleasant stimulus and is causally amplified by a brain system of several functionally interactive but anatomically distributed locations referred to as "hedonic hotspots." These hedonic hotspots are localized subregions within larger brain structures, and are relatively sensitive to disruption. By contrast, "wanting" or the subconscious desire for reward or reward-related cues is much more robust, and mediated by a larger brain system. "Wanting" can be generated by dopamine enhancements as well as by opioid enhancements in several broadly defined regions throughout mesocorticolimbic circuitry. In susceptible individuals, mesolimbic circuitry can become hyperreactive or sensitized (e.g., through previous drug experience), so that "rewards" and their related cues evoke even greater dopamine release and "wanting." Sensitized "wanting" becomes harder to resist, which can spur on excessive and compulsive pursuit and relapse in addiction. Importantly, this sensitization of brain "wanting" systems need not be accompanied by an enhancement of brain "liking" (i.e., dopamine manipulations do not appear to effect pleasure). In this chapter, we also highlight possible mechanisms for how some drugs or behaviors become the specific focus of excessive but narrow pursuit, usually involving mesolimbic brain interactions with areas such as the amygdala. Further we demonstrate that behavioral addictions such as food addiction and gambling, like drug addiction, are accompanied by sensitization of mesolimbic brain "wanting" systems in the transition to addiction.
Outbreaks of cyclosporiasis, a food-borne illness caused by the coccidian parasite Cyclospora cayetanensis have increased in the USA in recent years, with approximately 2300 laboratory-confirmed cases reported in 2018. Genotyping tools are needed to inform epidemiological investigations, yet genotyping Cyclospora has proven challenging due to its sexual reproductive cycle which produces complex infections characterized by high genetic heterogeneity. We used targeted amplicon deep sequencing and a recently described ensemble-based distance statistic that accommodates heterogeneous (mixed) genotypes and specimens with partial genotyping data, to genotype and cluster 648 C. cayetanensis samples submitted to CDC in 2018. The performance of the ensemble was assessed by comparing ensemble-identified genetic clusters to analogous clusters identified independently based on common food exposures. Using these epidemiologic clusters as a gold standard, the ensemble facilitated genetic clustering with 93.8% sensitivity and 99.7% specificity. Hence, we anticipate that this procedure will greatly complement epidemiologic investigations of cyclosporiasis.
Understanding the clinical risk factors for COVID-19 disease severity and outcomes requires a combination of data from electronic health records and patient reports. To facilitate the collection of patient-reported data, as well as accelerate and standardize the collection of data about host factors, we have constructed a COVID-19 survey. This survey is freely available to the scientific community to send electronically for patients to complete online. This patient survey is designed to be comprehensive, yet not overly burdensome, to gather data useful for a range of clinical investigations, and to accommodate a wide variety of implementation settings including at a COVID-19 testing site, at home during infection or after recovery, and/or for individuals while they are hospitalized. A widely adopted standardized survey that can be implemented online with minimal resources can serve as a critical tool for combining and comparing data across studies to improve our understanding of COVID-19 disease.
To establish how real-world evidence (RWE) has been used to inform single technology appraisals (STAs) of cancer drugs conducted by the National Institute for Health and Care Excellence (NICE).
STAs published by NICE from April 2011 to October 2018 that evaluated cancer treatments were reviewed. Information regarding the use of RWE to directly inform the company-submitted cost-effectiveness analysis was extracted and categorized by topic. Summary statistics were used to describe emergent themes, and a narrative summary was provided for key case studies.
Materials for a total of 113 relevant STAs were identified and analyzed, of which nearly all (96 percent) included some form of RWE within the company-submitted cost-effectiveness analysis. The most common categories of RWE use concerned the health-related quality of life of patients (71 percent), costs (46 percent), and medical resource utilization (40 percent). While sources of RWE were routinely criticized as part of the appraisal process, we identified only two cases where the use of RWE was overtly rejected; hence, in the majority of cases, RWE was accepted in cancer drug submissions to NICE.
RWE has been used extensively in cancer submissions to NICE. Key criticisms of RWE in submissions to NICE are seldom regarding the use of RWE in general; instead, these are typically concerned with specific data sources and the applicability of these to the decision problem. Within an appropriate context, RWE constitutes an extremely valuable source of information to inform decision making; yet the development of best practice guidelines may improve current reporting standards.
Passive acoustic monitoring is rapidly gaining recognition as a practical, affordable and robust tool for measuring gun hunting levels within protected areas, and consequently for its potential to evaluate anti-poaching patrols’ effectiveness based on outcome (i.e., change in hunting pressure) rather than effort (e.g., kilometres patrolled) or output (e.g., arrests). However, there has been no report to date of a protected area successfully using an acoustic grid to explore baseline levels of gun hunting activity, adapting its patrols in response to the evidence extracted from the acoustic data and then evaluating the effectiveness of the new patrol strategy. We report here such a case in Cameroon’s Korup National Park, where anti-poaching patrol effort was markedly increased in the 2015–2016 Christmas/New Year holiday season to curb the annual peak in gunshots recorded by a 12-sensor acoustic grid in the same period during the previous 2 years. Despite a three- to five-fold increase in patrol days, distance and area covered, the desired outcome – lower gun hunting activity – was not achieved under the new patrol scheme. The findings emphasize the need for adaptive wildlife law enforcement and how passive acoustic monitoring can help attain this goal, and they warn about the risks of using effort-based metrics of anti-poaching strategies as a surrogate for desired outcomes. We propose ways of increasing protected areas’ capacity to adopt acoustic grids as a law enforcement monitoring tool.
Poultry production is an important way of enhancing the livelihoods of rural populations, especially in low- and middle-income countries (LMICs). As poultry production in LMICs remains dominated by backyard systems with low inputs and low outputs, considerable yield gaps exist. Intensification can increase poultry productivity, production and income. This process is relatively recent in LMICs compared to high-income countries. The management practices and the constraints faced by smallholders trying to scale-up their production, in the early stages of intensification, are poorly understood and described. We thus investigated the features of the small-scale commercial chicken sector in a rural area distant from major production centres. We surveyed 111 commercial chicken farms in Kenya in 2016. We targeted farms that sell the majority of their production, owning at least 50 chickens, partly or wholly confined and provided with feeds. We developed a typology of semi-intensive farms. Farms were found mainly to raise dual-purpose chickens of local and improved breeds, in association with crops and were not specialized in any single product or market. We identified four types of semi-intensive farms that were characterized based on two groups of variables related to intensification and accessibility: (i) remote, small-scale old farms, with small flocks, growing a lot of their own feed; (ii) medium-scale, old farms with a larger flock and well located in relation to markets and (iii) large-scale recently established farms, with large flocks, (iii-a) well located and buying chicks from third-party providers and (iii-b) remotely located and hatching their own chicks. The semi-intensive farms we surveyed were highly heterogeneous in terms of size, age, accessibility, management, opportunities and challenges. Farm location affects market access and influences the opportunities available to farmers, resulting in further diversity in farm profiles. The future of these semi-intensive farms could be compromised by several factors, including the competition with large-scale intensive farmers and with importations. Our study suggests that intensification trajectories in rural areas of LMICs are potentially complex, diverse and non-linear. A better understanding of intensification trajectories should, however, be based on longitudinal data. This could, in turn, help designing interventions to support small-scale farmers.
OBJECTIVES/GOALS: Early age at menopause has been linked to increased risk of cardiovascular disease; however, there is limited evidence for a relationship between early menopause and heart failure (HF). We examined whether early menopause is associated with incident HF among women in the southeastern United States. METHODS/STUDY POPULATION: The Southern Community Cohort Study enrolled ~86,000 low-income black and white adults from 2002 to 2009. Participants for this analysis were 11,948 women who were postmenopausal at enrollment, had no history of HF, and were on Medicaid or Medicare. HF events were ascertained using ICD-9 codes 428.x via linkage of the cohort with CMS Research Identifiable Files through December 31, 2010. Early menopause was defined as self-reported age at menopause less than 45 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed from multivariable Cox regression models, overall and by race, adjusting for demographic, lifestyle, and reproductive factors, including reason for menopause. RESULTS/ANTICIPATED RESULTS: At baseline, mean age was 58±9 years, and 65% of participants were black. Among women with early menopause, 76% (n = 4,836) had menopause due to hysterectomy or oophorectomy. In women with later menopause, 74% (n = 4,102) reported natural menopause. During a median follow-up of 5.0 years (range 3.1-6.7), 2,157 incident HF events occurred. Compared with women with later onset of menopause, those with early menopause had increased HF risk (HR: 1.27, 95% CI: 1.10–1.47). Risk of HF associated with early menopause was similar in white and black women (p-value for interaction: 0.13). DISCUSSION/SIGNIFICANCE OF IMPACT: In this largely low-income population, early menopause was associated with an increased risk of developing HF. Women with early menopause represent a potential target population for future interventions to decrease risk of HF and cardiovascular risk factors.
We examined demographic, clinical, and psychological characteristics of a large cohort (n = 368) of adults with dissociative seizures (DS) recruited to the CODES randomised controlled trial (RCT) and explored differences associated with age at onset of DS, gender, and DS semiology.
Prior to randomisation within the CODES RCT, we collected demographic and clinical data on 368 participants. We assessed psychiatric comorbidity using the Mini-International Neuropsychiatric Interview (M.I.N.I.) and a screening measure of personality disorder and measured anxiety, depression, psychological distress, somatic symptom burden, emotional expression, functional impact of DS, avoidance behaviour, and quality of life. We undertook comparisons based on reported age at DS onset (<40 v. ⩾40), gender (male v. female), and DS semiology (predominantly hyperkinetic v. hypokinetic).
Our cohort was predominantly female (72%) and characterised by high levels of socio-economic deprivation. Two-thirds had predominantly hyperkinetic DS. Of the total, 69% had ⩾1 comorbid M.I.N.I. diagnosis (median number = 2), with agoraphobia being the most common concurrent diagnosis. Clinical levels of distress were reported by 86% and characteristics associated with maladaptive personality traits by 60%. Moderate-to-severe functional impairment, high levels of somatic symptoms, and impaired quality of life were also reported. Women had a younger age at DS onset than men.
Our study highlights the burden of psychopathology and socio-economic deprivation in a large, heterogeneous cohort of patients with DS. The lack of clear differences based on gender, DS semiology and age at onset suggests these factors do not add substantially to the heterogeneity of the cohort.
Implementation of genome-scale sequencing in clinical care has significant challenges: the technology is highly dimensional with many kinds of potential results, results interpretation and delivery require expertise and coordination across multiple medical specialties, clinical utility may be uncertain, and there may be broader familial or societal implications beyond the individual participant. Transdisciplinary consortia and collaborative team science are well poised to address these challenges. However, understanding the complex web of organizational, institutional, physical, environmental, technologic, and other political and societal factors that influence the effectiveness of consortia is understudied. We describe our experience working in the Clinical Sequencing Evidence-Generating Research (CSER) consortium, a multi-institutional translational genomics consortium.
A key aspect of the CSER consortium was the juxtaposition of site-specific measures with the need to identify consensus measures related to clinical utility and to create a core set of harmonized measures. During this harmonization process, we sought to minimize participant burden, accommodate project-specific choices, and use validated measures that allow data sharing.
Identifying platforms to ensure swift communication between teams and management of materials and data were essential to our harmonization efforts. Funding agencies can help consortia by clarifying key study design elements across projects during the proposal preparation phase and by providing a framework for data sharing data across participating projects.
In summary, time and resources must be devoted to developing and implementing collaborative practices as preparatory work at the beginning of project timelines to improve the effectiveness of research consortia.
Examine impact of audit and feedback on antipsychotic prescribing in schizophrenia over 4.5-years.
Clinical files in three outpatient psychiatric services in Auckland, New Zealand were reviewed at two time-points (March-2000;October-2004). After the first audit, feedback was provided to all three services. Baseline prescribing variations between services were found for antipsychotic combinations and atypical prescribing, in particular clozapine. In two services audit and feedback continued with two interim reviews (October-2001;March-2003). Specific feedback and interventions targeting clozapine use were introduced in both services. No further audit or feedback occurred in the third service until the final audit. Data were collected (patient characteristics, diagnosis, antipsychotic treatment) and analysed at each audit.
Three prescribing variables (antipsychotic monotherapy, atypical and clozapine use) were consistent with practice recommendations at the final audit (85.7%, 82.7% and 34.5% respectively) and had changed in the desired direction for all three services over 4.5-years. At baseline there were differences between the three services. One service had baseline prescribing variables closest to recommendations, was actively involved in audit, and improved further. The second service, also actively involved in audit had baseline prescribing variables further from recommendations but improved the most. The service not involved in continuing audit and feedback made smaller changes, and atypical and clozapine use at endpoint were significantly lower despite at baseline being comparable to the service which improved the most.
We found high intensity audit and feedback was an effective intervention in closing the gap between recommended and clinical practice for antipsychotic prescribing.
The regulation of pesticides in the European Union (EU) relies on a network of hard law (legislation and implementing acts) and soft law (non-legally binding guidance documents and administrative and scientific practices). Both hard and soft laws govern how risk assessments are conducted, but a significant role is left to the latter. Europe’s pesticide regulation is one of the most stringent in the world. Its stated objectives are to ensure an independent, objective and transparent assessment of pesticides and achieve a high level of protection for health and environment. However, a growing body of evidence shows that pesticides that have passed through this process and are authorised for use may harm humans, animals and the environment. The authors of the current paper – experts in toxicology, law and policy – identified shortcomings in the authorisation process, focusing on the EU assessment of the pesticide active substance glyphosate. The shortcomings mostly consist of failures to implement the hard or soft laws. But in some instances the law itself is responsible, as some provisions can only fail to achieve its objectives. Ways to improve the system are proposed, requiring changes in hard and soft laws as well as in administrative and scientific practices.
Carbapenem-resistant Enterobacterales (CRE) are common causes of healthcare-associated infections and are often multidrug resistant with limited therapeutic options. Additionally, CRE can spread within and between healthcare facilities, amplifying potential harms.
To better understand the burden, risk factors, and source of acquisition of carbapenemase genes in clinical Escherichia coli and Klebsiella spp isolates from patients in Washington to guide prevention efforts.
Multicenter prospective surveillance study.
Escherichia coli and Klebsiella spp isolates meeting the Washington state CRE surveillance case definition were solicited from clinical laboratories and tested at Washington Public Health Laboratories using polymerase chain reaction (PCR) for the 5 most common carbapenemase genes: blaKPC, blaNDM, blaIMP, blaVIM, and blaOXA-48. Case patients positive by PCR were investigated by the public health department.
From October 2012 through December 2017, 363 carbapenem-resistant E. coli and Klebsiella spp isolates were tested. Overall, 45 of 115 carbapenem-resistant K. pneumoniae (39%), 1 of 8 K. oxytoca (12.5%), and 28 of 239 carbapenem-resistant E. coli (11.7%) were carbapenemase positive. Of 74 carbapenemase-positive isolates, blaKPC was most common (47%), followed by blaNDM (30%), blaOXA-48 (22%), and blaIMP (1%). Although all cases had healthcare exposure, blaKPC acquisition was associated with US health care, whereas non-blaKPC acquisition was associated with international health care or travel.
We report that blaKPC, the most prevalent carbapenemase in the United States, accounts for nearly half of carbapenemase cases in Washington state and that most KPC-cases are likely acquired through in-state health care.