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OBJECTIVES/GOALS: In a familial case where 10 of 17 members inherited EA/LVNC in an autosomal dominant pattern, we discovered a novel, damaging missense variant in the gene KLHL26 that segregates with disease and comprises an altered electrostatic surface profile, likely decoupling the CUL3-interactome. We hypothesize that this KLHL26 variant is etiologic of EA/LVNC. METHODS/STUDY POPULATION: We differentiated a family trio (a heart-healthy daughter and EA/LVNC-affected mother and daughter) of induced pluripotent stem cells into cardiomyocytes (iPSC-CMs) in a blinded manner on three iPSC clones per subject. Using flow cytometry, immunofluorescence, and biomechanical, electrophysiological, and automated contraction methods, we investigated iPSC-CM differentiation efficiency between D10-20, contractility analysis and cell cycle regulation at D20, and sarcomere organization at D60. We further conducted differential analyses following label-free protein and RNA-Seq quantification at D20. Via CRISPR-Cas9 gene editing, we plan to characterize KLHL26 variant-specific iPSC-CM alterations and connect findings to discoveries from patient-specific studies. RESULTS/ANTICIPATED RESULTS: All iPSC lines differentiated into CMs with an increased percentage of cTnT+ cells in the affected daughter line. In comparison to the unaffected, affected iPSC-CMs had fewer contractions per minute and altered calcium transients, mainly a higher amount of total calcium release, faster rate of rise and faster rate of fall. The affected daughter line further had shorter shortening and relaxation times, higher proliferation, lower apoptosis, and a smaller cell surface area per cardiac nucleus. The affected mother line trended in a similar direction to the affected daughter line. There were no gross differences in sarcomere organization between the lines. We also discovered differential expression of candidate proteins such as kinase VRK1 and collagen COL5A1 from proteomic profiling. DISCUSSION/SIGNIFICANCE: These discoveries suggest that EA/LVNC characteristics or pathogenesis may result from decreased contractile ability, altered calcium transients, and cell cycle dysregulation. Through the KLHL26 variant correction and introduction in the daughter lines, we will build upon this understanding to inform exploration of critical clinical targets.
Aphidophagous hoverflies (Diptera, Syrphidae, Syrphinae) are common flower visitors and aphid predators in a range of flowering plants, including fruit crops. Here, we investigate whether aphid prey DNA can be detected in the gut contents of hoverfly larvae from a commercial strawberry field as a proof of concept that a molecular approach can be used to measure agricultural biocontrol. We used high-throughput sequencing (HTS) to target insect DNA and compared the resulting data to reference databases containing aphid and hoverfly DNA sequences. We explored what impact incorporating wildflowers within polythene-clad tunnels may have on aphid DNA detection rates in hoverfly larvae. In a randomized block experiment, coriander (Coriandrum sativum), field forget-me-not (Myosotis arvensis) and corn mint (Mentha arvensis) plants were inserted in rows of strawberries. Their effect on aphid DNA detection rates was assessed. Aphid DNA was found in 55 of 149 specimens (37%) validating the method in principle for measuring agricultural services provided by hoverflies. Interestingly, detection rates were higher near plots with forget-me-not than plots with coriander, though detection rates in control plots did not differ significantly from either wildflower species. These findings confirm that hoverflies predate aphids in UK strawberry fields, and that HTS is a viable method of identifying aphid DNA in predatory hoverflies. We comment on the need for further method development to narrow down identifications of both predator and prey. We furthermore provide some evidence that there is an effect of intercropping strawberry crops with wildflowers which may affect aphid consumption in hoverfly larvae.
Supporting Antarctic scientific investigation is the job of the national Antarctic programmes, the government entities charged with delivering their countries’ Antarctic research strategies. This requires sustained investment in people, innovative technologies, Antarctic infrastructures, and vessels with icebreaking capabilities. The recent endorsement of the International Maritime Organization (IMO) Polar Code (2015) means that countries must address challenges related to an ageing icebreaking vessel fleet. Many countries have recently invested in and begun, or completed, builds on new icebreaking Polar research vessels. These vessels incorporate innovative technologies to increase fuel efficiency, to reduce noise output, and to address ways to protect the Antarctic environment in their design. This paper is a result of a Council of Managers of National Antarctic Programs (COMNAP) project on new vessel builds which began in 2018. It considers the recent vessel builds of Australia’s RSV Nuyina, China’s MV Xue Long 2, France’s L’Astrolabe, Norway’s RV Kronprins Haakon, Peru’s BAP Carrasco, and the United Kingdom’s RRS Sir David Attenborough. The paper provides examples of purposeful consideration of science support requirements and environmental sustainability in vessel designs and operations.
Repeated antigen testing of 12 severe acute respiratory coronavirus virus 2 (SARS-CoV-2)–positive nursing home residents using Abbott BinaxNOW identified 9 of 9 (100%) culture-positive specimens up to 6 days after initial positive test. Antigen positivity lasted 2–24 days. Antigen positivity might last beyond the infectious period, but it was reliable in residents with evidence of early infection.
Parents who receive a diagnosis of a severe, life-threatening CHD for their foetus or neonate face a complex and stressful decision between termination, palliative care, or surgery. Understanding how parents make this initial treatment decision is critical for developing interventions to improve counselling for these families.
We conducted focus groups in four academic medical centres across the United States of America with a purposive sample of parents who chose termination, palliative care, or surgery for their foetus or neonate diagnosed with severe CHD.
Ten focus groups were conducted with 56 parents (Mage = 34 years; 80% female; 89% White). Results were constructed around three domains: decision-making approaches; values and beliefs; and decision-making challenges. Parents discussed varying approaches to making the decision, ranging from relying on their “gut feeling” to desiring statistics and probabilities. Religious and spiritual beliefs often guided the decision to not terminate the pregnancy. Quality of life was an important consideration, including how each option would impact the child (e.g., pain or discomfort, cognitive and physical abilities) and their family (e.g., care for other children, marriage, and career). Parents reported inconsistent communication of options by clinicians and challenges related to time constraints for making a decision and difficulty in processing information when distressed.
This study offers important insights that can be used to design interventions to improve decision support and family-centred care in clinical practice.
Microscopic examination of blood smears remains the gold standard for laboratory inspection and diagnosis of malaria. Smear inspection is, however, time-consuming and dependent on trained microscopists with results varying in accuracy. We sought to develop an automated image analysis method to improve accuracy and standardization of smear inspection that retains capacity for expert confirmation and image archiving. Here, we present a machine learning method that achieves red blood cell (RBC) detection, differentiation between infected/uninfected cells, and parasite life stage categorization from unprocessed, heterogeneous smear images. Based on a pretrained Faster Region-Based Convolutional Neural Networks (R-CNN) model for RBC detection, our model performs accurately, with an average precision of 0.99 at an intersection-over-union threshold of 0.5. Application of a residual neural network-50 model to infected cells also performs accurately, with an area under the receiver operating characteristic curve of 0.98. Finally, combining our method with a regression model successfully recapitulates intraerythrocytic developmental cycle with accurate lifecycle stage categorization. Combined with a mobile-friendly web-based interface, called PlasmoCount, our method permits rapid navigation through and review of results for quality assurance. By standardizing assessment of Giemsa smears, our method markedly improves inspection reproducibility and presents a realistic route to both routine lab and future field-based automated malaria diagnosis.
Approximately 70% of patients with bipolar disorder (BPD) are initially misdiagnosed, resulting in significantly delayed diagnosis of 7–10 years on average. Misdiagnosis and diagnostic delay adversely affect health outcomes and lead to the use of inappropriate treatments. As depressive episodes and symptoms are the predominant symptom presentation in BPD, misdiagnosis as major depressive disorder (MDD) is common. Self-rated screening instruments for BPD exist but their length and reliance on past manic symptoms are barriers to implementation, especially in primary care settings where many of these patients initially present. We developed a brief, pragmatic bipolar I disorder (BPD-I) screening tool that not only screens for manic symptoms but also includes risk factors for BPD-I (eg, age of depression onset) to help clinicians reduce the misdiagnosis of BPD-I as MDD.
Existing questionnaires and risk factors were identified through a targeted literature search; a multidisciplinary panel of experts participated in 2 modified Delphi panels to select concepts thought to differentiate BPD-I from MDD. Individuals with self-reported BPD-I or MDD participated in cognitive debriefing interviews (N=12) to test and refine item wording. A multisite, cross-sectional, observational study was conducted to evaluate the screening tool’s predictive validity. Participants with clinical interview-confirmed diagnoses of BPD-I or MDD completed a draft 10-item screening tool and additional questionnaires/questions. Different combinations of item sets with various item permutations (eg, number of depressive episodes, age of onset) were simultaneously tested. The final combination of items and thresholds was selected based on multiple considerations including clinical validity, optimization of sensitivity and specificity, and pragmatism.
A total of 160 clinical interviews were conducted; 139 patients had clinical interview-confirmed BPD-I (n=67) or MDD (n=72). The screening tool was reduced from 10 to 6 items based on item-level analysis. When 4 items or more were endorsed (yes) in this analysis sample, the sensitivity of this tool for identifying patients with BPD-I was 0.88 and specificity was 0.80; positive and negative predictive values were 0.80 and 0.88, respectively. These properties represent an improvement over the Mood Disorder Questionnaire, while using >50% fewer items.
This new 6-item BPD-I screening tool serves to differentiate BPD-I from MDD in patients with depressive symptoms. Use of this tool can provide real-world guidance to primary care practitioners on whether more comprehensive assessment for BPD-I is warranted. Use of a brief and valid tool provides an opportunity to reduce misdiagnosis, improve treatment selection, and enhance health outcomes in busy clinical practices.
Gender is a highly salient and important social group that shapes how children interact with others and how they are treated by others. In this Element, we offer an overview and review of the research on gender development in childhood from a developmental science perspective. We first define gender and the related concepts of sex and gender identity. Second, we discuss how variations in cultural context shape gender development around the world and how variations within gender groups add to the complexity of gender identity development. Third, we discuss major theoretical perspectives in developmental science for studying child gender. Fourth, we examine differences and similarities between girls and boys using the latest meta-analytic evidence. Fifth, we discuss the development of gender, gender identity, and gender socialization throughout infancy, early childhood, and middle childhood. We conclude with a discussion of future directions for the study of gender development in childhood.
Background: Documented transmission of infectious agents involving dental care is uncommon. However, increasing attention to dental infection control, along with several recent outbreaks, have identified infection control gaps in dental settings. We describe CDC consultations involving outbreaks or infection control lapses occurring in dental settings to identify areas for prevention efforts. Methods: We reviewed internal CDC records from January 1, 2010, through October 1, 2019, to identify consultations involving investigations of potential or confirmed disease transmission and infection control lapses in dental settings. We determined yearly number of consultations, number of patients infected, how disease transmission or infection control breaches were identified, suspected mode of transmission, type of infection control breaches identified, and whether at-risk patients were notified. Results: We identified 41 consultations, among 27 states, involving investigation of possible disease transmission or infection control lapses in dental facilities. The number of consultations increased from 11 to 30 between the first half (2010–2014) and the second half (2015–2019) of the period and involved at least 113 infections confirmed or suspected to be associated with dental procedures. Most investigations (n = 29, 71%) began with identification of infection control breaches absent known patient infections; 8 (20%) investigations were initiated after identification of a single patient infection raised concerns for possible transmission associated with dental care (eg, single case of acute hepatitis B infection absent other risk factors). Moreover, 4 investigations involved >1 patient infection; 3 were outbreaks confirmed to be due to poor infection control practices. The most common infection control breaches were lapses in dental instrument reprocessing (n = 28, 78%), for example, failure to sterilize dental handpieces or failure to use biologic indicators. Of the 23 consultations where patient notification activities were discussed, 17 (74%) resulted in notification; >20,000 patients received information about their potential exposure, usually accompanied by advice on seeking screening tests. Conclusions: Dental-related consultations have increased in recent years, and they highlight the need for improved infection control training of dental healthcare personnel, especially related to dental instrument reprocessing. The CDC Division of Oral Health and the Organization for Safety, Asepsis, and Prevention offers tools, training, and other resources to help dental facilities improve infection control practices. Not all investigations resulted in notifying at-risk patients, but notification should be strongly considered, especially when serious breaches are identified, to promote transparency and help identify disease transmission that could otherwise go undetected.
The Fontan Outcomes Network was created to improve outcomes for children and adults with single ventricle CHD living with Fontan circulation. The network mission is to optimise longevity and quality of life by improving physical health, neurodevelopmental outcomes, resilience, and emotional health for these individuals and their families. This manuscript describes the systematic design of this new learning health network, including the initial steps in development of a national, lifespan registry, and pilot testing of data collection forms at 10 congenital heart centres.
Chapter 1 introduced the basic ‘tools’ of performance and reward management, including key aspects of purpose and practice. In this chapter we introduce two overarching concepts of alignment that recur throughout this book: ‘strategic alignment’ and ‘psychological engagement’. The design, implementation and maintenance of effective performance and reward management systems requires simultaneous, systematic and constant attention to both of these dimensions of alignment.
‘Strategic alignment’ refers to the plans, processes and actions involved in establishing and maintaining an alignment between an organisation’s overarching purpose or intent and how it manages employee performance and reward, as well as all other aspects of people management.
− ESG–Agency scholarship highlights the fragmented, expanding, and complex forms of authority that prescribe, steer, and govern behaviour on environmental issues. − Agency scholarship on earth system governance covers interdisciplinary debates in four broad areas: the types of agents, the ways authority is exercised, the nature of agents’ influence, and the varieties of governance structures or architectures within which agents act.− Even with increasing scholarship into the fragmentation of authority and multiplication of the types agents to include nonstate, transnational, and subnational actors, states continue to be the centre of agency scholarship. Future research is needed on agency theory and the theoretical nature of relationships between actors and within differing geographic, economic, and political contexts.
In this chapter, we examine employee share ownership (ESO) as an example of a collective long-term incentive. An employee share plan is any type of plan that allows some or all employees to acquire shares in the organisation that employs them (Klein 1987). We begin with an overview of the nature and extent of employee share ownership in Western countries. We investigate the theoretical rationale for employee share ownership before examining the empirical research on impact of share plans on organisational performance and employee attitudes and behaviours. Finally, we consider the relationship between employee share ownership and other HR practices, with a particular focus on other forms of performance-related pay.
− Agency is one of five core analytical problems in the Earth System Governance (ESG) Project’s research framework, which offers a unique approach to the study of environmental governance. − Agency in Earth System Governance draws lessons from ESG–Agency research through a systematic review of 322 peer-reviewed journal articles published between 2008 and 2016 and contained in the ESG–Agency Harvesting Database.− ESG–Agency research draws on diverse disciplinary perspectives with distinct clusters of scholars rooted in the fields of global environmental politics, policy studies, and socio-ecological systems. − Collectively, the chapters in Agency in Earth System Governance provide an accessible synthesis of some of the field’s major questions and debates and a state-of-the-art understanding of how diverse actors engage with and exercise authority in environmental governance.