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OBJECTIVES/GOALS: Current approaches to drug development for the aggressive triple negative breast cancer rely on current 2D and 3D in vitro models which have limited capabilities. We have developed a translational microphysiological system that can maintain the human breast microenvironment to capture the complex interaction with the tumor microenvironment. METHODS/STUDY POPULATION: Three different TNBC cell lines were seeded in BC-MPS: MDA-MB-231 parental cell line, MDA-MB-231wiht the gene, LKB1 overexpressed, which is a tumor suppressor, and MDA-MB-231 with the enzyme, ERK5, an enzyme associated with increased metastasis and drug resistance, knocked out. These three TNBC cell lines were cultured in a standard 2D 96-well plate and in BC-MPS. Time-lapse videos were taken to track cellular mobility. RNA-sequencing was performed to compare different expression levels of various cancer related genes of the cell lines cultured in standard 2D and BC-MPS. RESULTS/ANTICIPATED RESULTS: The LKB1 overexpressed MDA-MB-231 and the ERK5-ko MDA-MB-231 cell lines are expected to have decreased mobility compared to the parental cells. The cell lines are expected to have increased expression of cancer related genes when cultured in BC-MPS than when cultured in standard 2D due to the presence of human breast tissue. DISCUSSION/SIGNIFICANCE: BC-MPS is a promising new translational MPS that facilitates studying long term interactions between real human breast tissue and cancer cells. The BC-MPS systems ability to support the growth of established cell lines has been demonstrated. Future studies will focus on developing the model for personalized medicine.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has high morbidity and mortality in older adults and people with dementia. Infection control and prevention measures potentially reduce transmission within hospitals.
We aimed to replicate our earlier study of London mental health in-patients to examine changes in clinical guidance and practice and associated COVID-19 prevalence and outcomes between COVID-19 waves 1 and 2 (1 March to 30 April 2020 and 14 December 2020 to 15 February 2021).
We collected the 2 month period prevalence of wave 2 of COVID-19 in older (≥65 years) in-patients and those with dementia, as well as patients’ characteristics, management and outcomes, including vaccinations. We compared these results with those of our wave 1 study.
Sites reported that routine testing and personal protective equipment were available, and routine patient isolation on admission occurred throughout wave 2. COVID-19 infection occurred in 91/358 (25%; 95% CI 21–30%) v. 131/344, (38%; 95% CI 33–43%) P < 0.001 in wave 1. Hospitals identified more asymptomatic carriers (26/91; 29% v. 16/130; 12%) and fewer deaths (12/91; 13% v. 19/131; 15%; odds ratio = 0.92; 0.37–1.81) compared with wave 1. The patient vaccination uptake rate was 49/58 (85%).
Patients in psychiatric in-patient settings, mostly admitted without known SARS-CoV-2 infection, had a high risk of infection compared with people in the community but lower than that during wave 1. Availability of infection control measures in line with a policy of parity of esteem between mental and physical health appears to have lowered within-hospital COVID-19 infections and deaths. Cautious management of vulnerable patient groups including mental health patients may reduce the future impact of COVID-19.
Whole-genome sequencing (WGS) shotgun metagenomics (metagenomics) attempts to sequence the entire genetic content straight from the sample. Diagnostic advantages lie in the ability to detect unsuspected, uncultivatable, or very slow-growing organisms.
To evaluate the clinical and economic effects of using WGS and metagenomics for outbreak management in a large metropolitan hospital.
Intensive care unit and burn unit of large metropolitan hospital.
Simulated intensive care unit and burn unit patients.
We built a complex simulation model to estimate pathogen transmission, associated hospital costs, and quality-adjusted life years (QALYs) during a 32-month outbreak of carbapenem-resistant Acinetobacter baumannii (CRAB). Model parameters were determined using microbiology surveillance data, genome sequencing results, hospital admission databases, and local clinical knowledge. The model was calibrated to the actual pathogen spread within the intensive care unit and burn unit (scenario 1) and compared with early use of WGS (scenario 2) and early use of WGS and metagenomics (scenario 3) to determine their respective cost-effectiveness. Sensitivity analyses were performed to address model uncertainty.
On average compared with scenario 1, scenario 2 resulted in 14 fewer patients with CRAB, 59 additional QALYs, and $75,099 cost savings. Scenario 3, compared with scenario 1, resulted in 18 fewer patients with CRAB, 74 additional QALYs, and $93,822 in hospital cost savings. The likelihoods that scenario 2 and scenario 3 were cost-effective were 57% and 60%, respectively.
The use of WGS and metagenomics in infection control processes were predicted to produce favorable economic and clinical outcomes.
The National Hospital for Neurology and Neurosurgery provides various services for patients with Functional Neurological Disorder (FND), including a four-week inpatient rehabilitation programme run by an integrated Multi-Disciplinary Team (MDT) of Occupational Therapists (OT), Physiotherapists (PT), Psychologists and Psychiatrists.
We had observed that patients with FND often have medical and psychiatric comorbidities including affective, dissociative, somatic symptom and pain disorders; pharmacological treatments are commonly used. We hypothesised that a high burden of medication, particularly of those which produce dependence, might limit one's ability to entrain therapeutic strategies and therefore benefit from treatment. We additionally hypothesised that patients who had previously tried individual physical or psychological therapies might gain less than those who were treatment-naïve.
In this service evaluation project, we reviewed records from 97 consecutive elective inpatient admissions, comprising the entire intake for 2019 and 2020. Data were extracted from the inpatient discharge summary and therapies discharge report of each patient. We recorded which therapies for FND patients had previously tried (OT; PT; Speech and Language Therapy; Psychology; Pain Service) and the classes of medications they were taking on admission (opiates; benzodiazepines; antidepressants; mood stabilisers; antipsychotics; gabapentinoids). We compared the differentials in outcome measures recorded on the first and last day, including the Canadian Occupational Performance Measure (n = 79) and EQ-5D-5L (n = 79). Statistical tests of effect size and significance were done using SPSS-25. Group comparisons of EQ-5D-5L were made with Paired t-tests; all other comparisons were done with Wilcoxon signed-rank tests due to non-normal data.
The most common medications used were antidepressants (72%), gabapentinoids (39%), opiates (36%) and benzodiazepines (25%). 69% of patients had tried PT, 57% psychology and 52% OT, while only 13% were treatment naïve. Whole-cohort analysis revealed highly significant improvements (p < 0.001) in occupational performance, satisfaction, ratings of general health, subjective difficulty in performing tasks and in pain and fatigue levels. We found no significant differences in outcome measures that correlated with past therapies or medication use.
Our analysis shows that the great majority of our patients gained meaningful benefits from their admission, both on clinician-rated metrics of occupational performance and patient-rated measures of subjective improvement. That there was no significant relationship with therapies or medications suggests, promisingly, that patients taking various medications and with suboptimal responses to previous therapy can still benefit from our MDT programme. Limitations include correlational design, limited generalisability to the general population, missing data for certain outcome measures and the absence of follow-up data.
ABSTRACT IMPACT: Identifying an important pathway in treatment resistant TNBC will allow for the future development of clinical therapeutics specific for this disease. OBJECTIVES/GOALS: Triple Negative Breast Cancer (TNBC) is a subtype of breast cancer characterized by negative expression of estrogen receptor, progesterone receptor, and HER2/neu amplification. It resists therapies and has a high recurrence rate after resection. The goal of my research is to identify & characterize a TNBC pathway for future development of therapies. METHODS/STUDY POPULATION: The project uses a combination of cell lines, patient derived xenograft (PDX) models, as well as patient databases. Standard cellular and molecular biology techniques will be used including: Cell culture, qPCR, western blotting, and flow cytometry. RESULTS/ANTICIPATED RESULTS: LKB1 is a master kinase that activates 14 possible downstream kinases. The signaling pathway has been demonstrated to play a role in energy homeostasis and metabolism. Mutation of LKB1 signaling results in Peutz-Jeghers Syndrome and is associated with neoplasias of the lung, pancreas, and breast. Based on preliminary analysis, overexpression of LKB1 by shRNA in TNBC cell lines results in suppression of EMT and reduction of the cancer stem cell population. Additional studies show that LKB1 overexpression has no effect on growth rate in 2D culture while significant reduction in 3D mammosphere formations can be seen. Downstream studies using commercially available SIK1 inhibitor HG-9-91-01 is able to induce a larger fraction of CSC from reduced LKB1 overexpression as well as from baseline levels. DISCUSSION/SIGNIFICANCE OF FINDINGS: Overall, our results suggest that LKB1 acts through SIK1 to suppress EMT and the generation of cancer stem cells. This results in reduced cancer functionality, as evidenced by inhibition of mammosphere formation. These results establishes a foundation for future mechanistic studies on the LKB1 axis and its mechanisms in TNBC.
This chapter tells the story of a research-engagement project called Making, Mapping and Mobilising in Merthyr (otherwise known as the 4Ms project). The project explored young people's sense of place and well-being while growing up in Merthyr Tydfil (hereafter referred to as Merthyr), a small post-industrial ex-mining and steel-making town of roughly 58,000 people in the South Wales Valleys. Once a hub of industrial activity and innovation, along with other geographically close regions, Merthyr has experienced a deep social rupture in recent years owing to deindustrialisation and the closure of ironworks, coal mines and manufacturing industries that had served as cultural links underpinning the rhythms and rituals of Valleys life (Walkerdine and Jimenez, 2011; Ivinson, 2014). Our project took place predominantly in a housing estate based on a design reputed to have been inspired in the 1950s by romantic Italian hilltop villages. The estate expanded in the 1970s, and by the 2000s, had become dilapidated and a place with high levels of unemployment. In a context of tightening austerity, this housing estate and the people living there have been subject to stigmatising media accounts fuelled by television's ‘poverty porn’ industry (Tyler, 2015) and, at times, by local residents themselves (Byrne et al, 2016; Thomas, 2016). The ‘realities’ of poverty tend to be portrayed in popular media through no-hope narratives of despair (Thomas, 2016; Thomas et al, 2018).
In contrast to other projects in the Productive Margins programme, the 4Ms project did not set out to investigate a specific element of regulation. Rather, we approached regulation as it occurred through the everyday experiences of living in a place that is in many ways at the margins, in terms of the explicit as well as the hidden effects and affects of poverty. The initial aim of the project was thus to attune to young people's knowledge as experts of living in this post-industrial place and to co-create research methods and encounters in order to find out how a range of regulatory regimes mediate and impact on their everyday lives.
The 4Ms project took shape across a series of three overlapping phases. We began by exploring the affective contours of the young people's neighbourhoods (Thomas, 2016).
Antipsychotics are associated with a polymorphic ventricular tachycardia, torsades de pointes, which, in the worst case, can lead to sudden cardiac death. The QT interval corrected for heart rate (QTc) is used as a clinical proxy for torsades de pointes. The QTc interval can be prolonged by antipsychotic monotherapy, but it is unknown if the QTc interval is prolonged further with antipsychotic polypharmaceutical treatment. Therefore, this study investigated the associations between QTc interval and antipsychotic monotherapy and antipsychotic polypharmaceutical treatment in schizophrenia, and measured the frequency of QTc prolongation among patients.
We carried out an observational cohort study of unselected patients with schizophrenia visiting outpatient facilities in the region of Central Jutland, Denmark. Patients were enrolled from January of 2013 to June of 2015, with follow-up until June of 2015. Data were collected from clinical interviews and clinical case records.
Electrocardiograms were available for 65 patients, and 6% had QTc prolongation. We observed no difference in average QTc interval for the whole sample of patients receiving no antipsychotics, antipsychotic monotherapy, or antipsychotic polypharmaceutical treatment (p=0.29). However, women presented with a longer QTc interval when receiving polypharmacy than when receiving monotherapy (p=0.01). A limitation of this study was its small sample size.
We recommend an increased focus on monitoring the QTc interval in women with schizophrenia receiving antipsychotics as polypharmacy.
Prosocial emotions related to self-blame are important in guiding human altruistic decisions. These emotions are elevated in major depressive disorder (MDD), such that MDD has been associated with guilt-driven pathological hyper-altruism. However, the impact of such emotional impairments in MDD on different types of social decision-making is unknown.
In order to address this issue, we investigated different kinds of altruistic behaviour (interpersonal cooperation and fund allocation, altruistic punishment and charitable donation) in 33 healthy subjects, 35 patients in full remission (unmedicated) and 24 currently depressed patients (11 on medication) using behavioural-economical paradigms.
We show a significant main effect of clinical status on altruistic decisions (p = 0.04) and a significant interaction between clinical status and type of altruistic decisions (p = 0.03). More specifically, symptomatic patients defected significantly more in the Prisoner's Dilemma game (p < 0.05) and made significantly lower charitable donations, whether or not these incurred a personal cost (p < 0.05 and p < 0.01, respectively). Currently depressed patients also reported significantly higher guilt elicited by receiving unfair financial offers in the Ultimatum Game (p < 0.05).
Currently depressed individuals were less altruistic in both a charitable donation and an interpersonal cooperation task. Taken together, our results challenge the guilt-driven pathological hyper-altruism hypothesis in depression. There were also differences in both current and remitted patients in the relationship between altruistic behaviour and pathological self-blaming, suggesting an important role for these emotions in moral and social decision-making abnormalities in depression.
Major depressive disorder (MDD) is associated with abnormalities in financial reward processing. Previous research suggests that patients with MDD show reduced sensitivity to frequency of financial rewards. However, there is a lack of conclusive evidence from studies investigating the evaluation of financial rewards over time, an important aspect of reward processing that influences the way people plan long-term investments. Beck's cognitive model posits that patients with MDD hold a negative view of the future that may influence the amount of resources patients are willing to invest into their future selves.
We administered a delay discounting task to 82 participants: 29 healthy controls, 29 unmedicated participants with fully remitted MDD (rMDD) and 24 participants with current MDD (11 on medication).
Patients with current MDD, relative to remitted patients and healthy subjects, discounted large-sized future rewards at a significantly higher rate and were insensitive to changes in reward size from medium to large. There was a main effect of clinical group on discounting rates for large-sized rewards, and discounting rates for large-sized rewards correlated with severity of depressive symptoms, particularly hopelessness.
Higher discounting of delayed rewards in MDD seems to be state dependent and may be a reflection of depressive symptoms, specifically hopelessness. Discounting distant rewards at a higher rate means that patients are more likely to choose immediate financial options. Such impairments related to long-term investment planning may be important for understanding value-based decision making in MDD, and contribute to ongoing functional impairment.
The Tonle Sap is the largest wetland in South-east Asia and the heart of the largest inland fishery in the world. Its unique flood pulse system and annual flow reversal is a hotspot for biodiversity and productivity, as well as an essential habitat for many endangered fishes and birds. Despite predicted changes to the wetland's hydrology due to climate change and hydropower development in the Mekong, the consequent impacts on the fauna of the lake are poorly understood. A spatial modelling framework was developed to simulate the impact of potential scenarios of change using relationships between fauna and biophysical characteristics. Potential impacts on 61 animal species with documented nutritional, conservation or ecological value were examined. A large number of species rely on gallery forest to provide important habitats for their life history, yet this area is likely to be highly impacted by permanent inundation. There is a strong synchronicity between life histories and the flood pulse; consequently continued hydrological disruptions will have a significant impact on ecosystem dynamics, imposing further challenges to conservation. Protecting areas that may become suitable for gallery forests and shrublands under a modified flood regime will be crucial to management planning and the maintenance of a diverse and healthy ecosystem.
The tribunals system in England and Wales has been transformed by the entry into force of the Tribunals, Courts and Enforcement Act 2007; among other things, tribunals are now located more firmly and explicitly than ever before within the judicial branch. Questions concerning the relationship between tribunals and regular courts fall to be confronted afresh within this new institutional landscape. Those questions form the focus of this article, which is particularly concerned with the issue recently considered by the Supreme Court in Cart whether, and if so to what extent, decisions taken within the tribunals system (by the Upper Tribunal) should be susceptible to judicial review by the High Court. In Cart, emphasis was placed upon the concept of “proportionate dispute resolution” as a means by which to delimit regular courts' oversight of tribunals' decisions, raising fundamental questions both of legal doctrine (relating to the relevance of the orthodox doctrinal tools of administrative law) and legal policy (concerning the degree of error on the part of a tribunal that a higher court should tolerate in the interests of the efficient, or proportionate, use of judicial resources).
Negative biases in emotional processing are well recognised in people who are currently depressed but are less well described in those with a history of depression, where such biases may contribute to vulnerability to relapse.
To compare accuracy, discrimination and bias in face emotion recognition in those with current and remitted depression.
The sample comprised a control group (n = 101), a currently depressed group (n = 30) and a remitted depression group (n = 99). Participants provided valid data after receiving a computerised face emotion recognition task following standardised assessment of diagnosis and mood symptoms.
In the control group women were more accurate in recognising emotions than men owing to greater discrimination. Among participants with depression, those in remission correctly identified more emotions than controls owing to increased response bias, whereas those currently depressed recognised fewer emotions owing to decreased discrimination. These effects were most marked for anger, fear and sadness but there was no significant emotion × group interaction, and a similar pattern tended to be seen for happiness although not for surprise or disgust. These differences were confined to participants who were antidepressant-free, with those taking antidepressants having similar results to the control group.
Abnormalities in face emotion recognition differ between people with current depression and those in remission. Reduced discrimination in depressed participants may reflect withdrawal from the emotions of others, whereas the increased bias in those with a history of depression could contribute to vulnerability to relapse. The normal face emotion recognition seen in those taking medication may relate to the known effects of antidepressants on emotional processing and could contribute to their ability to protect against depressive relapse.
This chapter reviews the current status of assisted reproduction techniques in the light of the best evidence available. In order to optimize the results of assisted reproduction, various laboratory modifications have been suggested. These include performing Intracytoplasmic sperm injection (ICSI) rather than in vitro fertilization (IVF) for all oocytes, using co-culturing techniques, assisted hatching techniques, as well as selecting the embryos with the best potential for implantation based on their morphology, their metabolism, or by prolonging their culture in vitro to the blastocyst stage. Embryo transfer (ET) is arguably the most critical step in assisted reproduction and the least successful. Various attempts have been made to improve endometrial receptivity in order to increase the clinical outcome of IVF and ICSI. These include various regimens of luteal support, the use of corticosteroids, the removal of hydrosalpinges, diminishing uterine contractions as well as enhancing the endometrial blood flow.