Macroscopic order from reversible and stochastic lattice growth models

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Physics, 1999.Includes bibliographical references (p. 197-209).This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.This thesis advances the understanding of how autonomous microscopic physical processes give rise to macroscopic structure. A unifying theme is the use of physically motivated microscopic models of discrete systems which incorporate the constraints of locality, uniformity, and exact conservation laws. The features studied include: stochastic nonequilibrium fluctuations; use of pseudo-randomness in dynamical simulations; the thermodynamics of pattern formation; recurrence times of finite discrete systems; and computation in physical models. I focus primarily on pattern formation: transitions from a disordered to an ordered macroscopic state. Using an irreversible stochastic model of pattern formation in an open system driven by an external source of noise, I study thin film growth. I focus on the regimes of growth and the average properties of the resulting rough surfaces. I also show that this model couples sensitively to the imperfections of various pseudorandom number generators, resulting in non-stochastic exploration of the accessible state space. Using microscopically reversible models, I explicitly model how macroscopic dissipation can arise. In discrete systems with invertible dynamics entropy cannot decrease, and most such systems approach fully ergodic. Therefore these systems are natural candidates for models of thermodynamic behavior. I construct reversible models of pattern formation by dividing the system in two: the part of primary interest, and a "heat bath". We can observe the exchange of heat, energy, and entropy between the two subsystems, and gain insight into the thermodynamics of self-assembly. I introduce a local, deterministic, microscopically reversible model of cluster growth via aggregation in a closed two-dimensional system. The model has a realistic thermodynamics. When started from a state with low coarse grained entropy the model exhibits an initial regime of rapid nonequilibrium growth followed by a quasistatic regime with a well defined temperature. The growth clusters generated display a rich variety of morphologies. I also show how sequences of conditional aggregation events can be used to implement reusable logic gates and how to simulate any digital logic circuit with this model.by Raissa Michelle D'Souza.Ph.D

Digital interventions in alcohol and drug prevention, treatment and recovery: Systematic maps of international research and interventions available in England

Executive Summary Background Digital interventions in alcohol and drug prevention, treatment and recovery have the potential to overcome barriers faced by non-digital interventions. However, we lack a clear understanding of the types of digital interventions that have been evaluated and where gaps in the evidence base exist. We also need to understand the effectiveness of different types of digital alcohol and drug interventions for various population groups. Further, we do not know which digital alcohol and drug interventions are being used in England, and whether the interventions in use align with those that have been evaluated. Research questions To address the above concerns, we sought to address the following questions: • RQ1: What is the possible range of digital alcohol and drug interventions? • RQ2: Which types of digital alcohol and drug interventions are currently available for use in England? • RQ3: What systematic reviews provide findings for digital alcohol and drug intervention strategies within a prevention/treatment/recovery pathway? • RQ4: Which types of digital alcohol and drug interventions have been evaluated in primary research? • RQ5: To what extent does the evaluation evidence overlap with digital alcohol and drug interventions that are currently available for use in England? • RQ6: What evidence is there that certain types of digital alcohol and drug interventions are (cost-) effective or ineffective for specific population groups or in particular contexts? This report covers our findings in relation to questions RQ1 - RQ5. Based on these findings we also provide suggestions as to what could be the focus of further work to answer RQ6. Methods To address RQ1 an initial typology was drafted, adapting and building on existing typologies of digital interventions. Through this process it became clear to OHID/PHE that a pathway, presenting a route through services, with different types of interventions recommended for use at different times would be more helpful than a typology of intervention characteristics. This pathway was then developed by OHID/PHE and trialled by the research team, with refinements made over time with discussions between the study team and PHE. To address RQ2 we contacted people in England in 2019, who were involved in developing, commissioning, prescribing, recommending or evaluating digital alcohol/drug interventions. Using an online survey, we asked them to describe the interventions they were involved with. To address RQ3, RQ4 and RQ5 we conducted systematic searching and screening to identify and describe existing systematic reviews (RQ3) and primary studies (RQ4). Included systematic reviews were appraised for quality and detailed information was extracted from full reports. For primary studies we extracted basic details using the information contained within the title and abstract. The pathway developed for RQ1 was employed to code and describe the nature of available interventions (RQ2), systematic reviews (RQ3) and primary studies (RQ4). EPPI-Mapper software was used to produce online interactive maps to visually display the findings

“Could You Work in My Team?”: Exploring How Professional Clinical Role Expectations Influence Decision-Making of Assessors During Exit-Level Medical School OSCEs

Decision-making in clinical assessment, such as exit-level medical school Objective Structured Clinical Examinations (OSCEs), is complex. This study utilized an empirical phenomenological qualitative approach with thematic analysis to explore OSCE assessors' perceptions of the concept of a “prototypical intern” expressed during focus group discussions. Topics discussed included the concept of a prototypical intern, qualities to be assessed, and approaches to clinical assessment decision-making. The thematic analysis was then applied to a theoretical framework (Cultural Historical Activity Theory—CHAT) that explored the complexity of making assessment decisions amidst potentially contradicting pressures from academic and clinical perspectives. Ten Australasian medical schools were involved with 15 experienced and five less experienced assessors participating. Thematic analysis of the data revealed four major themes in relation to how the prototypical intern concept influences clinical assessors' judgements: (a) Suitability of marking rubric based on assessor characteristics and expectations; (b) Competence as final year student vs. performance as a prototypical intern; (c) Safety, trustworthiness and reliability as constructs requiring assessment and (d) Contradictions in decision making process due to assessor differences. These themes mapped well within the interaction between two proposed activity systems in the CHAT model: academic and clinical. More clinically engaged and more experienced assessors tend to fall back on a heuristic, mental construct of a “prototypical intern,” to calibrate judgements, particularly, in difficult situations. Further research is needed to explore whether consensus on desirable intern qualities and their inclusion into OSCE marksheets decreases the cognitive load and increases the validity of assessor decision making

Biodiversity baselines : tracking insects in Kruger National Park with DNA barcodes

Reflecting their species richness and ecological diversification, insects play a central role in terrestrial ecosystems but difficulties in species-level assignments have restricted large-scale analysis of their community structure. Employing South Africa’s largest national park as a model system, we demonstrate that DNA barcoding can break this barrier. A year-long deployment of Malaise traps at 25 sites in Kruger National Park (KNP) generated 1000+ weekly collections containing about 800,000 specimens. Insect biomass averaged 1.05 g per trap-day but varied by up to 2-fold between months, being lower in the dry than wet season. Nearly 370,000 specimens were individually analyzed to reveal 19,730 Barcode Index Numbers (BINs; species proxy), a count equal to 43% of the known insect fauna of southern Africa. There was clear differentiation in insect richness and composition between KNP’s two ecoregions, but little among the vegetation types comprising them. The spatial gradient in annual rainfall explained more than half of the variation in compositional similarity among sites with less similarity among samples in the wet season, particularly among those in high rainfall areas. These results suggest that the factors organising insect communities in KNP are not fine-scale vegetation differences, but larger-scale processes associated with ecoregions and rainfall. Estimates of sample coverage indicate that the species not collected are rare, comprising only 4% of the individuals in the community. With a well-parameterized DNA barcode reference library in place, metabarcoding can be used to assess future shifts in the insect fauna of KNP rapidly and inexpensively.http://www.elsevier.com/locate/bioconpm2021Paraclinical Science

Identification of genes expressed by immune cells of the colon that are regulated by colorectal cancer-associated variants.

A locus on human chromosome 11q23 tagged by marker rs3802842 was associated with colorectal cancer (CRC) in a genome-wide association study; this finding has been replicated in case-control studies worldwide. In order to identify biologic factors at this locus that are related to the etiopathology of CRC, we used microarray-based target selection methods, coupled to next-generation sequencing, to study 103 kb at the 11q23 locus. We genotyped 369 putative variants from 1,030 patients with CRC (cases) and 1,061 individuals without CRC (controls) from the Ontario Familial Colorectal Cancer Registry. Two previously uncharacterized genes, COLCA1 and COLCA2, were found to be co-regulated genes that are transcribed from opposite strands. Expression levels of COLCA1 and COLCA2 transcripts correlate with rs3802842 genotypes. In colon tissues, COLCA1 co-localizes with crystalloid granules of eosinophils and granular organelles of mast cells, neutrophils, macrophages, dendritic cells and differentiated myeloid-derived cell lines. COLCA2 is present in the cytoplasm of normal epithelial, immune and other cell lineages, as well as tumor cells. Tissue microarray analysis demonstrates the association of rs3802842 with lymphocyte density in the lamina propria (p = 0.014) and levels of COLCA1 in the lamina propria (p = 0.00016) and COLCA2 (tumor cells, p = 0.0041 and lamina propria, p = 6 × 10(-5)). In conclusion, genetic, expression and immunohistochemical data implicate COLCA1 and COLCA2 in the pathogenesis of colon cancer. Histologic analyses indicate the involvement of immune pathways

rAAV-compatible MiniPromoters for restricted expression in the brain and eye

Abstract Background Small promoters that recapitulate endogenous gene expression patterns are important for basic, preclinical, and now clinical research. Recently, there has been a promising revival of gene therapy for diseases with unmet therapeutic needs. To date, most gene therapies have used viral-based ubiquitous promoters–however, promoters that restrict expression to target cells will minimize off-target side effects, broaden the palette of deliverable therapeutics, and thereby improve safety and efficacy. Here, we take steps towards filling the need for such promoters by developing a high-throughput pipeline that goes from genome-based bioinformatic design to rapid testing in vivo. Methods For much of this work, therapeutically interesting Pleiades MiniPromoters (MiniPs; ~4 kb human DNA regulatory elements), previously tested in knock-in mice, were “cut down” to ~2.5 kb and tested in recombinant adeno-associated virus (rAAV), the virus of choice for gene therapy of the central nervous system. To evaluate our methods, we generated 29 experimental rAAV2/9 viruses carrying 19 different MiniPs, which were injected intravenously into neonatal mice to allow broad unbiased distribution, and characterized in neural tissues by X-gal immunohistochemistry for icre, or immunofluorescent detection of GFP. Results The data showed that 16 of the 19 (84 %) MiniPs recapitulated the expression pattern of their design source. This included expression of: Ple67 in brain raphe nuclei; Ple155 in Purkinje cells of the cerebellum, and retinal bipolar ON cells; Ple261 in endothelial cells of brain blood vessels; and Ple264 in retinal Müller glia. Conclusions Overall, the methodology and MiniPs presented here represent important advances for basic and preclinical research, and may enable a paradigm shift in gene therapy

A review of the ecological value of Cusuco National Park an urgent call forconservation action in a highly threatened Mesoamerican cloud forest

Cloud forests are amongst the most biologically unique, yet threatened, ecosystems in Mesoamerica. We summarize the ecological value and conservation status of a well-studied cloud forest site: Cusuco National Park (CNP), a 23,440 ha protected area in the Merendón mountains, northwest Honduras. We show CNP to have exceptional biodiversity; of 966 taxa identified to a species-level to date, 362 (37.5%) are Mesoamerican endemics, 67 are red-listed by the IUCN, and at least 49 are micro-endemics known only from the Merendón range. CNP also provides key ecosystem services including provision of drinking water and downstream flood mitigation, as well as carbon sequestration, with an estimated stock of 3.5 million megagrams of carbon in 2000. Despite its ecological importance, CNP faces multiple environmental threats and associated stresses, including deforestation (1,759 ha since 2000 equating to 7% of total forest area), poaching (7% loss of mammal relative abundance per year), amphibian declines due to chytridiomycosis (70% of species threatened or near-threatened), and climate change (a mean 2.6 °C increase in temperature and 112 mm decrease in rainfall by 2100). Despite conservation actions, including community ranger patrols, captive-breeding programmes, and ecotourism initiatives, environmental degradation of CNP continues. Further action is urgently required, including reinforcement and expansion of ranger programmes, greater stakeholder engagement, community education programmes, development of alternative livelihood projects, and legislative enforcement and prosecution. Without a thorough and rapid response to understand and mitigate illegal activities, the extirpation and extinction of species and the loss of vital ecosystem services are inevitable in the coming decades

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London