Tracking subjects' strategies in behavioural choice experiments at trial resolution.

Investigating how, when, and what subjects learn during decision-making tasks requires tracking their choice strategies on a trial-by-trial basis. Here, we present a simple but effective probabilistic approach to tracking choice strategies at trial resolution using Bayesian evidence accumulation. We show this approach identifies both successful learning and the exploratory strategies used in decision tasks performed by humans, non-human primates, rats, and synthetic agents. Both when subjects learn and when rules change the exploratory strategies of win-stay and lose-shift, often considered complementary, are consistently used independently. Indeed, we find the use of lose-shift is strong evidence that subjects have latently learnt the salient features of a new rewarded rule. Our approach can be extended to any discrete choice strategy, and its low computational cost is ideally suited for real-time analysis and closed-loop control.

Pioglitazone and barriers to effective post-stroke comorbidity management in stroke survivors with diabetes.

OBJECTIVES: To explore the barriers preventing pioglitazone use in stroke survivors and primary and secondary stroke care services. METHODS: A qualitative grounded theory approached design was used to assess post-stroke diabetes treatments and to assess clinical applicability of pioglitazone as a preventive treatment to minimize its side effects (SEs) associated. Three focus groups were established with 48 participants from Scotland and Wales health board centers during January 2019 to July 2022. RESULTS: A qualitative grounded theory approached design was used to assess post-stroke diabetes treatments and to assess clinical applicability of pioglitazone as a preventive treatment to minimize its SEs associated. Three focus groups were established with 48 participants from Scotland and Wales health board centers during January 2019 to July 2022. CONCLUSION: These strategies might allow greater treatment adherence by stroke survivors and increased confidence of the health care professionals in their practice. The findings suggest that further research will be needed to facilitate wider usage of pioglitazone in treating people with stroke and health education is necessitate when using diabetes drugs post-stroke.

A survey of current practice in UK emergency department management of patients with blunt chest wall trauma not requiring admission to hospital.

INTRODUCTION: There is no universal agreement or supporting evidence for the content or format of a standardised guidance document for patients with blunt chest wall trauma. The aim of this study is to investigate current UK Emergency Medicine practice of the management of patients with blunt chest wall trauma, who do not require admission to hospital. METHODS: This was a cross-sectional survey study, with mixed quantitative / qualitative analysis methods. A convenience sample of all professions working in the Emergency Departments / Urgent Care Centres in the UK was used. A combination of closed and open-ended questions were included, covering demographics and current practice in the respondent's main place of work. Themes explored included management strategies for safe discharge home, risk prediction and variables considered relevant for inclusion in patient guidance. RESULTS: A total of 113 clinicians responded from all UK trauma networks, including all devolved nations. A total of 20 different risk prediction tools / pathways were reported to be used when assessing whether a patient is safe for discharge home, with over 35 different variables listed by respondents as being important to highlight to patients. Qualitative analysis revealed that a small number of respondents believe patients can be better managed through the improvement of the following; identification of the high-risk patient, initial assessment and current management strategies used in the ED / UCC. DISCUSSION: The wide variation in practice highlighted in this study may be due in part to a lack of national consensus guidelines on how to manage this complex patient group. Further research is needed into whether structured national guidelines for the assessment and management of such patients could potentially lead to an overall improvement in outcomes. Such guidelines should be developed by not only expert clinicians and researchers, but also and more importantly by those service-users who have lived experience of blunt chest wall trauma.

A National Registry Study of Patient and Renal Survival in Adult Nephrotic Syndrome.

INTRODUCTION: We aimed to determine the mortality rate, cause of death, and rate of end-stage kidney disease (ESKD) in adults with nephrotic syndrome (NS). METHODS: We conducted a national registry-based study, including all 522 adults who had a kidney biopsy for NS in Scotland in 2014-2017. We linked the Scottish Renal Registry to death certificate data. We performed survival and Cox proportional hazards analyses, accounting for competing risks of death and ESKD. We compared mortality rates with those in the age- and sex-matched general population. RESULTS: A total of 372 patients had primary NS; 150 had secondary NS. Over a median follow-up of 866 days, 110 patients (21%) died. In patients with primary NS, observed versus population 3-year mortality was 2.1% (95% CI 0.0%-4.6%) versus 0.9% (0.8%-1.0%) in patients aged <60 years and 24.9% (18.4%-30.8%) versus 9.4% (8.3%-10.5%) in those aged ≥60 years. In secondary NS, this discrepancy was 17.1% (5.6%-27.2%) versus 1.1% (0.9%-1.2%) in <60-year-olds and 49.4% (36.6%-59.7%) versus 8.1% (6.6%-9.6%) in ≥60-year-olds. In primary NS, cardiovascular causes accounted for 28% of deaths, compared with 18% in the general population. Eighty patients (15%) progressed to ESKD. Incidence of ESKD by 3 years was 8.4% (95% CI 4.9%-11.7%) in primary and 35.1% (24.3%-44.5%) in secondary NS. Early remission of proteinuria and the absence of early acute kidney injury (AKI) were associated with lower rates of death and ESKD. CONCLUSIONS: Adults with NS have high rates of death and ESKD. Cardiovascular causes account for excess mortality in primary NS.

COVID-19 in patients undergoing chronic kidney replacement therapy and kidney transplant recipients in Scotland: findings and experience from the Scottish renal registry.

BACKGROUND: Infection with the severe acute respiratory coronavirus 2 (SARS-CoV-2) has led to a worldwide pandemic with coronavirus disease 2019 (COVID-19), the disease caused by SARS-CoV-2, overwhelming healthcare systems globally. Preliminary reports suggest a high incidence of infection and mortality with SARS-CoV-2 in patients receiving kidney replacement therapy (KRT). The aims of this study are to report characteristics, rates and outcomes of all patients affected by infection with SARS-CoV-2 undergoing KRT in Scotland. METHODS: Study design was an observational cohort study. Data were linked between the Scottish Renal Registry, Health Protection Scotland and the Scottish Intensive Care Society Audit Group national data sets using a unique patient identifier (Community Health Index (CHI)) for each individual by the Public Health and Intelligence unit of Public Health, Scotland. Descriptive statistics and survival analyses were performed. RESULTS: During the period 1st March 2020 to 31st May 2020, 110 patients receiving KRT tested positive for SARS-CoV-2 amounting to 2% of the prevalent KRT population. Of those affected, 86 were receiving haemodialysis or peritoneal dialysis and 24 had a renal transplant. Patients who tested positive were older and more likely to reside in more deprived postcodes. Mortality was high at 26.7% in the dialysis patients and 29.2% in the transplant patients. CONCLUSION: The rate of detected SARS-CoV-2 in people receiving KRT in Scotland was relatively low but with a high mortality for those demonstrating infection. Although impossible to confirm, it appears that the measures taken within dialysis units coupled with the national shielding policy, have been effective in protecting this population from infection.

Impact of the first COVID-19 pandemic wave on the Scottish Multiple Sclerosis Register population.

Background: The impact of the coronavirus disease 2019 (COVID-19) pandemic on people with multiple sclerosis (MS) is a major current concern, in particular the risk of death. Here we describe the impact of the first wave of COVID-19 infections (Mar 2020-July 2020) on the Scottish MS Register (SMSR) population, a cohort of 4702 individuals with MS, all newly diagnosed in the past decade. Methods: We established a clinician alert system, linking the SMSR with the Electronic Communication of Surveillance in Scotland (ECOSS). This allows identification of patients within this cohort who had a positive SARS-CoV-2 PCR test. The SMSR was also linked to death records from National Records Scotland. Results: Of 4702 people with MS, 246 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR tests were performed, of which 17 were positive. The proportion of positive tests were similar to the general Scotland population (Observed PCR confirmed cases = 17, expected = 17.5, O/E = 0.97, 95% CI: 0.60 - 1.56, p=.90). Between 1 st March - 31 st July 2020 12 individuals on the SMSR died, 5 of which were linked to COVID-19 (1 PCR confirmed, 4 clinical diagnoses without PCR confirmation). This number of COVID-19-related deaths was higher than expected (observed deaths = 5, expected deaths = 1.2, O/E = 4.03, 95% CI = 1.48 - 8.94, p=.01). All COVID-19-related deaths in the SMSR occurred in individuals with advanced disability (Expanded Disability Status Scale ≥7), and no deaths occurred in patients receiving disease modifying therapy (DMT) therapies. Conclusion: In this nationally comprehensive cohort of MS patients diagnosed in Scotland within the past 10 years, we observed similar rates of PCR-confirmed SARS-CoV-2 infection compared to the general Scottish population, but a small number of excess COVID-19 related deaths. These deaths occurred in individuals with advanced disability who were not receiving DMTs.

Regional variation in the incidence rate and sex ratio of multiple sclerosis in Scotland 2010-2017: findings from the Scottish Multiple Sclerosis Register.

BACKGROUND: Fifteen regional studies published over the last six decades surveying prevalence, mortality and hospital admissions have suggested that Scotland is amongst the highest risk nations for multiple sclerosis (MS) in the world. However, substantial intranational variation in rates (between regions) has been described in numerous countries, including in the only previous Scottish national survey, which used hospital admission data, to address this issue. Against this backdrop, the Scottish Multiple Sclerosis Register (SMSR) was established in 2010 to prospectively collect nationally comprehensive incidence data and to allow for regional comparisons. METHODS: Here, we present the SMSR and analyse the variation in crude and age-sex standardized incidence rates, lifetime risk (cumulative incidence), and the sex distribution of cases and rates, between the 14 administrative Health Boards or regions of Scotland: 01 January 2010 to 31 December 2017. RESULTS: The overall incidence rate for Scotland was 8.76/100,000 person-years (standardized: 8.54). Regional incidence rates varied significantly-up to threefold-between Health Boards (p < 1 × 10-13). The national female-to-male sex ratio was 2.3:1, but this too varied regionally (outlier regions result in a range from 1.0 to 4.2:1). Lifetime risk ranged from 19.9/1000 for females in Orkney (58.98°N) to 1.6/1000 for males in the Borders (55.60°N). Comparison with a previous national survey suggests that these differences are longstanding. In 6 of 14 regions the lifetime risk for women exceeds 1%. CONCLUSIONS: This study introduces a national incidence register: a valuable research tool and the result of substantial public investment. The wide variation in incidence rates and sex ratios between regions, in a relatively homogenous population, raises questions for future study.

Predictive coding of the statistical parameters of uncertain rewards by orbitofrontal neurons.

Uncertain reward outcomes are characterised by statistical parameters that capture the numerical values of the underlying probability distributions of reward values, including the expected value, risk (variance) and probability. Here we show coding of an integrated expected value signal by single orbitofrontal neurons in response to visual cues predicting uncertain rewards. Separate subpopulations of orbitofrontal neurons predominantly code the prediction of one statistical parameter with few neurons showing combined coding. These signals are likely combined with subjective value signals to inform learning and decision making under conditions of uncertainty.

Challenges of Designing and Implementing High Consequence Infectious Disease Response.

Ebola is a high consequence infectious disease-a disease with the potential to cause outbreaks, epidemics, or pandemics with deadly possibilities, highly infectious, pathogenic, and virulent. Ebola's first reported cases in the United States in September 2014 led to the development of preparedness capabilities for the mitigation of possible rapid outbreaks, with the Centers for Disease Control and Prevention (CDC) providing guidelines to assist public health officials in infectious disease response planning. These guidelines include broad goals for state and local agencies and detailed information concerning the types of resources needed at health care facilities. However, the spatial configuration of populations and existing health care facilities is neglected. An incomplete understanding of the demand landscape may result in an inefficient and inequitable allocation of resources to populations. Hence, this paper examines challenges in implementing CDC's guidance for Ebola preparedness and mitigation in the context of geospatial allocation of health resources and discusses possible strategies for addressing such challenges. (Disaster Med Public Health Preparedness. 2018;12:563-566).

Quantifying Access Disparities in Response Plans.

Effective response planning and preparedness are critical to the health and well-being of communities in the face of biological emergencies. Response plans involving mass prophylaxis may seem feasible when considering the choice of dispensing points within a region, overall population density, and estimated traffic demands. However, the plan may fail to serve particular vulnerable subpopulations, resulting in access disparities during emergency response. For a response plan to be effective, sufficient mitigation resources must be made accessible to target populations within short, federally-mandated time frames. A major challenge in response plan design is to establish a balance between the allocation of available resources and the provision of equal access to PODs for all individuals in a given geographic region. Limitations on the availability, granularity, and currency of data to identify vulnerable populations further complicate the planning process. To address these challenges and limitations, data driven methods to quantify vulnerabilities in the context of response plans have been developed and are explored in this article.

Conceptual framework and quantification of population vulnerability for effective emergency response planning.

OBJECTIVE: The study focused on the methodological advancement and analytical approach of using multilevel data to define population vulnerability and risk in bioemergency disaster planning. METHODS: The authors considered two types of vulnerabilities, transportation vulnerability that stems from lack of access to transportation (public or private) and communication vulnerability that stems from unavailability of needed language-specific communication resources. The authors used Transit Authority general transit feed data and the American Community Survey 5-year estimate data (2006-2010 summary files) to quantify these vulnerabilities. These data were integrated with Topologically Integrated Geographic Encoding and Referencing (TIGER) data for spatial analysis. A response plan was generated for Tarrant County, TX, and deemed feasible before consideration of vulnerable populations. RESULTS: The results point to the importance of integrating geographical and population demographic features that represent potential barriers to the optimum distribution and utilization of resources into the analysis of response plans. An examination of transportation vulnerabilities indicate that, of those vulnerable in Tarrant County, nearly 23,000 individuals will be at-risk of not being able to reach the Point Of Dispensing (POD) to obtain services as they are beyond walking distance to the POD and lack access to transportation resources. The analysis of language vulnerability depicts an uneven distribution resulting in nonuniform demand at PODs for translation resources. There are more than 11,000 at-risk households in the South East region of Tarrant County alone that are truly in need of translation services. CONCLUSIONS: The authors demonstrated that multiple vulnerabilities at each POD can be quantified by aggregating the vulnerability at the available granularity (ie, all blocks or block groups) in a given service area. The quantification of vulnerability at each service area facilitates a POD-based at-risk analysis for the response plan. Disparities stemming from social, behavioral, cultural, economic, and health characteristics of diverse subpopulations could induce the need for additional targeted resources to support emergency response efforts.

Economic risk coding by single neurons in the orbitofrontal cortex.

Risk is a ubiquitous feature of the environment for all organisms. Very few things in life are achieved with absolute certainty. Therefore, it is essential that organisms process risky information efficiently to promote adaptive behaviour and enhance survival. Here we outline a clear definition of economic risk derived from economic theory and focus on two experiments in which we have shown subpopulations of single neurons in the orbitofrontal cortex of rhesus macaques that code either economic risk per se or an error-related risk signal, namely a risk prediction error. These biological risk signals are essential for processing and updating risky information in the environment to contribute to efficient decision making and adaptive behaviour.

RE-PLAN: An Extensible Software Architecture to Facilitate Disaster Response Planning.

Computational tools are needed to make data-driven disaster mitigation planning accessible to planners and policymakers without the need for programming or GIS expertise. To address this problem, we have created modules to facilitate quantitative analyses pertinent to a variety of different disaster scenarios. These modules, which comprise the REsponse PLan ANalyzer (RE-PLAN) framework, may be used to create tools for specific disaster scenarios that allow planners to harness large amounts of disparate data and execute computational models through a point-and-click interface. Bio-E, a user-friendly tool built using this framework, was designed to develop and analyze the feasibility of ad hoc clinics for treating populations following a biological emergency event. In this article, the design and implementation of the RE-PLAN framework are described, and the functionality of the modules used in the Bio-E biological emergency mitigation tool are demonstrated.

Risk prediction error coding in orbitofrontal neurons.

Risk is a ubiquitous feature of life. It plays an important role in economic decisions by affecting subjective reward value. Informed decisions require accurate risk information for each choice option. However, risk is often not constant but changes dynamically in the environment. Therefore, risk information should be updated to the current risk level. Potential mechanisms involve error-driven updating, whereby differences between current and predicted risk levels (risk prediction errors) are used to obtain currently accurate risk predictions. As a major reward structure, the orbitofrontal cortex is involved in coding key reward parameters such as reward value and risk. In this study, monkeys viewed different visual stimuli indicating specific levels of risk that deviated from the overall risk predicted by a common earlier stimulus. A group of orbitofrontal neurons displayed a risk signal that tracked the discrepancy between current and predicted risk. Such neuronal signals may be involved in the updating of risk information.

Gastrointestinal gene delivery by cyclodextrins--in vitro quantification of extracellular barriers.

Local gene delivery represents a promising therapeutic approach for diseases of the intestine. However, the gastrointestinal tract poses significant challenges to successful gene delivery. Cyclodextrins (CDs) have been extensively investigated as non-viral vectors. Here, we assessed the suitability of an amphiphilic cationic CD for intestinal gene transfer, with particular focus on extracellular barriers. Stability and transfection efficiency of CD·DNA complexes were assessed post incubation in simulated gastric and intestinal fluids, bile salts and mucin, or with intestinal enzymes to represent extracellular barriers to intestinal gene delivery. Stability was determined by gel electrophoresis and transfection was measured by luciferase expression in intestinal epithelial cells (Caco-2). Transfection efficiency of CD·DNA complexes was enhanced after incubation in bile salts but was reduced after incubation in gastric and intestinal fluids and mucin. CD·DNA complexes were stable after incubation with pancreatic enzymes and with a model lower intestinal enzyme. Furthermore, the CD protected pDNA from degradation by DNase. In summary, physiologically relevant in vitro models were established and used to quantify the barriers posed by the intestinal extracellular environment to gene delivery. This systematic assessment identified the advantages and limitations of the CD vector and facilitated the proposal of formulation strategies to overcome these barriers.

Targeted gene delivery to hepatocytes with galactosylated amphiphilic cyclodextrins.

OBJECTIVES: Achieving targeted delivery of gene medicines is desirable to maximise activity. Here, galactosylated amphiphilic cyclodextrins (CDs) are examined in terms of their ability to transfect asialoglycoprotein receptor-bearing HepG2 cells. METHODS: Cationic amphiphilic CDs were synthesised as well as amphiphilic CDs bearing galactose-targeting ligands with different linker lengths. Binding of galactosylated CDs to a galactose-specific lectin was examined by surface plasmon resonance. CDs were formulated with and without the helper lipid DOPE and complexed with plasmid DNA. Transfection was evaluated by luciferase assay. Intracellular trafficking was assessed by confocal microscopy. KEY FINDINGS: Binding of targeted CDs to a galactose-specific lectin was achieved. Binding decreased with linker length between the galactosyl group and the CD core. Contrary to the lectin binding results, transfection levels increased with an increase in linker length from 7 atoms to 15. Compared to non-targeted formulations, a significant increase in transfection was observed only in the presence of the helper lipid DOPE. Confocal microscopy revealed that DOPE caused a pronounced effect on cellular distribution. CONCLUSIONS: The galactose-targeting ligand induced substantial increases in transfection over non-targeted formulations when DOPE was included, indicating the potential for targeted gene delivery using CD-based delivery systems.

Neuronal signals for reward risk in frontal cortex.

Rewards can be viewed as probability distributions of reward values. Besides expected (mean) value, a key parameter of such distributions is variance (or standard deviation), which constitutes a measure of risk. Single neurons in orbitofrontal cortex signal risk mostly separately from value. Comparable risk signals in human frontal cortex reflect risk attitudes of individual participants. Subjective outcome value constitutes the primary economic decision variable. The terms risk avoidance and risk taking suggest that risk affects subjective outcome value, a basic tenet of economic decision theories. Correspondingly, risk reduces neuronal value signals in frontal cortex of human risk avoiders and enhances value signals in risk takers. Behavioral contrast effects and reference-dependent valuation demonstrate flexible reward valuation. As a potential correlate, value signals in orbitofrontal neurons adjust reward discrimination to variance (risk). These neurophysiological mechanisms of reward risk on economic decisions inform and validate theories of economic decision making under uncertainty.

Mechanistic studies on the uptake and intracellular trafficking of novel cyclodextrin transfection complexes by intestinal epithelial cells.

Oral delivery of gene therapeutics would facilitate treatment of local intestinal disease, including colon cancer and inflammatory bowel disease, thus avoiding invasive surgery. The aims of this study were to investigate; if the orientation of the lipid tail on the cyclodextrin (CD) influenced the efficacy of a novel poly-6-cationic amphiphilic CD to transfect intestinal enterocytes; the endocytotic uptake pathway(s), and, the intracellular trafficking of the CD·DNA complexes. Inhibitors of clathrin- and caveolae-mediated endocytosis and macropinocytosis were used to determine the mechanism(s) of CD·DNA uptake by both undifferentiated and differentiated Caco-2 cells. Cell surface heparan sulphate proteoglycans were involved in the association of CD·DNA complexes with undifferentiated Caco-2 cells. Complexation of pDNA with CD facilitated significant levels of pDNA uptake and gene expression (comparable to PEI) in both undifferentiated and differentiated Caco-2 cells. Disruption of intracellular vesicular trafficking reduced transfection activity. CD was also capable of transfecting the more physiologically relevant differentiated Caco-2 model. Macropinocytosis was responsible for the uptake of CD·DNA transfection complexes by both undifferentiated and differentiated Caco-2 cells. The ability of this novel CD to transfect differentiated intestinal cells indicates the potential of this vector for oral gene delivery.