Conveying meaning through design in a safety critical medical system

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel UniversityMedication errors account for a significant number of medical errors. Giving medications to patients is an activity that carries a high risk of error. In an effort to improve patient safety in this area several approaches have been employed. Many of these have taken a systems approach in that they consider how organisational factors such as medicines management, staffing levels, ward layout, shift patterns and staff training have contributed to the errors. None of these studies describe errors in detailed form at task level. This Thesis addresses the gap in knowledge by presenting a systematic analysis of the component tasks of hospital drug administration where none exists and goes on to describe novel design artefacts that assist the identification of drugs. The thesis highlights how hierarchical task analysis, a human factors technique, can be applied to the hospital drug administration task. Task analysis techniques have been used in many high-risk domains in industry as a means of analysing human activity in complex systems but remains an underused technique in health care. Used with the Systematic Human Error Reduction and Prediction Approach (SHERPA), hierarchical task analysis provides an effective way of predicting where errors in the drug administration task are likely to occur. SHERPA uses a taxonomy of human error modes to highlight types of error and makes suggestions to reduce these errors. Medication errors take many forms however it was decided to focus on the immediate interaction between the nurse and the patient. The measures considered to potentially have a significant influence were adding conspicuous labelling to medication packages. These were enhanced by icons intended to represent categories of drugs. Constructing a three dimensional representation of the icon design was considered to provide nurses with an additional channel of information. Technological solutions were proposed and a patient identity bracelet that uses a programmable chip to link the patient to their prescribed medication was viewed as having a huge potential to simplify the checking aspect of administering medications in which the nurse compares a medication order which is often badly written with available drug stock. The device prevents nurses giving medications to the wrong patient. It also prevents them administering an overdose.Anthony Anson medical fun

Increases in Cytosolic Calcium Ion Levels in Human Natural Killer Cells in Response to Butyltin Exposure

This study investigated whether exposures to butyltins (BTs), tributylin (TBT), and dibutyltin (DBT) were able to alter cytosolic calcium levels in human natural killer (NK) cells. Additionally, the effects of cytosolic calcium ion increases on the activation state of mitogen-activated protein kinases (MAPKs) in NK cells were also investigated. NK cells are an intital immune defense against the development of tumors or viral infections. TBT and DBT are widespread environmental contaminants, due to their various industrial applications. Both TBT and DBT have been shown to decrease the ability of NK cells to lyse tumor cells (lytic function). TBT has also been shown to activate MAPKs in NK cells. The results of this study indicated that TBT increased cytosolic calcium levels by as much as 100% after a 60-min exposure to 500 nM TBT, whereas DBT increased cytosolic calcium levels to a much smaller extent (and required higher concentrations). The results also indicated that increases in cytosolic calcium could activate MAPKs but only for a short period of time (5 min), whereas previous studies showed that activation of MAPKs by TBT last for at least 6 h. Thus, it appears that TBT-stimulated increases in cytosolic calcium might contribute to, but are not fully responsible for, TBT-induced activation of MAPKs

Traditional and Virtual Hypertension Self-Management Health Education Program Delivered Through Cooperative Extension

Fewer than 25% of individuals in the United States with hypertension have controlled blood pressure (Centers for Disease Control and Prevention, 2021). Hypertension Management Program (HMP) adopted the Health Coaches for Hypertension Control© (HCHC©) curriculum and adapted it for delivery by Extension agents. Eight lessons with intermittent health coaching calls were delivered. Pre/post-participation surveys determined changes in knowledge and self-reported weight, systolic (SBP), and diastolic blood pressure (DBP). The pandemic forced a shift in methodology from in-person to virtual delivery, and results were compared. In both traditional and virtual programs, significant differences were found in weight, knowledge scores, and SBP from pre- to post-participation. Mean reduction in weight for in-person and virtual programs was 1.9 lb (p = 0.0047) and 3.5 lb (p = 0.043) respectively. Knowledge scores increased significantly for in-person (p = 0.000) and virtual program (p = 0.0006) participants. Mean reduction in SBP of 5.5 mmHg (p = 0.0009) and 1.9 (p = 0.0338) was observed in in-person and virtual participants, respectively. DBP significantly decreased by a mean of 8.5 mmHg (p = 0.0421) for virtual HMP participants and approached significance in traditional programs (decrease of 5.5 mmHg, p = 0.0649). Results suggest that participation in HMP, whether in-person or virtual, could help participants reduce their risk of cardiovascular events through blood pressure self-management

Speaking out about gender imbalance in invited speakers improves diversity.

Omissions of qualified women scientists from major meeting programs continue to occur despite a surge in articles indicating persistent gender-discriminatory practices in hiring and promotion, and calls for gender balance in conference organizing committees

Damaged Intestinal Epithelial Integrity Linked to Microbial Translocation in Pathogenic Simian Immunodeficiency Virus Infections

The chronic phase of HIV infection is marked by pathological activation of the immune system, the extent of which better predicts disease progression than either plasma viral load or CD4+ T cell count. Recently, translocation of microbial products from the gastrointestinal tract has been proposed as an underlying cause of this immune activation, based on indirect evidence including the detection of microbial products and specific immune responses in the plasma of chronically HIV-infected humans or SIV-infected Asian macaques. We analyzed tissues from SIV-infected rhesus macaques (RMs) to provide direct in situ evidence for translocation of microbial constituents from the lumen of the intestine into the lamina propria and to draining and peripheral lymph nodes and liver, accompanied by local immune responses in affected tissues. In chronically SIV-infected RMs this translocation is associated with breakdown of the integrity of the epithelial barrier of the gastrointestinal (GI) tract and apparent inability of lamina propria macrophages to effectively phagocytose translocated microbial constituents. By contrast, in the chronic phase of SIV infection in sooty mangabeys, we found no evidence of epithelial barrier breakdown, no increased microbial translocation and no pathological immune activation. Because immune activation is characteristic of the chronic phase of progressive HIV/SIV infections, these findings suggest that increased microbial translocation from the GI tract, in excess of capacity to clear the translocated microbial constituents, helps drive pathological immune activation. Novel therapeutic approaches to inhibit microbial translocation and/or attenuate chronic immune activation in HIV-infected individuals may complement treatments aimed at direct suppression of viral replication

Reactive Oxygen Species Play a Role in the Infection of the Necrotrophic Fungi, Rhizoctonia solani in Wheat

Rhizoctonia solani is a nectrotrophic fungal pathogen that causes billions of dollars of damage to agriculture worldwide and infects a broad host range including wheat, rice, potato and legumes. In this study we identify wheat genes that are differentially expressed in response to the R. solani isolate, AG8, using microarray technology. A significant number of wheat genes identified in this screen were involved in reactive oxygen species (ROS) production and redox regulation. Levels of ROS species were increased in wheat root tissue following R. solani infection as determined by Nitro Blue Tetrazolium (NBT), 3,3'-diaminobenzidine (DAB) and titanium sulphate measurements. Pathogen/ROS related genes from R. solani were also tested for expression patterns upon wheat infection. TmpL, a R. solani gene homologous to a gene associated with ROS regulation in Alternaria brassicicola, and OAH, a R. solani gene homologous to oxaloacetate acetylhydrolase which has been shown to produce oxalic acid in Sclerotinia sclerotiorum, were highly induced in R. solani when infecting wheat. We speculate that the interplay between the wheat and R. solani ROS generating proteins may be important for determining the outcome of the wheat/R. solani interaction

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons—Leu844, Cys845, Ala846, Leu847, and Gly848—located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844–848 exists and will be valuable in the management and genetic counseling of a significant number of individuals

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Effects of tributyltin on cytosolic calcium and actin in human natural killer cells

Natural killer (NK) cells are lymphocytes that non-specifically kill tumor cells, virally infected cells and antibody coated cells. Tributyltin (TBT) is an environmental pollutant widely used for commercial purposes and found in human blood. TBT has been shown to inhibit cytotoxic function of NK cells. Cell damage to T-lymphocytes exposed to TBT has been attributed to changes in cytosolic Ca2+ concentrations ([Ca2+] cyt) and modifications to the cytoskeleton. Studies have also shown a correlation between exposures of NK cells to TBT and decreased cytotoxic function coupled with phosphorylation of mitogen-activated protein kinases (MAPKs). Therefore, it is reasonable that exposure to TBT will cause an increase in [Ca2+]cyt, that this increase will initiate significant rearrangement of actin, contributing to the decrease in cytotoxicity, and that some of this process will be regulated through the activation of MAPKs. These studies investigated fluctuations in [Ca 2+]cyt in NK cells in response to TBT and whether [Ca 2+]cyt changes play a role in reduced cytotoxic function of NK cells due to alteration of the ability of the cytoskeleton to rearrange. Exposures of 500 nM TBT caused increases in [Ca2+]cyt of approximately 100% after 60 min. Exposures to 300 and 200 nM TBT caused increases of about 40% after 60 min and exposure to 100 nM TBT caused an increase of about 20% after 60 min. These increases in [Ca2+] cyt were shown to be primarily from an influx of extracellular calcium. Exposure of NK cells to 500 nM TBT caused a 25% decrease in F-actin after 60 min. Confocal images showed rearrangement of F-actin from the normal polarized configuration to a symmetrical “net-like” appearance. Calcium influx due to a 5 uM calcium ionophore (A23187) was compared to the influx induced by TBT. These studies showed that A23187 produced increases in [Ca 2+]cyt up to 253% while only causing F-actin to depolymerize to a maximum of 32%. Conversely, when exposed to 500 nM TBT, the maximum increase in [Ca2+]cyt was only 82%, whereas maximum F-actin decrease of 38% remained similar to that of A23187. Effects on MAPK activation in NK cells resulting from ionophore-induced changes in [Ca2+] cyt were investigated. Exposure of NK cells to A23187 increased phosphorylation of p44/42 and p38 at 5 min, but not at any other time point. The 500 nM TBT caused no significant increase in phospho-p38, while A23187 caused an approximately 2.6 fold increase at 5 min