A case-controlled study of relatives’ complaints concerning patients who died in hospital: the role of treatment escalation / limitation planning

Objectives To independently assess quality of care among patients who died in hospital and whose next-of-kin submitted a letter of complaint and make comparisons with matched controls. To identify whether use of a treatment escalation limitation plan (TELP) during the terminal illness was a relevant background factor. Design The study was an investigator-blinded retrospective case-note review of 42 complaints cases and 72 controls matched for age, sex, ward location and time of death. Setting The acute medical and surgical wards of three District General Hospitals administered by NHS Lanarkshire, Scotland. Participants None. Intervention None. Outcome measures Quality of care: Clinical ‘problems’, non-beneficial interventions (NBIs) and harms were evaluated using the Structured Judgment Review Method. Complaints were categorized using the Healthcare Complaints Analysis Tool. Results The event frequencies and rate ratios for clinical ‘problems’, NBIs and harms were consistently higher in complaint cases compared to controls. The difference was only significant for NBIs (P = 0.05). TELPs were used less frequently in complaint cases compared to controls (23.8 versus 47.2%, P = 0.013). The relationship between TELP use and the three key clinical outcomes was nonsignificant. Conclusions Care delivered to patients at end-of-life whose next-of-kin submitted a complaint was poorer overall than among control patients when assessed independently by blinded reviewers. Regular use of a TELP in acute clinical settings has the potential to influence complaints relating to end-of-life care, but this requires further prospective study

Validation of an automated seizure detection algorithm for term neonates

Objective: The objective of this study was to validate the performance of a seizure detection algorithm (SDA) developed by our group, on previously unseen, prolonged, unedited EEG recordings from 70 babies from 2 centres. Methods: EEGs of 70 babies (35 seizure, 35 non-seizure) were annotated for seizures by experts as the gold standard. The SDA was tested on the EEGs at a range of sensitivity settings. Annotations from the expert and SDA were compared using event and epoch based metrics. The effect of seizure duration on SDA performance was also analysed. Results: Between sensitivity settings of 0.5 and 0.3, the algorithm achieved seizure detection rates of 52.6–75.0%, with false detection (FD) rates of 0.04–0.36 FD/h for event based analysis, which was deemed to be acceptable in a clinical environment. Time based comparison of expert and SDA annotations using Cohen’s Kappa Index revealed a best performing SDA threshold of 0.4 (Kappa 0.630). The SDA showed improved detection performance with longer seizures. Conclusion: The SDA achieved promising performance and warrants further testing in a live clinical evaluation. Significance: The SDA has the potential to improve seizure detection and provide a robust tool for comparing treatment regimens

The influence of particle composition and size on in vitro and in vivo biological models.

Particulate air pollution has been consistently linked with an increase in morbidity and mortality due to respiratory complications and cardiovascular disease. The aim of this study was to investigate which components of PM10 are important in driving its biological effects. In vivo studies: PM10 was collected daily for one year onto Teflon filters at 6 sites in the UK, each having air pollution sources of different characteristics. Particulate was extracted from the filters, before being either entered into a rat lung instillation model (in vivo) or used to treat cells in culture (in vitro). Estimated daily concentrations of primary, secondary and coarse particles at each location were calculated by source apportionment modelling (AEA Technology). For 6 months of the collection period concurrent PM10 samples were collected and analysed for metal content by ICP-MS (Edinburgh University).Each 24h PM10 sample was extracted into 1 ml of sterile saline and the concentration of particulate extract was estimated by turbidometry. There was a strong correlation between PM10 mass on filters and the mass extracted. PM10 suspensions were not equalised for mass prior to instillation, instead extracts were instilled neat in order to represent the dose of particulate at respective sites on the dates studied. Each PM10 sample (0.5 ml) was intratracheally instilled into the lungs of one rat on one occasion. After 18 hours the lungs were washed to obtain broncho-alveolar lavage (BAL) cells and fluid. Preparations of BAL cells were counted to assess the presence of different cell types, especially neutrophils as an indicator of inflammation. BAL fluid was analysed for various biochemical parameters to determine the extent of lung damage.On taking an average of the data obtained for PM10 at each location, the percentage of neutrophils in BAL cells was raised in lungs exposed to PM10 from all sites, but most notably Marylebone Road and Belfast. The concentration of macrophage inflammatory protein-2 (MIP-2), lactate dehydrogenase (LDH) and protein in BAL fluid were not significantly different from the control suggesting that the inflammation measured was not induced by gross lung damage.On considering each instillation result independently, inflammation was found to be highly influenced by mass dose of PM10 instilled. Stepwise regression analysis of the results on the basis of composition, however, highlighted the importance of other factors in driving inflammation. Statistical analysis of PM10 samples selected from the entire 12 month sampling period revealed that primary particulate was a strong factor in determining potency whereas secondary and coarse particles were not. Analysis of PM10 samples selected from the last 6 months of sampling, coinciding with the PM10 collection for metal determination, revealed zinc to be highly inflammogenic, overriding the primary component in its influence on potency.In conclusion, the results of the in vivo study indicate that mass continues to be an appropriate metric by which to monitor air pollution and confirm that a reduction in particulate concentration reduces the potency risk. However these results suggest that mass alone is not the only driving force behind PM10 induced inflammation, and that the transition metal components, including zinc are of great importance. The data also suggests that decreasing the coarse and secondary components of PM10 are unlikely of to be of much benefit to public health.PM10 and PM2.5 TEOM filters were obtained from the AUN archive. PM10 from three locations, with collection periods corresponding to dates of Teflon PM10 samples tested, was extracted and diluted to the mean concentration instilled for each location in the main in vivo study. For Marylebone Road, PM10 extracted from Teflon filters induced a significantly greater inflammatory reaction in the rat lung than corresponding material from TEOM filters. For North Kensington and Belfast locations there was no difference in potency between Teflon (non-heated) and TEOM (heated) PM10. This data suggests that at some locations such as busy roadside or kerbside locations heating of the PM10 sample by the TEOM may lead to loss of volatile components with the potential to drive inflammation in vivo. However, further investigation is required to confirm such a conclusion.TEOM PM2.5 and TEOM PM10 from Marylebone Road and from the same sampling period was compared for potency on an equal mass basis in the instillation model. PM10 consistently induced a greater inflammatory response than PM2.5. In vitro studies: Lung epithelial and macrophage cell lines were treated in culture with PM10 suspensions for 4 and 18 hours. Release of the cytokines interleukin-8 (IL-8) and tumour necrosis factor- (TNF-) (respectively) into the supernatant media was used as the marker of a pro-inflammatory effect. However, IL-8 protein released from epithelial cells was adsorbed onto particle surfaces, especially onto Marylebone Road and Birmingham PM10 and hence was rendered unreliable as a marker. Biochemical analysis indicated that PM10 exerted toxicity to epithelial cells resulting in release of lactate dehydrogenase (LDH) and a slight depletion in cellular glutathione (GSH) and adenosine triphosphate (ATP). As an alternative inflammatory marker, IL-8 gene expression (mRNA) was determined. In both bronchial and alveolar epithelial cells lines PM10, notably from Birmingham, Marylebone Road and Belfast, up-regulated IL-8 mRNA expression compared to that in control cells.PM10 induced a strong inflammatory response in macrophages. TNF- was released in response to treatment of particulate from all locations. Decreased TNF- release upon treatment with Marylebone Road and Birmingham PM10 was shown to be due to increased cellular toxicity leading to reduced capacity to generate cytokine, rather than adsorption of PM10.This study highlighted the difference in sensitivity to PM10 exposure of macrophages compared to epithelial cells. PM10 from all locations strongly stimulated TNF- production and release from macrophages. However, notable toxicity was induced by 4 hours of PM10 treatment of the macrophages in vitro, to the extent that the cells’ capacity to generate TNF- was severely impaired in response to Birmingham and Marylebone Road particulate. Toxicity was demonstrated by very high LDH release and marked depletion in GSH and ATP. In common with the in vivo study there was particularly strong correlation between markers of inflammation and cellular toxicity and the water soluble metal content of PM10 used to treat macrophages. TNF- was negatively correlated with metal content due to the toxicity mentioned above, as was GSH and ATP, whereas increasing LDH release was strongly correlated with total combined water soluble metal concentration. Of the individual metal analysed, manganese was most strongly associated with the biochemical markers followed by zinc.In conclusion this project has confirmed the importance of mass in driving the inflammatory effects of PM10 and suggests that mass remains an appropriate metric by which to measure air pollution and implement reduction strategies. Furthermore this study has highlighted the benefit of reducing certain contributing components including primary particulate and zin

The influence of particle composition and size on in vitro and in vivo biological models.

Particulate air pollution has been consistently linked with an increase in morbidity and mortality due to respiratory complications and cardiovascular disease. The aim of this study was to investigate which components of PM10 are important in driving its biological effects. In vivo studies: PM10 was collected daily for one year onto Teflon filters at 6 sites in the UK, each having air pollution sources of different characteristics. Particulate was extracted from the filters, before being either entered into a rat lung instillation model (in vivo) or used to treat cells in culture (in vitro). Estimated daily concentrations of primary, secondary and coarse particles at each location were calculated by source apportionment modelling (AEA Technology). For 6 months of the collection period concurrent PM10 samples were collected and analysed for metal content by ICP-MS (Edinburgh University).Each 24h PM10 sample was extracted into 1 ml of sterile saline and the concentration of particulate extract was estimated by turbidometry. There was a strong correlation between PM10 mass on filters and the mass extracted. PM10 suspensions were not equalised for mass prior to instillation, instead extracts were instilled neat in order to represent the dose of particulate at respective sites on the dates studied. Each PM10 sample (0.5 ml) was intratracheally instilled into the lungs of one rat on one occasion. After 18 hours the lungs were washed to obtain broncho-alveolar lavage (BAL) cells and fluid. Preparations of BAL cells were counted to assess the presence of different cell types, especially neutrophils as an indicator of inflammation. BAL fluid was analysed for various biochemical parameters to determine the extent of lung damage.On taking an average of the data obtained for PM10 at each location, the percentage of neutrophils in BAL cells was raised in lungs exposed to PM10 from all sites, but most notably Marylebone Road and Belfast. The concentration of macrophage inflammatory protein-2 (MIP-2), lactate dehydrogenase (LDH) and protein in BAL fluid were not significantly different from the control suggesting that the inflammation measured was not induced by gross lung damage.On considering each instillation result independently, inflammation was found to be highly influenced by mass dose of PM10 instilled. Stepwise regression analysis of the results on the basis of composition, however, highlighted the importance of other factors in driving inflammation. Statistical analysis of PM10 samples selected from the entire 12 month sampling period revealed that primary particulate was a strong factor in determining potency whereas secondary and coarse particles were not. Analysis of PM10 samples selected from the last 6 months of sampling, coinciding with the PM10 collection for metal determination, revealed zinc to be highly inflammogenic, overriding the primary component in its influence on potency.In conclusion, the results of the in vivo study indicate that mass continues to be an appropriate metric by which to monitor air pollution and confirm that a reduction in particulate concentration reduces the potency risk. However these results suggest that mass alone is not the only driving force behind PM10 induced inflammation, and that the transition metal components, including zinc are of great importance. The data also suggests that decreasing the coarse and secondary components of PM10 are unlikely of to be of much benefit to public health.PM10 and PM2.5 TEOM filters were obtained from the AUN archive. PM10 from three locations, with collection periods corresponding to dates of Teflon PM10 samples tested, was extracted and diluted to the mean concentration instilled for each location in the main in vivo study. For Marylebone Road, PM10 extracted from Teflon filters induced a significantly greater inflammatory reaction in the rat lung than corresponding material from TEOM filters. For North Kensington and Belfast locations there was no difference in potency between Teflon (non-heated) and TEOM (heated) PM10. This data suggests that at some locations such as busy roadside or kerbside locations heating of the PM10 sample by the TEOM may lead to loss of volatile components with the potential to drive inflammation in vivo. However, further investigation is required to confirm such a conclusion.TEOM PM2.5 and TEOM PM10 from Marylebone Road and from the same sampling period was compared for potency on an equal mass basis in the instillation model. PM10 consistently induced a greater inflammatory response than PM2.5. In vitro studies: Lung epithelial and macrophage cell lines were treated in culture with PM10 suspensions for 4 and 18 hours. Release of the cytokines interleukin-8 (IL-8) and tumour necrosis factor- (TNF-) (respectively) into the supernatant media was used as the marker of a pro-inflammatory effect. However, IL-8 protein released from epithelial cells was adsorbed onto particle surfaces, especially onto Marylebone Road and Birmingham PM10 and hence was rendered unreliable as a marker. Biochemical analysis indicated that PM10 exerted toxicity to epithelial cells resulting in release of lactate dehydrogenase (LDH) and a slight depletion in cellular glutathione (GSH) and adenosine triphosphate (ATP). As an alternative inflammatory marker, IL-8 gene expression (mRNA) was determined. In both bronchial and alveolar epithelial cells lines PM10, notably from Birmingham, Marylebone Road and Belfast, up-regulated IL-8 mRNA expression compared to that in control cells.PM10 induced a strong inflammatory response in macrophages. TNF- was released in response to treatment of particulate from all locations. Decreased TNF- release upon treatment with Marylebone Road and Birmingham PM10 was shown to be due to increased cellular toxicity leading to reduced capacity to generate cytokine, rather than adsorption of PM10.This study highlighted the difference in sensitivity to PM10 exposure of macrophages compared to epithelial cells. PM10 from all locations strongly stimulated TNF- production and release from macrophages. However, notable toxicity was induced by 4 hours of PM10 treatment of the macrophages in vitro, to the extent that the cells’ capacity to generate TNF- was severely impaired in response to Birmingham and Marylebone Road particulate. Toxicity was demonstrated by very high LDH release and marked depletion in GSH and ATP. In common with the in vivo study there was particularly strong correlation between markers of inflammation and cellular toxicity and the water soluble metal content of PM10 used to treat macrophages. TNF- was negatively correlated with metal content due to the toxicity mentioned above, as was GSH and ATP, whereas increasing LDH release was strongly correlated with total combined water soluble metal concentration. Of the individual metal analysed, manganese was most strongly associated with the biochemical markers followed by zinc.In conclusion this project has confirmed the importance of mass in driving the inflammatory effects of PM10 and suggests that mass remains an appropriate metric by which to measure air pollution and implement reduction strategies. Furthermore this study has highlighted the benefit of reducing certain contributing components including primary particulate and zin

Interactions between ultrafine particles and transition metals in vivo and in vitro.

Both the ultrafine particle and transition metal components of particulate air pollution (PM10) have been hypothesized to be important factors in determining toxicity and potential adverse health effects. In this study we aimed to investigate interactions between transition metal salts and a surrogate environmental particle–ultrafine carbon black (ufCB). In all experimental systems employed, the ufCB was found to be more reactive than its fine counterpart (CB). Incubation of ufCB with the reactive oxygen species (ROS)-sensitive probe dichlorofluorescin in the absence of cells generated significantly more ROS than CB. With addition of either cupric sulfate (CuSO4), ferrous sulfate (FeSO4), or ferric chloride (FeCl3), the ROS generation in the presence of ufCB was enhanced in a potentiative manner. In Mono Mac 6 macrophages, ufCB again produced more ROS than CB. However, addition of iron salts had no additive effect over and above that induced in the macrophages by ufCB. In the mouse macrophage cell line J774, ufCB decreased the cellular content of GSH and ATP. Addition of iron further decreased both GSH and ATP and a potentiative interaction between ufCB and FeSO4 was observed, but only at the highest iron concentrations tested. A concentration-dependent increase in tumor necrosis factor- production by J774 cells was also observed following exposure to ufCB, which was not further enhanced by the addition of iron. J774 cells were also found to sequester or chelate iron without inducing toxicity. In the rat lung ufCB induced a significant neutrophil influx and this inflammatory effect was potentiativelly enhanced by the addition of FeCl3 (100 μM). These findings suggest that (1) ultrafine particles and metals interact by chemical potentiation in a cell-free environment to generate ROS, (2) potentiation between ultrafine particles and metal salts is not observed in the presence of macrophages as iron is sequestered or chelated by the cells, (3) in the lung, ultrafine particles and iron salts interact in a potentiative manner to generate inflammation

Cost impact of introducing a treatment escalation/limitation plan during patients’ last hospital admission before death

Objective: A recent study found that the use of a treatment escalation/limitation plan (TELP) was associated with a significant reduction in non-beneficial interventions (NBIs) and harms in patients admitted acutely who subsequently died. We quantify the economic benefit of the use of a TELP. Design: NBIs were micro-costed. Mean costs for patients with a TELP were compared to patients without a TELP using generalized linear model regression, and results were extrapolated to the Scottish population. Setting: Medical, surgical and intensive care units of district general hospital in Scotland, UK. Participants: Two hundred and eighty-seven consecutive patients who died over 3 months in 2017. Of these, death was ‘expected’ in 245 (85.4%) using Gold Standards Framework criteria. Intervention: Treatment escalation/limitation plan. Main Outcome Measure: Between-group difference in estimated mean cost of NBIs. Results: The group with a TELP (n = 152) had a mean reduction in hospital costs due to NBIs of GB £220.29 (US $;281.97) compared to those without a TELP (n = 132) (95$413.84) to GB £117.27 (US 150.11), P = <0.001). Assuming that a TELP could be put in place for all expected deaths in Scottish hospitals, the potential annual saving would be GB £2.4 million (US 3.1 million) from having a TELP in place for all ‘expected’ deaths in hospital. Conclusions: The use of a TELP in an acute hospital setting may result in a reduction in costs attributable to NBIs

Investigating the potential for interaction between the components of PM10

The adverse health effects of elevated exposures to PM10 (particulate matter collected through a size selective inlet with an efficiency of 50% for particles with an aerodynamic diameter of 10 μm) in relation to morbidity and mortality, especially in susceptible individuals, are now well recognised. PM10 consists of a variable cocktail of components differing in chemical composition and size. Epidemiological and toxicological data suggest that transition metals and ultrafine particles are both able to drive the cellular and molecular changes that underlie PM10-induced inflammation and so worsen disease status. Toxicological evidence also suggest roles for the biological components of PM10 including volatile organic compounds (VOC's), allergens and bacterial-derived endotoxin. Many of these components, in particular transition metals, ultrafine particles, endotoxin and VOC's induce a cellular oxidative stress which initiates an intracellular signaling cascade involving the activation of phosphatase and kinase enzymes as well as transcription factors such as nuclear factor kappa B. Activation of these signaling mechanisms results in an increase in the expression of proinflammatory mediators, and hence enhanced inflammation. Given that many of the components of PM10 stimulate similar or even identical intracellular signaling pathways, it is conceivable that this will result in synergistic or additive interactions so that the biological response induced by PM10 exposure is a response to the composition rather than the mass alone. A small number of studies suggest that synergistic interactions occur between ultrafine particles and transition metals, between particles and allergens, and between particles and VOC's. Elucidation of the consequences of interaction between the components of PM10 in relation to their biological activity implies huge consequences for the methods used to monitor and to legislate pollution exposure in the future, and may drive a move from mass based measurements to composition