Impact of animation-supported consent on complaints and serious incidents due to failure to inform.

BACKGROUND: Introduction of digital animations to explain medical procedures before consent to treatment (animation-supported consent) has been shown to improve patient-reported understanding of a procedure's benefits, risks and alternatives. AIM: We examined whether introduction of animation-supported consent is associated with a change in the incidence of complaints and serious incidents due to failure to inform. METHODS: Multi-language animations explaining 10 cardiac procedures, in coronary intervention, electrophysiology and cardiac surgery, (www.explainmyprocedure.com) were introduced at a London cardiac centre from April 2019. Complaints and serious incidents due to failure to inform were identified from the hospital Datix database for the two years before introducing animation-supported consent (no animation group) and the two years afterwards (animation group), together with the total number of procedures and major complications recorded during these periods. We compared the incidence of complaints and serious incidents, expressed as a proportion of the number of major complications, recorded during each period. RESULTS: There were 580 complications among 21 855 procedures performed in the no animation group and 411 complications among 18 254 procedures in the animation group. There were 14 complaints or serious incidents due to failure to inform in the no animation group and 3 in the animation group; rates of 2.41% (14/580) and 0.73% (3/411), respectively (P < 0.001 for difference). CONCLUSION: In this observational comparison, introduction of animation-supported consent was associated with a 70% reduction in complaints or serious incidents due to failure to inform before consent. This has significant quality and cost implications for improving consent pathways in clinical practice.

The effect of the Montgomery judgment on settled claims against the National Health Service due to failure to inform before giving consent to treatment.

BACKGROUND: A landmark legal judgment in March 2015 (Montgomery) changed the test for determining negligence due to failing to inform patients before consent, by moving away from asking what a reasonable doctor should disclose and asking instead what a reasonable patient would expect to know. AIM: We sought to determine the effect Montgomery has had on settled claims due to failure to inform compared with claims for other reasons and whether legal firms are adding contributory claims of failure to inform to other principal allegations of negligence. METHODS: A Freedom of Information request to NHS Resolution provided data on the number of settled claims against the NHS (2005-19) for any cause and where failure to inform before consent was the principal or contributory cause. Time-series regression was used to compare trends before and after 31 March 2015. RESULTS: The trend in claims/year increased 4-fold for failure to inform (an increase of 9.8/year before 2015 vs. 39.5/year after 2015, P < 0.01), 2.7-fold when failure to inform was the principal cause (7.9/year vs. 21.2/year, P = 0.02) and 9.9-fold as a contributory cause (1.9/year vs. 18.3/year, P < 0.01). There was no material difference in claims due to other causes (334/year vs. 318/year, P = 0.84). CONCLUSIONS: Montgomery has led to a substantial increase in settled claims of failure to inform before consent, with no coincident change in claims for other causes. The increase in contributory compared with principal causes suggests that lawyers are using the judgment to increase the chances of a successful claim against the NHS.

Mortality from aortic stenosis: prospective study of serum calcium and phosphate.

PURPOSE: To investigate the associations between levels of serum calcium and phosphate and subsequent death from aortic stenosis, and the implications for prevention. METHODS: A prospective (nested case-control) analysis of serum calcium and phosphate levels was performed in stored samples from the British United Provident Association prospective study of 21 520 men aged 35-64, followed for up to 32 years. There were 49 men without baseline valvular heart disease who subsequently died of aortic stenosis. Each was matched, for age, duration of sample storage and number of freeze-thaw cycles, with four unaffected control subjects. Odds ratios for death from aortic stenosis were estimated by logistic regression. RESULTS: Mean serum calcium concentration was higher in men who died of aortic stenosis than in those who did not (2.44 vs. 2.39 mmol L-1 ; P = 0.01). The risk of death from aortic stenosis in the highest calcium tertile was 2.87-fold higher than in the lowest tertile (95% confidence interval 1.22-6.76). There was a continuous dose-response relationship; risk of death from aortic stenosis increased by 51% (11-105%) per 0.1 mmol L-1 increase in serum calcium, equivalent to a 34% (10-52%) lower risk per 0.1 mmol L-1 decrease. Serum phosphate was not significantly higher in men who died of aortic stenosis than in those who did not (1.0 vs. 0.99 mmol L-1 ; P = 0.76). CONCLUSIONS: The association between serum calcium and subsequent mortality from aortic stenosis is of potential preventive significance. If confirmed quantitatively in other similar cohort studies, the results suggest that a very small reduction in serum calcium (about 5%) could translate into a large (about one-third) reduction in aortic stenosis.

Using a shape prior for robust modeling of the mitral annulus on 4D ultrasound data.

PURPOSE: Over 40,000 annuloplasty rings are implanted each year in the USA to treat mitral regurgitation. However, the used measuring techniques to select a suitable annuloplasty ring are imprecise and highly depending on the expert's experience. This can cause a re-occurrence of the mitral regurgitation or an annuloplasty ring dehiscence, and thus the necessity of a re-operation. We propose a method to create a 4D model of the mitral annulus from ultrasound data to enable precise measurement and patient-specific implant planning. METHODS: An initial mitral annulus model is placed interactively in the 4D image data by defining commissure points and the annulus plane for one time step in diastole and systole. The model is automatically optimized using distinct image features. A shape and pose prior of the mitral annulus is used to compensate for artifacts and to enforce a plausible anatomical morphology, while a temporal alignment ensures a natural motion of the 4D model. RESULTS: Ground truth data were created for 4D images of 42 patients with varying image quality. A parameter and shape prior training was performed on a third of the ground truth data, while the rest was used to validate the method. The average error of the resulting mitral annulus models was computed as 2.25 ( +/-0.38 ) mm. The average expert standard deviation was determined as 1.86 (+/-0.32 ) mm. CONCLUSION: The proposed method enables the 4D modeling of mitral annuli based on ultrasound data in less than 2 min. The resulting models are comparable to manually delineated models and can be used for measurements of annular geometries and patient-specific annuloplasty treatment planning.

N-(phosphonacetyl)-L-aspartate induces TAp73-dependent apoptosis by modulating multiple Bcl-2 proteins: potential for cancer therapy.

p53 is essential for the cellular responses to DNA damage that help to maintain genomic stability. However, the great majority of human cancers undergo disruption of the p53-network. Identification and characterization of molecular components important in both p53-dependent and -independent apoptosis might be useful in developing novel therapies for cancers. In the complete absence of p53, cells treated with N-(phosphonacetyl)-L-aspartate (PALA) continue to synthesize DNA slowly and eventually progress through S-phase, suffering severe DNA damage that in turn triggers apoptosis, whereas cells with functional p53 undergo growth arrest. In this study, we investigated apoptotic signaling in response to PALA and the role of p53 expression in this pathway. We found that treatment of cells lacking p53 with PALA induced TAp73, Noxa and Bim and inactivation of these proteins with dominant-negative plasmids or small interfering RNAs significantly inhibited apoptosis, suggesting that PALA-induced apoptosis was mediated via TAp73-dependent expression of Noxa and Bim. However, PALA treatment inhibited the expression of ΔNp73 only in cells lacking p53 but not in cells expressing p53. In addition, PALA treatment inhibited Bcl-2, and overexpression of Bcl-2 significantly inhibited PALA-induced apoptosis. Moreover, expression of p53 in these cells protected them from PALA-induced apoptosis by activating p21, sustaining the expression of ΔNp73 and inhibiting the induction of Noxa and Bim. Taken together, our study identifies novel but opposing roles for the p53 and TAp73 in the induction of Noxa and Bim and regulation of apoptosis. Our data will help to develop strategies to eliminate cancer cells lacking p53 while protecting normal cells with wild-type p53.

GSK3 is a regulator of RAR-mediated differentiation.

Acute myeloid leukemia (AML) is the most common form of leukemia in adults. Unfortunately, the standard therapeutic agents used for this disease have high toxicities and poor efficacy. The one exception to these poor outcomes is the use of the retinoid, all-trans retinoic acid (ATRA), for a rare subtype of AML (APL). The use of the differentiation agent, ATRA, in combination with low-dose chemotherapy leads to the long-term survival and presumed cure of 75-85% of patients. Unfortunately ATRA has not been clinically useful for other subtypes of AML. Though many non-APL leukemic cells respond to ATRA, they require significantly higher concentrations of ATRA for effective differentiation. Here we show that the combination of ATRA with glycogen synthase kinase 3 (GSK3) inhibition significantly enhances ATRA-mediated AML differentiation and growth inhibition. These studies have revealed that ATRA's receptor, the retinoic acid receptor (RAR), is a novel target of GSK3 phosphorylation and that GSK3 can impact the expression and transcriptional activity of the RAR. Overall, our studies suggest the clinical potential of ATRA and GSK3 inhibition for AML and provide a mechanistic framework to explain the promising activity of this combination regimen.

Use and cost of branded and generic drugs in patients with coronary heart disease--results from a prospective survey of 1008 patients in two London hospitals.

BACKGROUND: Combination therapy with three classes of drug, antiplatelet, cholesterol and blood pressure lowering treatment markedly reduce the risk of recurrent cardiovascular events in patients with coronary heart disease (CHD). Within each class, generic and branded (patented) drugs are available which have similar efficacy but differ in cost. AIMS: (i) To assess the extent to which preventive medical drugs are prescribed in patients with CHD and to examine the reasons for drug omissions and (ii) to assess the relative use of branded and generic drugs and the reasons for drug selection. METHODS: The medication charts and hospital notes of consecutive patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) at a large cardiothoracic centre were reviewed over a 3-month period. Interviews with patients, attending cardiologists and general practitioners were undertaken to establish why drugs were and were not prescribed. RESULTS: Among 1008 patients (755 who had PCI and 253 who had CABG) the use of aspirin, statins, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), beta blockers and calcium channel blockers were, respectively, 97, 98, 81, 76 and 18%. The combination of any 4 classes of drug were used in 65% of patients. Almost all patients who did not receive aspirin or a statin had clinical contraindications and were on alternative drugs. In about 12% of patients without an ACE inhibitor (or ARB) and 7% of patients without a beta blocker, no reason to withhold such treatment was identified. Branded drugs were used in 52% of patients; the most commonly prescribed being atorvastatin in 33%. Clinical reasons for using branded rather than generic drugs were identified in 13% of cases. CONCLUSION: Our results show a high rate of use of secondary preventive cardiac medications in patients undergoing coronary revascularization procedures, but the use of ACE inhibitors or beta blockers is still overlooked in about 1 in 10 patients. Branded drugs are prescribed in about half of all patients undergoing PCI and CABG, but in almost 90% of cases, a generic equivalent could have been used to achieve similar risk reduction. If our results reflect wider practice, an estimated 11 million pounds a year would be saved by the National Health Service by switching to generic alternative drugs.

IRAK and TAK1 are required for IL-18-mediated signaling.

Interleukin-18 (IL-18), a pleiotropic cytokine produced by activated macrophages, plays significant roles in the immune response, inducing the secretion of IFN-gamma, TNF-alpha and IL-2, enhancing NK cell activity and potentiating the differentiation of Th1 cells. The intercellular signal transduction pathways through which IL-18 functions have not been thoroughly defined. We have generated a mutant cell line, I1A, that lacks the IRAK protein. In this line which has low or no expression of the other known IRAK family members, we find that the IL-1 receptor-associated kinase (IRAK) is essential for the activation of NFkappaB and JNK in response to IL-18. Furthermore, the death domain, but not the kinase activity of IRAK, is necessary for NFkappaB activation in response to IL-18. Interestingly, the N-proximal undetermined region of IRAK is necessary for NFkappaB activation, but not for JNK activation in response to IL-18, indicating IRAK may be a branchpoint in IL-18 signaling. In addition to IRAK, we implicate two other components in IL-18 signaling, TAK1 (TGF-beta-activated kinase 1) and its activator and substrate TAB1. A dominant negative mutant of TAK1 inhibits the IL-18-mediated NFkappaB activation, while IL-18 stimulation leads to the phosphorylation of TAB1. Finally, analysis of IL-18 signaling in IL-1-unresponsive mutant cell lines suggests that the IL-1- and IL-18-mediated pathways are similar, but may not be identical.

Therapeutic procedures in the emergency department patient with acute myocardial infarction.

Life-threatening cardiac arrhythmias and other peri-infarct complications are often unexpected and commonly present with little warning. The therapeutic procedures reviewed often require immediate implementation and should be second nature to any physician involved in the management of patients with an AMI.

Randomized trial of folic acid supplementation and serum homocysteine levels.

BACKGROUND: Lowering serum homocysteine levels with folic acid is expected to reduce mortality from ischemic heart disease. Homocysteine reduction is known to be maximal at a folic acid dosage of 1 mg/d, but the effect of lower doses (relevant to food fortification) is unclear. METHODS: We randomized 151 patients with ischemic heart disease to 1 of 5 dosages of folic acid (0.2, 0.4, 0.6, 0.8, and 1.0 mg/d) or placebo. Fasting blood samples for serum homocysteine and serum folate analysis were taken initially, after 3 months of supplementation, and 3 months after folic acid use was discontinued. RESULTS: Median serum homocysteine level decreased with increasing folic acid dosage, to a maximum at 0.8 mg of folic acid per day, when the homocysteine reduction (placebo adjusted) was 2.7 micromol/L (23%), similar to the known effect of folic acid dosages of 1 mg/d and above. The higher a person's initial serum homocysteine level, the greater was the response to folic acid, but there were statistically significant reductions regardless of the initial level. Serum folate level increased approximately linearly (5.5 nmol/L for every 0.1 mg of folic acid). Within-person fluctuations over time in serum homocysteine levels, measured in the placebo group, were large compared with the effect of folic acid, indicating that monitoring of the reduction in an individual is impractical. CONCLUSIONS: A dosage of folic acid of 0.8 mg/d appears necessary to achieve the maximum reduction in serum homocysteine level across the range of homocysteine levels in the population. Current US food fortification levels will achieve only a small proportion of the achievable homocysteine reduction.

Quantifying the effect of folic acid.

BACKGROUND: Folic acid is known to prevent neural-tube defects (NTDs) but the size of the effect for a given dose is unclear. We aimed to quantify such an effect. METHODS: We used published data from 13 studies of folic acid supplementation on serum folate concentrations and results from a large cohort study of the risk of NTDs according to serum folate, to measure the preventive effect of specified increases in intake of folic acid. FINDINGS: Serum folate concentrations increase by 0.94 ng/mL (95% CI 0.77-1.10) for every 0.1 mg/day increase in folic acid intake in women aged 20-35 years, and about double that in people aged 40-65. Every doubling of serum folate concentration roughly halves the risk of an NTD. These two effects can be combined to predict the reduction in risk according to intake of extra folic acid and background serum folate concentration. Such results predict that the preventive effect is greater in women with low serum folate than in those with higher concentrations. The results have also been used to predict direct observations from large randomised trials and the effect of food fortification. From a typical western background serum folate of 5 ng/mL, about 0.2 mg/day (the US level of folic acid fortification) would be expected to reduce NTDs by about 20%; a similar effect can be expected from the current British recommendation (0.24 mg/day). An increase of 0.4 mg/day would reduce risk by about 36%, of 1 mg/day by 57%, and taking a 5-mg tablet daily would reduce risk by about 85%. INTERPRETATION: Folic acid fortification levels should be increased. Additionally women planning a pregnancy should take 5 mg folic acid tablets daily, instead of the 0.4 mg dose presently recommended.