A universal, high-performance ECG signal processing engine to reduce clinical burden.

BACKGROUND: Electrocardiogram (ECG) signal conditioning is a vital step in the ECG signal processing chain that ensures effective noise removal and accurate feature extraction. OBJECTIVE: This study evaluates the performance of the FDA 510 (k) cleared HeartKey Signal Conditioning and QRS peak detection algorithms on a range of annotated public and proprietary ECG databases (HeartKey is a UK Registered Trademark of B-Secur Ltd). METHODS: Seven hundred fifty-one raw ECG files from a broad range of use cases were individually passed through the HeartKey signal processing engine. The algorithms include several advanced filtering steps to enable significant noise removal and accurate identification of the QRS complex. QRS detection statistics were generated against the annotated ECG files. RESULTS: HeartKey displayed robust performance across 14 ECG databases (seven public, seven proprietary), covering a range of healthy and unhealthy patient data, wet and dry electrode types, various lead configurations, hardware sources, and stationary/ambulatory recordings from clinical and non-clinical settings. Over the NSR, MIT-BIH, AHA, and MIT-AF public databases, average QRS Se and PPV values of 98.90% and 99.08% were achieved. Adaptable performance (Se 93.26%, PPV 90.53%) was similarly observed on the challenging NST database. Crucially, HeartKey's performance effectively translated to the dry electrode space, with an average QRS Se of 99.22% and PPV of 99.00% observed over eight dry electrode databases representing various use cases, including two challenging motion-based collection protocols. CONCLUSION: HeartKey demonstrated robust signal conditioning and QRS detection performance across the broad range of tested ECG signals. It should be emphasized that in no way have the algorithms been altered or trained to optimize performance on a given database, meaning that HeartKey is potentially a universal solution capable of maintaining a high level of performance across a broad range of clinical and everyday use cases.

Are prehospital deaths from trauma and accidental injury preventable? A direct historical comparison to assess what has changed in two decades.

BACKGROUND & OBJECTIVES: In 1994, Hussain and Redmond revealed that up to 39% of prehospital deaths from accidental injury might have been preventable had basic first aid care been given. Since then there have been significant advances in trauma systems and care. The exclusion of prehospital deaths from the analysis of trauma registries, giv en the high rate of those, is a major limitation in prehospital research on preventable death. We have repeated the 1994 study to identify any changes over the years and potential developments to improve patient outcomes. METHODS: We examined the full Coroner's inquest files for prehospital deaths from trauma and accidental injury over a three-year period in Cheshire. Injuries were scored using the Abbreviated-Injury-Scale (AIS-1990) and Injury Severity Score (ISS), and probability of survival estimated using Bull's probits to match the original protocol. RESULTS: One hundred and thirty-four deaths met our inclusion criteria; 79% were male, average age at death was 53.6 years. Sixty-two were found dead (FD), fifty-eight died at scene (DAS) and fourteen were dead on arrival at hospital (DOA). The predominant mechanism of injury was fall (39%). The median ISS was 29 with 58 deaths (43%) having probability of survival of >50%. Post-mortem evidence of head injury was present in 102 (76%) deaths. A bystander was on scene or present immediately after injury in 45% of cases and prior to the Emergency Medical Services (EMS) in 96%. In 93% of cases a bystander made the call for assistance, in those DAS or DOA, bystander intervention of any kind was 43%. CONCLUSIONS: The number of potentially preventable prehospital deaths remains high and unchanged. First aid intervention of any kind is infrequent. There is a potentially missed window of opportunity for bystander intervention prior to the arrival of the ambulance service, with simple first-aid manoeuvres to open the airway, preventing hypoxic brain injury and cardiac arrest.

Prehospital deaths from trauma: Are injuries survivable and do bystanders help?

BACKGROUND AND OBJECTIVES: Deaths from trauma occurring in the prehospital phase of care are typically excluded from analysis in trauma registries. A direct historical comparison with Hussain and Redmond's study on preventable prehospital trauma deaths has shown that, two decades on, the number of potentially preventable deaths remains high. Using updated methodology, we aimed to determine the current nature, injury severity and survivability of traumatic prehospital deaths and to ascertain the presence of bystanders and their role following the point of injury including the frequency of first-aid delivery. METHODS: We examined the Coroners' inquest files for deaths from trauma, occurring in the prehospital phase, over a three-year period in the Cheshire and Manchester (City), subsequently referred to as Manchester, Coronial jurisdictions. Injuries were scored using the Abbreviated-Injury-Scale (AIS-2008), Injury Severity Score (ISS) calculated and probability of survival estimated using the Trauma Audit and Research Network's outcome prediction model. RESULTS: One hundred and seventy-eight deaths were included in the study (one hundred and thirty-four Cheshire, forty-four Manchester). The World Health Organisation's recommendations consider those with a probability of survival between 25-50% as potentially preventable and those above 50% as preventable. The median ISS was 29 (Cheshire) and 27.5 (Manchester) with sixty-two (46%) and twenty-six (59%) respectively having a probability of survival in the potentially preventable and preventable ranges. Bystander presence during or immediately after the point of injury was 45% (Cheshire) and 39% (Manchester). Bystander intervention of any kind was 25% and 30% respectively. Excluding those found dead and those with a probability of survival less than 25%, bystanders were present immediately after the point of injury or "within minutes" in thirty-three of thirty-five (94%) Cheshire and ten of twelve (83%) Manchester. First aid of any form was attempted in fourteen of thirty-five (40%) and nine of twelve (75%) respectively. CONCLUSIONS: A high number of prehospital deaths from trauma occur with injuries that are potentially survivable, yet first aid intervention is infrequent. Following injury there is a potential window of opportunity for the provision of bystander assistance, particularly in the context of head injury, for simple first-aid manoeuvres to save lives.

Fluorinated phenylcyclopropylamines. Part 3: Inhibition of monoamine oxidase A and B.

Fluorinated phenylcyclopropylamines and alkylamines were examined as inhibitors of recombinant human liver monoamine oxidase A (MAO A) and B (MAO B). For a series of trans- and cis-2-fluoro-2-phenylcyclopropylamine analogues, the presence of fluorine attached to a cyclopropane ring was found to result in an increase in inhibitory activity towards both MAO A and B. In addition, p-substitution of electron-withdrawing groups such as Cl and F in the aromatic ring of the trans-isomers increased the inhibition of both enzymes. (1S,2S)-2-Fluoro-2-phenylcyclopropylamine was a more potent inhibitor of both MAO A and B than was the (1R,2R)-enantiomer, indicating that the presence of fluorine has no influence on the enantioselectivity of MAO inhibition, since a similar effect of stereochemistry has been reported for tranylcypromine. Interestingly, fluorination at the 2-position of 1-phenycyclopropylamine, which is known as a selective inhibitor of MAO B relative to MAO A, reversed the selectivity and resulted in a potent inhibitor selective for MAO A. All inhibitors showed time- and concentration-dependent inhibition for both enzymes, with the exception of trans-2-fluoro-2-phenylcyclopropyl ethylamine, which acts as a competitive and reversible MAO A selective inhibitor.

Fluorinated phenylcyclopropylamines. 1. Synthesis and effect of fluorine substitution at the cyclopropane ring on inhibition of microbial tyramine oxidase.

Two series of diastereopure phenylcyclopropylamine analogues, 2-fluoro-2-phenylcyclopropylamines and 2-fluoro-2-phenylcyclopropylalkylamines, as well as 2-fluoro-1-phenylcyclopropylamines and 2-fluoro-1-phenylcyclopropylmethylamines, were synthesized in order to study the effects of fluorine substitution on monoamine oxidase inhibition. Inhibitory activity was assayed using commercially available microbial tyramine oxidase. Characterization of tyramine oxidase, carried out prior to the inhibition experiments, confirmed earlier suggestions that this enzyme is a semicarbazide-sensitive copper-containing monoamine oxidase. The most potent competitive inhibitor was trans-2-fluoro-2-phenylcyclopropylamine, which had an IC(50) value 10 times lower than that of the nonfluorinated compound, tranylcypromine. 2-Fluoro-1-phenylcyclopropylmethylamine was found to be a weak noncompetitive inhibitor of tyramine oxidase. The presence of a free amino group, directly bonded to the cyclopropane ring, and a fluorine atom in a relationship cis to the amino group were structural features that increased tyramine oxidase inhibition.

The international validation of a fixed-dose procedure as an alternative to the classical LD50 test.

In an international study involving 33 laboratories in 11 countries, the acute oral toxicity to the rat of 20 substances and preparations was evaluated using a fixed-dose procedure and the results compared with those obtained for the test materials using the classical LD50 test. The study has shown that the fixed-dose approach to acute oral toxicity testing: (1) produces consistent results that are not substantially affected by inter-laboratory variations; (2) provides adequate information for risk assessment purposes on signs of toxicity, including their nature, time to onset, duration and outcome; (3) uses fewer animals than the current internationally agreed OECD procedure (Guideline 401-revised); (4) subjects animals to less pain and distress than the classical LD50 test and causes less compound-related mortality; and (5) enables substances and preparations to be ranked according to the EEC classification system on the basis of their acute oral toxicity, such ranking being compatible with that allocated by the results of classical LD50 studies.

An in vitro model for identifying skin-corrosive chemicals. I. Initial validation.

An in vitro epidermal slice technique has been developed for identifying chemicals with the potential to cause a corrosive lesion in animal skin in vivo. Skin-corrosive potential has been correlated with the ability to reduce the skin's penetration barrier by lysis of the stratum corneum. This effect was measured as a lowering of the electrical resistance of an epidermal slice following chemical contact in vitro. An initial validation with 68 chemicals showed the technique to have a high sensitivity for corrosive chemicals. The model has potential as a pre-screen for conventional animal tests and, in contrast to in vivo screening methods, has the advantage of providing quantitative and objective data.

Urinary enzymes and protein patterns as indicators of injury to different regions of the kidney.

Acute experimental models of renal damage to the proximal tubular, glomerular, and papillary regions of the rat were produced by administration of hexachloro-1:3-butadiene (HCBD), puromycin aminonucleoside (PAN), and 2-bromoethylamine (BEA), respectively. Several routine indicators of nephrotoxicity, the enzymes alkaline phosphatase and N-acetyl-beta-glucosaminidase, and the molecular weight of protein excretion were determined on urine samples. Tubular damage produced by HCBD or BEA was discriminated both quantitatively and qualitatively from glomerular damage produced by PAN. The latter was characterized by a pronounced increase in protein excretion, especially proteins with molecular weight greater than 40,000 Da. In contrast, protein excretion in tubular damage was raised only slightly and characterized by excretion of proteins of a wide range of molecular weights. Proximal tubular damage caused by HCBD and papillary damage caused by BEA were distinguished both by conventional urinalysis (volume and specific gravity) and by measurement of the two urinary enzymes. Alkaline phosphatase and glucose were markedly and transiently elevated in proximal tubular damage and N-acetyl-beta-glucosaminidase showed a sustained elevation in papillary damage. It is concluded that both selective urinary enzymes and the molecular weight pattern of urinary proteins can be used to provide diagnostic information about the possible site of renal damage.

A balanced approach to the detection, characterisation and mechanism of the toxicity of industrial chemicals.

Several thousands of new chemical entities are synthesised each year in the laboratories of the world. Currently there are estimated to be some 100,000 substances used commercially of the 7 million chemicals recorded by chemical abstracts (Ca 1.5%). Public attention is mainly attracted to the potential life threatening and ill health effects of chemicals such as systemic poisoning, carcinogenicity, teratogenicity and mutagenicity, although there are relatively few proven human chemical carcinogens, teratogens or mutagens. Many substances have been examined in animal toxicity studies for their acute toxic effects, far fewer for chronic toxic effects. The public's perception is that chemicals are toxic. In our laboratory, minimal to no lethal toxic effects were recorded for more than 60% of substances examined at doses below 2000 mg/kg/bwt by either oral or dermal routes. A similar spectrum of chemicals did not elicit skin or ocular irritant or skin sensitisation response in 70-80% of studies. Perversely although toxicity studies reasonably predict the probable human response following exposure, they are a focus of a strong public lobby supported by many scientists to curtail studies in experimental animals. Consequently, much effort is devoted towards the development of "alternative" in vitro and ex-vivo procedures. Often these are empirically based without consideration of the underlying fundamental physiology, biochemistry or toxic mechanism of action. Consequently there can be an over-estimation or expectation of their ability to predict potential toxicity. Attention is seldom directed towards the design requirements of the validation studies needed to test, performance and reproducibility and the evaluation of the parameters of sensitivity and specificity.(ABSTRACT TRUNCATED AT 250 WORDS)

A quantitative assessment of pyrethroid-induced paraesthesia in the guinea-pig flank model.

Pyrethroids are known to induce cutaneous effects in man which are distinct from the classical irritation and vascular responses. These effects are characterised by transient facial burning and tingling sensations. The aetiology of this cutaneous effect is related to the ability of pyrethroids to produce trains of nerve impulses in afferent nerves by prolonging the opening of the neuronal sodium channel. The veratrum alkaloids which are structurally dissimilar to the pyrethroids are known to affect the sodium channel in a similar manner. Using the guinea-pig flank model which has been developed to study this cutaneous phenomenon we have constructed dose-response curves to three structurally related pyrethroids (permethrin, cypermethrin and deltamethrin) and to a mixture of veratrum alkaloids (veratrine). In addition we have examined the time course over which these chemicals elicit a response.

An in vitro skin corrosivity test--modifications and validation.

An in vitro rat epidermal slice technique has been developed for identifying chemicals with potential to cause a corrosive lesion in animal skin in vivo. This potential has been correlated with the ability to lyse stratum corneum and has been measured as a lowering of the electrical resistance of the skin slice. Initial validation of the technique with 63 chemicals resulted in a high sensitivity for corrosive chemicals but a lower specificity for irritant chemicals. Subsequent modification relating to chemical contact resulted in an improved specificity (i.e. fewer false positives) at the expense of a small loss in sensitivity (i.e. an increase in the number of false negatives). An intralaboratory double blind trial with 34 corrosive chemicals and 36 irritants showed the technique to have total sensitivity (i.e. no false negatives) and a specificity of 88%. The results of the initial validation and the double blind trial illustrate the robust nature and high reproducibility of this in vitro technique for identifying skin-corrosive chemicals. Overall the model has considerable potential as a pre-screen for conventional animal tests with the additional advantage of providing objective and quantifiable information.

An in vitro epidermal slice technique for identifying chemicals with potential for severe cutaneous effects.

We have developed an in vitro model, using epidermal slices, to identify skin-corrosive potential. Such potential has been correlated with the ability to lyse stratum corneum, indicated by a lowered electrical resistance of the skin slice. Using 41 corrosive and 22 irritant chemicals, a comparison of in vitro and in vivo classifications has shown that this in vitro technique identifies corrosive agents with high precision. Therefore the model has considerable potential as a prescreen to conventional animal tests and, unlike in vivo screening tests, can provide both objective and quantifiable data.

A comparison of techniques for the measurement of transepidermal water loss.

An Evaporimeter and a ventilated chamber technique have been compared in their ability to measure transepidermal water loss (TEWL) through rat skin. These techniques measure TEWL under very different conditions; the Evaporimeter measures the net TEWL under ambient relative humidity (RH) whereas the ventilated chamber employs a constant atmosphere, usually of low RH and thus measured the uni-directional diffusion of water. Paired Evaporimeter and ventilated chamber measurements were made of TEWL through normal skin and through skin whose barrier properties had been altered by tape-stripping (15 applications) or single applications of n-hexadecane (28.4 mumol cm-2). Both measuring techniques indicated the same level of TEWL through normal skin (mean 0.3 mg cm-2 h-1) and during increases in TEWL induced by n-hexadecane (max TEWL c 3.5 mg cm-2 h-1). However, the Evaporimeter was found to underestimate the higher rates of TEWL induced by tape-stripping, ie above TEWL raters of 7.5 mg cm-2 h-1. The Evaporimeter is portable, easy to use and suitable for measurements of net water loss up to 7.5 mg cm-2 h-1; it can only be used for comparative assessment of epidermal barrier function if used at a particular ambient RH. The more cumbersome ventilated chamber is to be preferred for accurate assessments of barrier function where high rates of TEWL occur.

The transfer of mannose to dolichol diphosphate oligosaccharides in pig liver endoplasmic reticulum.

The transfer, catalysed by pig liver microsomal preparations, of mannose, from GDP-mannose, to lipid-linked oligosaccharides and the properties of the products are described. Solubility, hydrolytic and chromatographic data suggest that they are dolichol diphosphate derivatives. The presence of two N-acetyl groups in at least part of the heterogenous oligosaccharide portion was tentatively deduced. Reduction with borohydride of the oligosaccharide showed that the newly added mannose residues were not at its reducing end. Periodate oxidation suggested that 60% of these were at the non-reducing terminus and that 40% were positioned internally. T.l.c. showed the presence of seven oligosaccharide fractions with chromatographic mobilities corresponding to glucose oligomers with 7-13 residues. The molar proportions of the oligosaccharide fractions in the mixture were determined by borotritiide reduction and the number of mannose residues added to each oligosaccharide fraction during the incubation was calculated. Two of the oligosaccharide fractions had received on average one, or slightly more than one, mannose residue per chain during the incubation; four of the other fractions were each shown to be a mixture, 20-25% of which had received one mannose residue during the incubation and 75-80% of which had not been mannosylated during the incubation. This supported other evidence for the presence of endogenous lipid-linked oligosaccharides in the microsomal preparation which had been formed before the incubation in vitro. Evidence for the possibility of two pools of dolichol monophosphate mannose, one being more closely associated with mannosyl transfer to dolichol diphosphate oligosaccharides than the other, is also discussed.

The mannosylation of dolichol-diphosphate oligosaccharides in relation to the formation of oligosaccharides and glycoproteins in pig-liver endoplasmic reticulum.

In the chain-lengthening of the oligosaccharide chains of endogenous dolichol-diphosphate oligosaccharides (DOL-P-P-oligosaccharides) by a pig liver microsomal preparation dolichol-monophosphate mannose (Dol-P-Man) was a more efficient donor of mammose (a maximum of 35% transferred by 5 min) than was GDP-Man (reaching 16% by 45 min). The effects of an excess of GDP, an excess of GDP-Man, a lack of Mn2+ and an excess of EDTA showed that the transfer from GDP-Man was via Dol-P-Man. The evidence also indicated the presence of two pools of Dol-P-Man one of which was difficult to extract and which was possibly closely associated with the Dol-P-P-oligosaccharides and the appropriate transferase. After 1 h of incubation transfer of 14C to 'insoluble polymer' from GDP-[14C]Man, Dol-P-[14C]Man and Dol-P-P-[14C]oligosaccharides reached approximately 3%, 3% and 13% respectively, of that available. The result of adding excess unlabelled GDP-Man to an incubation with GDP-[14C]Man in progressconfirmed the sequence GDP-Man leads to Dol-P-Man leads to Dol-P-P-oligosaccharide leads to insoluble polymer. Solubilisation with sodium dodecyl sulphate of the radioactive 'insoluble polymer' followed by gel chromatography showed the presence of radioactive glycoprotein and oligosaccharide when either GDP-[14C]Man or Dol-P-P-[14C]oligosaccharide was used as donor. The proportion of oligosaccharide formed rose sharply when excess EDTA was present and GDP-[14C]Man was the donor. Under these conditions the oligosaccharide contained 5--6 units and all of the radioactivity could be released by alpha-mannosidase. The glycoprotein was susceptible to proteolysis.