Are suspected stroke patients identified by paramedics transported to appropriate stroke centres in Victoria, Australia?

Emergency medical services (EMS) are vital to ensuring acute stroke patients are transported to thrombolysis and/or stroke unit centres. This 6-month audit of Victorian EMS cases found the majority of suspected acute strokes are transported to appropriate stroke centres. However, there is still room for improvement, in particular, strategies to improve access to stroke services in some rural regions and to ensure patients/relatives are fully informed when requesting transport to a non-stroke service hospital.

Effectiveness of ultraportable automated external defibrillators: A scoping review.

Background: Ultraportable automated external defibrillators (AEDs) are a new generation of defibrillators that are small, lightweight, easy to carry on one's person, and affordable for personal and home use. They offer the opportunity to increase AED availability in case of out-of-hospital cardiac arrest (OHCA) and therefore improve outcomes.We aimed to review evidence supporting the potential effect on outcomes and the performance of these ultraportable AEDs. Methods: We searched Ovid Medline, Embase and Cochrane databases from 2012 to July 4th, 2024 to identify any studies related to ultraportable AED. The population was adult and children with OHCA who were treated with an ultra-portable AED. All outcomes were accepted. We limited study designs to randomized controlled trials and non-randomized studies. Data charting was done by the primary author using standardized data abstraction forms. Results: The search strategy identified 54 studies (Pubmed = 26, Embase = 28, with 19 duplicates). We included three articles in the final review. One study was a medico-economic simulation study including 600,000 simulated patients, one is the study protocol of cluster randomized trial of providing ultraportable AEDs to first responders and one is an abstract with preliminary results of this trial reporting 1805 community responders recruited, 903 allocated to ultraportable AED. No studies to date have reported patient outcomes. Conclusion: This review found no evidence of ultraportable AED device performance, clinical or safety outcomes. There is an urgent need for further research to determine the safety and effectiveness of ultraportable AEDs.

Do we need cardiac arrest centres in Australia?

The mortality rate post admission to hospital after successful resuscitation from out-of-hospital cardiac arrest is high, with significant variation between regions and individual institutions. While prehospital factors such as age, bystander cardiopulmonary resuscitation and total cardiac arrest time are known to influence outcome, several aspects of post-resuscitative care including therapeutic hypothermia, coronary intervention and goal-directed therapy may also influence patient survival. Regional systems of care have improved provider experience and patient outcomes for those with ST elevation myocardial infarction and life-threatening traumatic injury. In particular, hospital factors such as hospital size and interventional cardiac care capabilities have been found to influence patient mortality. This paper reviews the evidence supporting the possible development and implementation of Australian cardiac arrest centres.

Thrombolytic therapy for acute ischaemic stroke: successful implementation in an Australian tertiary hospital.

The use of tissue-type plasminogen activator (t-PA) in ischaemic stroke outside of experienced stroke centres remains controversial. The aim of this study was to present the initial experience with t-PA in patients with ischaemic stroke at an institution with no prior experience in i.v. stroke thrombolysis and to compare results to published reports. Prospective audit of 888 patients with consecutive stroke and transient ischaemic attack admitted to a 426-bed tertiary referral hospital from March 2003 to October 2005. Main outcome measures were treatment rate, exclusion criteria, protocol violations, intracerebral haemorrhage, disability (modified Rankin scale) and mortality at 3 months. Over the study period, 72 patients received t-PA (11% of ischaemic strokes). The main reason for exclusion was presentation beyond 3 h of onset (44%); if all eligible patients had arrived within 3 h, treatment rate was estimated at 32.5%. Protocol violations occurred in 15 (21%) patients. There were seven (10%) asymptomatic intracerebral haemorrhage and one (1%) non-fatal symptomatic intracerebral haemorrhage. At 3 months, 37% had achieved excellent recovery (modified Rankin scale 0-1) and seven (10%) had died. The delivery and outcomes associated with the use of t-PA were comparable to the results of the National Institute of Neurological Disorders and Stroke trial and meta-analysis of open-labelled studies. With appropriate infrastructure and protocols, previously inexperienced tertiary referral centres can replicate the experience and outcome measures reported by clinical trials of t-PA in patients with stroke.

The CATH database: an extended protein family resource for structural and functional genomics.

The CATH database of protein domain structures (http://www.biochem.ucl.ac.uk/bsm/cath_new) currently contains 34 287 domain structures classified into 1383 superfamilies and 3285 sequence families. Each structural family is expanded with domain sequence relatives recruited from GenBank using a variety of efficient sequence search protocols and reliable thresholds. This extended resource, known as the CATH-protein family database (CATH-PFDB) contains a total of 310 000 domain sequences classified into 26 812 sequence families. New sequence search protocols have been designed, based on these intermediate sequence libraries, to allow more regular updating of the classification. Further developments include the adaptation of a recently developed method for rapid structure comparison, based on secondary structure matching, for domain boundary assignment. The philosophy behind CATHEDRAL is the recognition of recurrent folds already classified in CATH. Benchmarking of CATHEDRAL, using manually validated domain assignments, demonstrated that 43% of domains boundaries could be completely automatically assigned. This is an improvement on a previous consensus approach for which only 10-20% of domains could be reliably processed in a completely automated fashion. Since domain boundary assignment is a significant bottleneck in the classification of new structures, CATHEDRAL will also help to increase the frequency of CATH updates.

A rapid classification protocol for the CATH Domain Database to support structural genomics.

In order to support the structural genomic initiatives, both by rapidly classifying newly determined structures and by suggesting suitable targets for structure determination, we have recently developed several new protocols for classifying structures in the CATH domain database (http://www.biochem.ucl.ac.uk/bsm/cath). These aim to increase the speed of classification of new structures using fast algorithms for structure comparison (GRATH) and to improve the sensitivity in recognising distant structural relatives by incorporating sequence information from relatives in the genomes (DomainFinder). In order to ensure the integrity of the database given the expected increase in data, the CATH Protein Family Database (CATH-PFDB), which currently includes 25,320 structural domains and a further 160,000 sequence relatives has now been installed in a relational ORACLE database. This was essential for developing more rigorous validation procedures and for allowing efficient querying of the database, particularly for genome analysis. The associated Dictionary of Homologous Superfamilies [Bray,J.E., Todd,A.E., Pearl,F.M.G., Thornton,J.M. and Orengo,C.A. (2000) Protein Eng., 13, 153-165], which provides multiple structural alignments and functional information to assist in assigning new relatives, has also been expanded recently and now includes information for 903 homologous superfamilies. In order to improve coverage of known structures, preliminary classification levels are now provided for new structures at interim stages in the classification protocol. Since a large proportion of new structures can be rapidly classified using profile-based sequence analysis [e.g. PSI-BLAST: Altschul,S.F., Madden,T.L., Schaffer,A.A., Zhang,J., Zhang,Z., Miller,W. and Lipman,D.J. (1997) Nucleic Acids Res., 25, 3389-3402], this provides preliminary classification for easily recognisable homologues, which in the latest release of CATH (version 1.7) represented nearly three-quarters of the non-identical structures.

The significance of pre-arrest factors in out-of-hospital cardiac arrests witnessed by emergency medical services: a report from the Victorian Ambulance Cardiac Arrest Registry.

BACKGROUND: The significance of pre-arrest factors in out-of-hospital cardiac arrests (OHCA) witnessed by emergency medical services (EMS) is not well established. The purpose of this study was to assess the association between prodromal symptoms and pre-arrest clinical observations on the arresting rhythm and survival in EMS witnessed OHCA. METHODS: Between 1st January 2003 and 31st December 2011, 1056 adult EMS witnessed arrests of a presumed cardiac aetiology were identified from the Victorian Ambulance Cardiac Arrest Registry. Pre-arrest prodromal features and clinical characteristics were extracted from the patient care record. Backward elimination logistic regression was used to identify pre-arrest factors associated with an initial shockable rhythm and survival to hospital discharge. RESULTS: The median age was 73.0 years, 690 (65.3%) were male, and the rhythm of arrest was shockable in 465 (44.0%) cases. The most commonly reported prodromal symptoms prior to arrest were chest pain (48.8%), dyspnoea (41.8%) and altered consciousness (37.8%). An unrecordable systolic blood pressure was observed in 34.4%, a respiratory rate <13 or >24min(-1) was present in 43.1%, and 45.5% had a Glasgow coma score <15. In the multivariable analysis, the following pre-arrest factors were significantly associated with survival: age, public location, aged care facility, chest pain, arm or shoulder pain, dyspnoea, dizziness, vomiting, ventricular tachycardia, pulse rate, systolic blood pressure, respiratory rate, Glasgow coma score, aspirin and inotrope administration. CONCLUSION: Pre-arrest factors are strongly associated with the arresting rhythm and survival following EMS witnessed OHCA. Potential opportunities to improve outcomes exist by way of early recognition and management of patients at risk of OHCA.

Direction of first bystander call for help is associated with outcome from out-of-hospital cardiac arrest.

BACKGROUND: Preventable bystander delays following out-of-hospital cardiac arrest (OHCA) are common, and include bystanders inappropriately directing their calls for help. METHODS: We retrospectively extracted Utstein-style data from the Victorian Ambulance Cardiac Arrest Registry (VACAR) for adult OHCA occurring in Victoria, Australia, between July 2002 and June 2012. Emergency medical service (EMS) witnessed events were excluded. Cases were assigned into two groups on the basis of the first bystander call for help being directed to EMS. Study outcomes were: likelihood of receiving EMS treatment; survival to hospital, and; survival to hospital discharge. RESULTS: A total of 44499 adult OHCA cases attended by EMS were identified, of which first bystander calls for help were not directed to EMS in 2842 (6.4%) cases. Calls to a relative, friend or neighbour accounted for almost 60% of the total emergency call delays. Patient characteristics and survival outcomes were consistently less favourable when calls were directed to others. First bystander call to others was independently associated with older age, male gender, arrest in private location, and arrest in a rural region. The risk-adjusted odds of treatment by EMS (OR 1.33, 95% CI 1.20-1.48), survival to hospital (OR 1.64, 95% CI 1.37-1.96) and survival to hospital discharge (OR 1.64, 95% CI 1.13-2.36) were significantly improved if bystanders called EMS first. CONCLUSION: The frequency of inappropriate bystander calls following OHCA was low, but associated with a reduced likelihood of treatment by EMS and poorer survival outcomes.

Resuscitation of out-of-hospital cardiac arrests in residential aged care facilities in Melbourne, Australia.

INTRODUCTION: CPR in patients in residential aged care facilities (RACF) deserves careful consideration. We examined the characteristics, management and outcomes of out-of-hospital cardiac arrest (OHCA) in RACF patients in Melbourne, Australia. METHODS: The Victorian Ambulance Cardiac Arrest Registry (VACAR) was searched for all OHCAs occurring in RACFs in Melbourne. The characteristics and outcomes were compared to non-RACF patients in the VACAR. RESULTS: Between 2000 and 2009 there were 30,006 OHCAs, 2350 (7.8%) occurring in a RACF. A shockable rhythm was present in 179 (7.6%) patients on arrival of paramedics of whom bystander CPR had been performed in 118 (66%); 173 (97%) received an EMS attempted resuscitation. ROSC was achieved in 71 (41%) patients and 15 (8.7%) patients survived to leave hospital. Non shockable rhythm was present in 2171 patients (92%) of whom 804 (37%) had an attempted resuscitation by paramedics. ROSC was achieved in 176 patients (22%) and 10 patients (1.2%) were discharged alive. Survival from OHCA occurring in a RACF was less than survival in those aged >70 years of age who suffered OHCA in their own homes (1.8% vs. 4.7%, p=0.001). On multivariable analysis, witnessed OHCA (OR 3.0, 95% CI 2.4-3.7) and the presence of bystander CPR (OR 4.6, 95% CI 3.7-5.8) was associated with the paramedic decision to resuscitate. CONCLUSION: Resuscitation of patients in RACF is not futile. However, informed decisions concerning resuscitation status should be made by patients and their families on entry to a RACF. Where it is appropriate to perform resuscitation, outcomes may be improved by the provision of BLS training and possibly AED equipment to RACF staff.

Out-of-hospital cardiac arrests in young adults in Melbourne, Australia-adding coronial data to a cardiac arrest registry.

AIM: We aim to describe the coronial findings of young adults where the out-of-hospital cardiac arrest (OHCA) aetiology was 'presumed cardiac'. METHODS: Presumed cardiac aetiology OHCAs occurring in young adults aged 16-39 years were identified using the Victorian Ambulance Cardiac Arrest Registry (VACAR) and available coronial findings reviewed. RESULTS: We identified 841 young adult OHCAs where the Utstein aetiology was 'presumed cardiac'. Of these 740 died and 572 (77%) OHCAs were matched to coroner's findings. On review of the coroner's cause of death, 230 (40.2%) had a 'confirmed cardiac' aetiology, 221 (38.6%) were proven 'non-cardiac', 97 (17%) were inconclusive and 24 (4.2%) cases remained 'open'. 'Confirmed cardiac' causes of OHCA were ischemic heart disease (n=126, 55%), cardiomegaly (n=26, 11.3%), cardiomyopathy (n=25, 11%), congenital heart disease (n=15, 6.5%), cardiac tamponade due to dissecting thoracic aorta aneurysm (n=10, 4.3%), myocarditis (n=8, 3.5%), arrhythmia (n=7, 3%), others (n=13, 5.7%). 'Non-cardiac' causes of OHCA were epilepsy/sudden unexplained death in epilepsy (SUDEP) (n=56, 25%), pulmonary embolism (n=29, 13%), subarachnoid haemorrhage (n=17, 7.7%), other intracranial bleed (n=7, 3.2%), pneumonia (n=17, 7.7%), DKA (n=16, 7.2%), other complications of diabetes mellitus (n=8, 3.6%), complications of obesity (n=9, 4%), haemorrhage (n=12, 5.4%), sepsis (n=8, 3.6%), peritonitis (n=6, 2.7%), aspiration (n=6, 2.7%), renal failure (n=5, 2.3%), asthma (n=5, 2.3%), complications of anorexia (n=3) and alcohol abuse (n=2), thyrotoxicosis (n=2), meningitis (n=1) and others (n=12). Compared with coroner's diagnosed 'non-cardiac' OHCAs, 'confirmed cardiac' were more likely to be witnessed (41% vs 23%, p≤0.01), receive bystander CPR (35% vs 20%, p≤0.001), have a shockable rhythm (27% vs 6.3%, p<0.001) and have EMS attempted resuscitation (62% vs 44%, p<0.001). DISCUSSION: Linking OHCA registries with coronial databases for aetiology of the arrest will improve the quality of the data and should be considered by all OHCA registries, particularly for young adult OHCA.

Cardiac arrest outcomes before and after the 2005 resuscitation guidelines implementation: evidence of improvement?

BACKGROUND: Previous studies have reported improvements in out-of-hospital cardiac arrest (OHCA) outcomes with the introduction of the 2005 cardiopulmonary resuscitation guidelines however they have not adjusted for underlying trends in OHCA survival. We compare outcomes before and after the 2005 guideline changes adjusting for underlying trends in OHCA survival. METHODS: The Victorian Ambulance Cardiac Arrest Registry (VACAR) was searched for adult (≥16 years) OHCA of presumed cardiac aetiology, unwitnessed by paramedics with attempted resuscitation. Outcomes for OHCA occurring between 2003 and 2005 were compared with 2007-2009. Segmented regression analysis of interrupted time series data was performed, adjusting for known predictors, to examine changes in survival to hospital and survival to hospital discharge. RESULTS: For the pre- and post- guideline periods there were 3115 and 3248 OHCAs, respectively. Asystole increased as presenting rhythm (33-43%, p<0.001) as did median EMS response times (7.1-7.8 min, p<0.001) over the two periods. VF/VT arrests decreased (40-35.5%, p=0.001) as did bystander witnessed arrests (63-59%, p=0.002). On univariate analysis survival to hospital discharge improved between the two periods (9.4-11.8%, p=0.002) due to improved outcomes in VF/VT (19-28%, p<0.001). Segmented regression analysis of interrupted time series data showed improvement in the rate of survival to get to hospital for shockable and non-shockable rhythms [OR (95% CI)=1.54 (1.10-2.15, p=0.01) and 1.45 (1.10-2.00, p=0.02), respectively] following implementation of the guidelines however survival to hospital discharge did not improve [OR=1.07 (0.70-1.62, p=0.70) and 1.40 (0.69-2.85, p=0.40), respectively]. CONCLUSIONS: OHCA outcomes have improved since introduction of the 2005 CPR guidelines, but multivariable segmented regression analysis adjusting for pre-existing trends in survival suggests that this improvement may not be due to implementation of the 2005 resuscitation guidelines.

Out-of-hospital cardiac arrests in young adults in Melbourne, Australia.

BACKGROUND: Characteristics and outcomes of out-of-hospital cardiac arrest (OHCA) in young adults are not well described in Australia. METHODS: A 10-year retrospective case review of all OHCA in young adults (aged 16-39) and not witnessed by EMS, was performed using data from the Victorian Ambulance Cardiac Arrest Registry (VACAR). RESULTS: Between 2000 and 2009 there were 30,006 adult cardiac arrests of which 3912 (13%) were in this age group. The median (IQR) age was 30 (25-35) years for both sexes with a 3:1 male to female ratio. Overdose was the most common precipitant (33.5%) followed by presumed cardiac (20%). Bystander CPR occurred in 21.2%, EMS median response time was 7 min and resuscitation was attempted in 36% of OHCAs. The presenting rhythm was asystole in 84.6%, PEA in 8.8% and VF/VT in 6.6%. Survival to hospital discharge, for all cause OHCA where resuscitation was attempted, was similar for young adult and older adults (8.8% vs 8.4%, p=0.2). However, for presumed cardiac aetiology OHCA, young adults had a greater proportion of survivors (14.8% vs 9.0%, p<0.001). Cardiac arrest with shockable rhythm (VF/pulseless VT) had a survival rate of 31.2% for young adults compared to 18.5% for older adults (p<0.001). CONCLUSION: Survival to hospital discharge rates from OHCA due to a 'presumed cardiac' precipitant in young adults is much better than older adults, however, all cause OHCA survival is similar. Multi agency novel upstream preventive strategies aimed at tackling drug overdose may reduce this aetiology of OHCA and save lives.

Out-of-hospital cardiac arrests in the older age groups in Melbourne, Australia.

BACKGROUND: Controversy exists around CPR in the elderly. The characteristics and outcomes of out-of-hospital cardiac arrest (OHCA) in this age group were studied in Melbourne, Australia. METHODS: The Victorian Ambulance Cardiac Arrest Registry (VACAR) was searched for all OHCAs not witnessed by Emergency Medical Services (EMS) occurring in those aged 65 years and older. RESULTS: Between 2000 and 2009 there were 30,006 OHCAs of which 9703 (32%) were in people 65-79 years of age, 6430 (21%) in octogenarians, 1530 (5%) in nonagenarian and 40 (0.1%) in centenarians. Rates of attempted resuscitation decreased with advancing age: 48% for those aged 65-79 years, 39% for octogenarians, 31% for nonagenarians and 17% for centenarians. Similarly rates of survival to hospital discharge decreased with age: 8% for those aged 65-79 years, 4% for octogenarians, 2% for nonagenarians; for 65-79 year olds, octogenarians and nonagenarians survival if in VF/VT was - 17%, 10% and 4%; asystole - 1%, 1% and 0.5%; and PEA - 6%, 3% and 3%, respectively. Multivariable logistic regression shows that between 2000 and 2009 rates of transportation with return of spontaneous circulation have improved for both shockable and non-shockable rhythms [OR 95% CI 1.07(1.04-1.10) and 1.16(1.12-1.20), respectively] but survival to hospital discharge has improved in the shockable rhythm group only [OR 1.12(1.07-1.16)]. CONCLUSION: Outcomes for OHCA with shockable rhythm have improved over the last 10 years for people aged 65 years and over. Quality of life studies should be performed to help inform the community and EMS on appropriate resuscitative efforts.

Clinical recognition of neurally mediated syncope.

BACKGROUND: Most cases of syncope are due to hypotension, with a vasovagal response the commonest single mechanism. Neurally mediated syncope (NMS) is a vasovagal response evoked by common physical or psychological stress factors in susceptible individuals. Although upright tilt table testing (TTT) has been developed to diagnose this condition, the clinical recognition of this common syndrome in the general community remains poor. AIMS: To evaluate the clinical presentation of patients with NMS and pre-syncope, proven by TTT, and compare them to patients with syncope that have a low probability of having NMS (e.g. older patients with cardiac disease and negative TTT). METHODS: Prospective evaluation by questionnaire at the time of TTT, including documentation of presenting symptoms and signs, and provoking factors in consecutive patients. Comparisons between patient groups analyzed using chi-squared tests and logistic regression. RESULTS: Neurally mediated syncope patients were more likely to present with both syncope and pre-syncope, often with prolonged histories of pre-syncope. Certain provoking stress factors were more common in NMS, with multiple factors often present. Most NMS patients had a hypotensive prodrome before syncope, whereas control patients had a higher incidence of syncope without warning. CONCLUSION: Neurally mediated syncope patients present with situational syncope that is not only stereotypical for the individual, but shares common features with other similar patients. While none of the clinical observations is unique to NMS, a carefully detailed history can elicit a convincing diagnostic pattern that can often obviate the need for extensive and expensive investigation, and in younger patients a TTT may not be required to make the diagnosis.

Analysis and assessment of ab initio three-dimensional prediction, secondary structure, and contacts prediction.

CASP3 saw a substantial increase in the volume of ab initio 3D prediction data, with 507 datasets for fifteen selected targets and sixty-one groups participating. As with CASP2, methods ranged from computationally intensive strategies that attempt to recreate the physical and chemical forces involved in protein folding to the more recent knowledge-based approaches. These exploit information from the structure databases, extracting potentially similar fragments and/or distance constraints derived from multiple sequence alignments. The knowledge-based approaches generally gave more consistently successful predictions across the range of targets, particularly that of the Baker group (Bystroff and Baker, J Mol Biol 1998;281:565-577; Simons et al. Proteins Suppl 1999;3:171-176), which used a fragment library. In the secondary structure prediction category, the most successful approaches built on the concepts used in PHD (Rost et al. Comput Appl Biosci 1994;10:53-60), an accepted standard in this field. Like PHD, they exploit neural networks but have different strategies for incorporating multiple sequence data or position-dependent weight matrices for training the networks. Analysis of the contact data, for which only six groups participated, suggested that as yet this data provides a rather weak signal. However, in combination with other types of prediction data it can sometimes be a useful constraint for identifying the correct structure.

The CATH Dictionary of Homologous Superfamilies (DHS): a consensus approach for identifying distant structural homologues.

A consensus approach has been developed for identifying distant structural homologues. This is based on the CATH Dictionary of Homologous Superfamilies (DHS), a database of validated multiple structural alignments annotated with consensus functional information for evolutionary protein superfamilies (URL: http://www. biochem.ucl.ac.uk/bsm/dhs). Multiple structural alignments have been generated for 362 well-populated superfamilies in the CATH structural domain database and annotated with secondary structure, physicochemical properties, functional sequence patterns and protein-ligand interaction data. Consensus functional information for each superfamily includes descriptions and keywords extracted from SWISS-PROT and the ENZYME database. The Dictionary provides a powerful resource to validate, examine and visualize key structural and functional features of each homologous superfamily. The value of the DHS, for assessing functional variability and identifying distant evolutionary relationships, is illustrated using the pyridoxal-5'-phosphate (PLP) binding aspartate aminotransferase superfamily. The DHS also provides a tool for examining sequence-structure relationships for proteins within each fold group.

Assigning genomic sequences to CATH.

We report the latest release (version 1.6) of the CATH protein domains database (http://www.biochem.ucl. ac.uk/bsm/cath ). This is a hierarchical classification of 18 577 domains into evolutionary families and structural groupings. We have identified 1028 homo-logous superfamilies in which the proteins have both structural, and sequence or functional similarity. These can be further clustered into 672 fold groups and 35 distinct architectures. Recent developments of the database include the generation of 3D templates for recognising structural relatives in each fold group, which has led to significant improvements in the speed and accuracy of updating the database and also means that less manual validation is required. We also report the establishment of the CATH-PFDB (Protein Family Database), which associates 1D sequences with the 3D homologous superfamilies. Sequences showing identifiable homology to entries in CATH have been extracted from GenBank using PSI-BLAST. A CATH-PSIBLAST server has been established, which allows you to scan a new sequence against the database. The CATH Dictionary of Homologous Superfamilies (DHS), which contains validated multiple structural alignments annotated with consensus functional information for evolutionary protein superfamilies, has been updated to include annotations associated with sequence relatives identified in GenBank. The DHS is a powerful tool for considering the variation of functional properties within a given CATH superfamily and in deciding what functional properties may be reliably inherited by a newly identified relative.

Using the CATH domain database to assign structures and functions to the genome sequences.

The CATH database of protein structures contains approximately 18000 domains organized according to their (C)lass, (A)rchitecture, (T)opology and (H)omologous superfamily. Relationships between evolutionary related structures (homologues) within the database have been used to test the sensitivity of various sequence search methods in order to identify relatives in Genbank and other sequence databases. Subsequent application of the most sensitive and efficient algorithms, gapped blast and the profile based method, Position Specific Iterated Basic Local Alignment Tool (PSI-BLAST), could be used to assign structural data to between 22 and 36 % of microbial genomes in order to improve functional annotation and enhance understanding of biological mechanism. However, on a cautionary note, an analysis of functional conservation within fold groups and homologous superfamilies in the CATH database, revealed that whilst function was conserved in nearly 55% of enzyme families, function had diverged considerably, in some highly populated families. In these families, functional properties should be inherited far more cautiously and the probable effects of substitutions in key functional residues carefully assessed.

The CATH Database provides insights into protein structure/function relationships.

We report the latest release (version 1.4) of the CATH protein domains database (http://www.biochem.ucl.ac.uk/bsm/cath). This is a hierarchical classification of 13 359 protein domain structures into evolutionary families and structural groupings. We currently identify 827 homologous families in which the proteins have both structual similarity and sequence and/or functional similarity. These can be further clustered into 593 fold groups and 32 distinct architectures. Using our structural classification and associated data on protein functions, stored in the database (EC identifiers, SWISS-PROT keywords and information from the Enzyme database and literature) we have been able to analyse the correlation between the 3D structure and function. More than 96% of folds in the PDB are associated with a single homologous family. However, within the superfolds, three or more different functions are observed. Considering enzyme functions, more than 95% of clearly homologous families exhibit either single or closely related functions, as demonstrated by the EC identifiers of their relatives. Our analysis supports the view that determining structures, for example as part of a 'structural genomics' initiative, will make a major contribution to interpreting genome data.