Identification of Sources of Sclerotinia sclerotiorum Resistance in a Collection of Wild Cicer Germplasm.

Sclerotinia sclerotiorum is an important fungal pathogen of chickpea (Cicer arietinum L.), and it can cause yield losses up to 100%. The wild progenitors are much more diverse than domesticated chickpea, and this study describes how this relates to S. sclerotiorum resistance. Initially, the pathogenicity of nine Australian S. sclerotiorum isolates was examined on three Cicer lines to develop a robust phenotyping assay, and significant differences in isolate aggressiveness were identified with six isolates being classed as highly aggressive and three as moderately aggressive. We identified two S. sclerotiorum isolates, CU8.20 and CU10.12, to be highly aggressive and moderately aggressive, respectively. A subsequent phenotyping assay was conducted using the two isolates to evaluate 86 wild Cicer accessions (Cicer reticulatum and Cicer echinospermum) and two C. arietinum varieties for resistance to S. sclerotiorum. A subset of 12 genotypes was further evaluated, and subsequently, two wild Cicer accessions with consistently high levels of resistance to S. sclerotiorum were examined using the initially characterized nine isolates. Wild Cicer accessions Karab_084 and Deste_063 demonstrated consistent partial resistance to S. sclerotiorum. There were significant differences in responses to S. sclerotiorum across wild Cicer collection sites. The Cermik, Karabahce, and Destek sites' responses to the aggressive isolate CU8.20 ranged from resistant to susceptible, highlighting an interaction between isolate genotype and chickpea collection site for sclerotinia stem rot resistance. This is the first evidence of partial stem resistance identified in wild Cicer germplasm, which can be adopted in chickpea breeding programs to enhance S. sclerotiorum resistance in future chickpea varieties.

Impact of the COVID-19 pandemic on emergency department attendances and acute medical admissions.

BACKGROUND: To better understand the impact of the COVID-19 pandemic on hospital healthcare, we studied activity in the emergency department (ED) and acute medicine department of a major UK hospital. METHODS: Electronic patient records for all adult patients attending ED (n = 243,667) or acute medicine (n = 82,899) during the pandemic (2020-2021) and prior year (2019) were analysed and compared. We studied parameters including severity, primary diagnoses, co-morbidity, admission rate, length of stay, bed occupancy, and mortality, with a focus on non-COVID-19 diseases. RESULTS: During the first wave of the pandemic, daily ED attendance fell by 37%, medical admissions by 30% and medical bed occupancy by 27%, but all returned to normal within a year. ED attendances and medical admissions fell across all age ranges; the greatest reductions were seen for younger adults in ED attendances, but in older adults for medical admissions. Compared to non-COVID-19 pandemic admissions, COVID-19 admissions were enriched for minority ethnic groups, for dementia, obesity and diabetes, but had lower rates of malignancy. Compared to the pre-pandemic period, non-COVID-19 pandemic admissions had more hypertension, cerebrovascular disease, liver disease, and obesity. There were fewer low severity ED attendances during the pandemic and fewer medical admissions across all severity categories. There were fewer ED attendances with common non-respiratory illnesses including cardiac diagnoses, but no change in cardiac arrests. COVID-19 was the commonest diagnosis amongst medical admissions during the first wave and there were fewer diagnoses of pneumonia, myocardial infarction, heart failure, cellulitis, chronic obstructive pulmonary disease, urinary tract infection and other sepsis, but not stroke. Levels had rebounded by a year later with a trend to higher levels of stroke than before the pandemic. During the pandemic first wave, 7-day mortality was increased for ED attendances, but not for non-COVID-19 medical admissions. CONCLUSIONS: Reduced ED attendances in the first wave of the pandemic suggest opportunities for reducing low severity presentations to ED in the future, but also raise the possibility of harm from delayed or missed care. Reassuringly, recent rises in attendance and admissions indicate that any deterrent effect of the pandemic on attendance is diminishing.

Camellia Plant Resistance and Susceptibility to Petal Blight Disease Are Defined by the Timing of Defense Responses.

The family Sclerotiniaceae includes important phytopathogens, such as Botrytis cinerea and Sclerotinia sclerotiorum, that activate plant immune responses to facilitate infection propagation. The mechanisms of plant resistance to these necrotrophic pathogens are still poorly understood. To discover mechanisms of resistance, we used the Ciborinia camelliae (Sclerotiniaceae)-Camellia spp. pathosystem. This fungus induces rapid infection of the blooms of susceptible cultivar Nicky Crisp (Camellia japonica × Camellia pitardii var. pitardii), while Camellia lutchuensis is highly resistant. Genome-wide analysis of gene expression in resistant plants revealed fast modulation of host transcriptional activity 6 h after ascospore inoculation. Ascospores induced the same defense pathways in the susceptible Camellia cultivar but much delayed and coinciding with disease development. We next tested the hypothesis that differences in defense timing influences disease outcome. We induced early defense in the susceptible cultivar using methyl jasmonate and this strongly reduced disease development. Conversely, delaying the response in the resistant species, by infecting it with actively growing fungal mycelium, increased susceptibility. The same plant defense pathways, therefore, contribute to both resistance and susceptibility, suggesting that defense timing is a critical factor in plant health, and resistance against necrotrophic pathogens may occur during the initial biotrophy-like stages.

Reduction in early stroke risk in carotid stenosis with transient ischemic attack associated with statin treatment.

BACKGROUND AND PURPOSE: Statins reduce stroke risk when initiated months after transient ischemic attack (TIA)/stroke and reduce early vascular events in acute coronary syndromes, possibly via pleiotropic plaque stabilization. Few data exist on acute statin use in TIA. We aimed to determine whether statin pretreatment at TIA onset modified early stroke risk in carotid stenosis. METHODS: We analyzed data from 2770 patients with TIA from 11 centers, 387 with ipsilateral carotid stenosis. ABCD2 score, abnormal diffusion weighted imaging, medication pretreatment, and early stroke were recorded. RESULTS: In patients with carotid stenosis, 7-day stroke risk was 8.3% (95% confidence interval [CI], 5.7-11.1) compared with 2.7% (CI, 2.0%-3.4%) without stenosis (P<0.0001; 90-day risks 17.8% and 5.7% [P<0.0001]). Among carotid stenosis patients, nonprocedural 7-day stroke risk was 3.8% (CI, 1.2%-9.7%) with statin treatment at TIA onset, compared with 13.2% (CI, 8.5%-19.8%) in those not statin pretreated (P=0.01; 90-day risks 8.9% versus 20.8% [P=0.01]). Statin pretreatment was associated with reduced stroke risk in patients with carotid stenosis (odds ratio for 90-day stroke, 0.37; CI, 0.17-0.82) but not nonstenosis patients (odds ratio, 1.3; CI, 0.8-2.24; P for interaction, 0.008). On multivariable logistic regression, the association remained after adjustment for ABCD2 score, smoking, antiplatelet treatment, recent TIA, and diffusion weighted imaging hyperintensity (adjusted P for interaction, 0.054). CONCLUSIONS: In acute symptomatic carotid stenosis, statin pretreatment was associated with reduced stroke risk, consistent with findings from randomized trials in acute coronary syndromes. These data support the hypothesis that statins started acutely after TIA symptom onset may also be beneficial to prevent early stroke. Randomized trials addressing this question are required.

Ciborinia camelliae (Sclerotiniaceae) induces variable plant resistance responses in selected species of Camellia.

Ciborinia camelliae is the causal agent of Camellia flower blight. This fungal pathogen is a significant pest of the Camellia floriculture industry because it specifically infects the floral tissue of ornamental camellia cultivars leading to the rapid development of necrotic lesions and blight. This study aims to characterize natural resistance to Ciborinia camelliae within a selection of Camellia spp. Based on macroscopic lesion development, Camellia 'Nicky Crisp' and Camellia lutchuensis were chosen as compatible and incompatible hosts, respectively. Microscopic analyses of the incompatible Camellia lutchuensis-Ciborinia camelliae interaction revealed several hallmarks of induced plant resistance, including papillae formation, H2O2 accumulation, and localized cell death. The compatible Camellia Nicky Crisp-Ciborinia camelliae interaction failed to trigger a similar resistance response. Ciborinia camelliae growth in compatible tissue demonstrated a switch from biotrophy to necrotrophy, evident from the simultaneous development of secondary hyphae and necrotic lesions. Extension of resistance analyses to 39 additional Camellia spp. identified variable levels of resistance within the Camellia genus. The evidence presented supports a resistance breeding strategy for controlling Ciborinia camelliae on ornamental Camellia hybrids.

Zinc acquisition and its contribution to Klebsiella pneumoniae virulence.

Klebsiella pneumoniae is a World Health Organization priority pathogen and a significant clinical concern for infections of the respiratory and urinary tracts due to widespread and increasing resistance to antimicrobials. In the absence of a vaccine, there is an urgent need to identify novel targets for therapeutic development. Bacterial pathogens, including K. pneumoniae, require the d-block metal ion zinc as an essential micronutrient, which serves as a cofactor for ~6% of the proteome. During infection, zinc acquisition necessitates the use of high affinity uptake systems to overcome niche-specific zinc limitation and host-mediated nutritional immunity. Here, we report the identification of ZnuCBA and ZniCBA, two ATP-binding cassette permeases that are highly conserved in Klebsiella species and contribute to K. pneumoniae AJ218 zinc homeostasis, and the high-resolution structure of the zinc-recruiting solute-binding protein ZniA. The Znu and Zni permeases appear functionally redundant with abrogation of both systems required to reduce K. pneumoniae zinc accumulation. Disruption of both systems also exerted pleiotropic effects on the homeostasis of other d-block elements. Zinc limitation perturbed K. pneumoniae cell morphology and compromised resistance to stressors, such as salt and oxidative stress. The mutant strain lacking both systems showed significantly impaired virulence in acute lung infection models, highlighting the necessity of zinc acquisition in the virulence and pathogenicity of K. pneumoniae.

Modeling first order additive × additive epistasis improves accuracy of genomic prediction for sclerotinia stem rot resistance in canola.

The fungus Sclerotinia sclerotiorum infects hundreds of plant species including many crops. Resistance to this pathogen in canola (Brassica napus L. subsp. napus) is controlled by numerous quantitative trait loci (QTL). For such polygenic traits, genomic prediction may be useful for breeding as it can capture many QTL at once while also considering nonadditive genetic effects. Here, we test application of common regression models to genomic prediction of S. sclerotiorum resistance in canola in a diverse panel of 218 plants genotyped at 24,634 loci. Disease resistance was scored by infection with an aggressive isolate and monitoring over 3 wk. We found that including first-order additive × additive epistasis in linear mixed models (LMMs) improved accuracy of breeding value estimation between 3 and 40%, depending on method of assessment, and correlation between phenotypes and predicted total genetic values by 14%. Bayesian models performed similarly to or worse than genomic relationship matrix-based models for estimating breeding values or overall phenotypes from genetic values. Bayesian ridge regression, which is most similar to the genomic relationship matrix-based approach in the amount of shrinkage it applies to marker effects, was the most accurate of this family of models. This confirms several studies indicating the highly polygenic nature of sclerotinia stem rot resistance. Overall, our results highlight the use of simple epistasis terms for prediction of breeding values and total genetic values for a complex disease resistance phenotype in canola.

Systematic review and pooled analysis of published and unpublished validations of the ABCD and ABCD2 transient ischemic attack risk scores.

BACKGROUND AND PURPOSE: The ABCD system was derived to predict early risk of stroke after transient ischemic attack. Independent validations have reported conflicting results. We therefore systematically reviewed published and unpublished data to determine predictive value and generalizability to different clinical settings and users. METHODS: Validations of the ABCD and ABCD2 scores were identified by searching electronic databases, reference lists, relevant journals, and conference abstracts. Unpublished tabulated data were obtained where available. Predictive value, expressed as pooled areas under the receiver operator characteristic curves (AUC), was calculated using random-effects meta-analysis, and analyses for heterogeneity were performed by categorization according to study setting and method. RESULTS: Twenty cohorts were identified reporting the performance of the ABCD system in 9808 subjects with 456 strokes at 7 days. Among the 16 studies of both the ABCD and ABCD2 scores, pooled AUC for the prediction of stroke at 7 days were 0.72 (0.66 to 0.78) and 0.72 (0.63 to 0.82), respectively (P diff=0.97). The pooled AUC for the ABCD and ABCD2 scores in all cohorts reporting relevant data were 0.72 (0.67 to 0.77) and 0.72 (0.63 to 0.80), respectively (both P<0.001). Predictive value varied significantly between studies (P<0.001), but 75% of the variance was accounted for by study method and setting, with the highest pooled AUC for face-to-face clinical evaluation and the lowest for retrospective extraction of data from emergency department records. CONCLUSION: Independent validations of the ABCD system showed good predictive value, with the exception of studies based on retrospective extraction of nonsystematically collected data from emergency department records.

Addition of brain infarction to the ABCD2 Score (ABCD2I): a collaborative analysis of unpublished data on 4574 patients.

BACKGROUND AND PURPOSE: The ABCD system was developed to predict early stroke risk after transient ischemic attack. Incorporation of brain imaging findings has been suggested, but reports have used inconsistent methods and been underpowered. We therefore performed an international, multicenter collaborative study of the prognostic performance of the ABCD(2) score and brain infarction on imaging to determine the optimal weighting of infarction in the score (ABCD(2)I). METHODS: Twelve centers provided unpublished data on ABCD(2) scores, presence of brain infarction on either diffusion-weighted imaging or CT, and follow-up in cohorts of patients with transient ischemic attack diagnosed by World Health Organization criteria. Optimal weighting of infarction in the ABCD(2)I score was determined using area under the receiver operating characteristic curve analyses and random effects meta-analysis. RESULTS: Among 4574 patients with TIA, acute infarction was present in 884 (27.6%) of 3206 imaged with diffusion-weighted imaging and new or old infarction was present in 327 (23.9%) of 1368 imaged with CT. ABCD(2) score and presence of infarction on diffusion-weighted imaging or CT were both independently predictive of stroke (n=145) at 7 days (after adjustment for ABCD(2) score, OR for infarction=6.2, 95% CI=4.2 to 9.0, overall; 14.9, 7.4 to 30.2, for diffusion-weighted imaging; 4.2, 2.6 to 6.9, for CT; all P<0.001). Incorporation of infarction in the ABCD(2)I score improved predictive power with an optimal weighting of 3 points for infarction on CT or diffusion-weighted imaging. Pooled areas under the curve increased from 0.66 (0.53 to 0.78) for the ABCD(2) score to 0.78 (0.72 to 0.85) for the ABCD(2)I score. CONCLUSIONS: In secondary care, incorporation of brain infarction into the ABCD system (ABCD(2)I score) improves prediction of stroke in the acute phase after transient ischemic attack.

Process of care and activity in a clinically inclusive ambulatory emergency care unit: progressive effect over time on clinical outcomes and acute medical admissions.

Clinically relevant outcomes for same-day emergency care provided by ambulatory emergency care units (AECs) are largely unknown. We report the activity and outcomes for a large UK adult AEC operating an ambulatory-care-by-default model without specific exclusion criteria. The AEC consultant triaged all acute medical referrals to either the AEC or the standard non-ambulatory 'take' pathway during AEC opening hours. The proportion of acute medical referrals seen in the AEC increased to 42% (mean 700 referrals seen per month) in the last 6 months of the study and numbers seen in the non-ambulatory pathway fell. The most common diagnoses were for chest pain, pneumonia, cellulitis, heart failure and urinary system disorders. Seventy-four point eight per cent of patients completed their care in a single visit. In the last calendar year, the conversion rate from AEC to inpatient admission was 12%, and the 30-day readmission rate was 6.9% and 18% for the AEC and non-ambulatory pathways, respectively. Across the whole study period, the 30-day mortality was 1.6% and 6.9% for the AEC and non-ambulatory pathway, respectively. This ambulatory approach is safe and effective.

Conservation and expansion of a necrosis-inducing small secreted protein family from host-variable phytopathogens of the Sclerotiniaceae.

Fungal effector proteins facilitate host-plant colonization and have generally been characterized as small secreted proteins (SSPs). We classified and functionally tested SSPs from the secretomes of three closely related necrotrophic phytopathogens: Ciborinia camelliae, Botrytis cinerea, and Sclerotinia sclerotiorum. Alignment of predicted SSPs identified a large protein family that share greater than 41% amino acid identity and that have key characteristics of previously described microbe-associated molecular patterns (MAMPs). Strikingly, 73 of the 75 SSP family members were predicted within the secretome of the host-specialist C. camelliae with single-copy homologs identified in the secretomes of the host generalists S. sclerotiorum and B. cinerea. To explore the potential function of this family of SSPs, 10 of the 73 C. camelliae proteins, together with the single-copy homologs from S. sclerotiorum (SsSSP3) and B. cinerea (BcSSP2), were cloned and expressed as recombinant proteins. Infiltration of SsSSP3 and BcSSP2 into host tissue induced rapid necrosis. In contrast, only one of the 10 tested C. camelliae SSPs was able to induce a limited amount of necrosis. Analysis of chimeric proteins consisting of domains from both a necrosis-inducing and a non-necrosis-inducing SSP demonstrated that the C-terminus of the S. sclerotiorum SSP is essential for necrosis-inducing function. Deletion of the BcSSP2 homolog from B. cinerea did not affect growth or pathogenesis. Thus, this research uncovered a family of highly conserved SSPs present in diverse ascomycetes that exhibit contrasting necrosis-inducing functions.

Transient ischaemic attack: clinical relevance, risk prediction and urgency of secondary prevention.

PURPOSE OF REVIEW: Transient ischaemic attack (TIA) is increasingly recognized as a harbinger of stroke and an important opportunity for secondary prevention. We have reviewed recent evidence on the burden of TIA and prediction and prevention of stroke in the acute phase. RECENT FINDINGS: Although recent data on the incidence and prevalence of TIA are lacking, available data suggest that the burden of TIA is higher than previously estimated and may be expected to increase with the ageing of the population. Prospective prognostic studies have shown that the early risk of stroke after TIA is approximately 5% at 7 days and 10-15% at 90 days depending on clinical settings and study methodology. This risk can be reliably predicted by risk scores based on clinical features (the ABCD system), TIA aetiology and findings on brain imaging, although the optimal combined prognostic strategy is uncertain because the interaction between individual predictors is not established. Studies of the urgent assessment and initiation of secondary prevention in specialist centres suggest that the early risk of stroke after TIA can be reduced by up to 80%. SUMMARY: The risk of stroke after TIA is considerable. However, recent advances have shown that this risk can be predicted for individuals and substantially reduced by appropriate secondary prevention measures.

The host generalist phytopathogenic fungus Sclerotinia sclerotiorum differentially expresses multiple metabolic enzymes on two different plant hosts.

Sclerotinia sclerotiorum is a necrotrophic fungal pathogen that infects upwards of 400 plant species, including several economically important crops. The molecular processes that underpin broad host range necrotrophy are not fully understood. This study used RNA sequencing to assess whether S. sclerotiorum genes are differentially expressed in response to infection of the two different host crops canola (Brassica napus) and lupin (Lupinus angustifolius). A total of 10,864 of the 11,130 genes in the S. sclerotiorum genome were expressed. Of these, 628 were upregulated in planta relative to in vitro on at least one host, suggesting involvement in the broader infection process. Among these genes were predicted carbohydrate-active enzymes (CAZYmes) and secondary metabolites. A considerably smaller group of 53 genes were differentially expressed between the two plant hosts. Of these host-specific genes, only six were either CAZymes, secondary metabolites or putative effectors. The remaining genes represented a diverse range of functional categories, including several associated with the metabolism and efflux of xenobiotic compounds, such as cytochrome P450s, metal-beta-lactamases, tannases and major facilitator superfamily transporters. These results suggest that S. sclerotiorum may regulate the expression of detoxification-related genes in response to phytotoxins produced by the different host species. To date, this is the first comparative whole transcriptome analysis of S. sclerotiorum during infection of different hosts.

Submaximal exercise cardiac output is increased by 4 weeks of sprint interval training in young healthy males with low initial Q̇-V̇O2: Importance of cardiac response phenotype.

Cardiovascular adaptations to exercise, particularly at the individual level, remain poorly understood. Previous group level research suggests the relationship between cardiac output and oxygen consumption ([Formula: see text]-[Formula: see text]) is unaffected by training as submaximal [Formula: see text] is unchanged. We recently identified substantial inter-individual variation in the exercise [Formula: see text]-[Formula: see text] relationship that was correlated to stroke volume (SV) as opposed to arterial oxygen content. Therefore we explored the effects of sprint interval training (SIT) on modulating [Formula: see text]-[Formula: see text] given an individual's specific [Formula: see text]-[Formula: see text] relationship. 22 (21±2 yrs) healthy, recreationally active males participated in a 4-week SIT (8, 20 second sprints; 4x/week, 170% of the work rate at [Formula: see text] peak) study with progressive exercise tests (PET) until exhaustion. Cardiac output ([Formula: see text] L/min; inert gas rebreathe, Finometer Modelflow™), oxygen consumption ([Formula: see text] L/min; breath-by-breath pulmonary gas exchange), quadriceps oxygenation (near infrared spectroscopy) and exercise tolerance (6-20; Borg Scale RPE) were measured throughout PET both before and after training. Data are mean Δ from bsl±SD. Higher [Formula: see text] ([Formula: see text]) and lower [Formula: see text] ([Formula: see text]) responders were identified post hoc (n = 8/group). SIT increased the [Formula: see text]-[Formula: see text] post-training in [Formula: see text] (3.8±0.2 vs. 4.7±0.2; P = 0.02) while [Formula: see text] was unaffected (5.8±0.1 vs. 5.3±0.6; P = 0.5). [Formula: see text] was elevated beyond 80 watts in [Formula: see text] due to a greater increase in SV (all P<0.04). Peak [Formula: see text] (ml/kg/min) was increased in [Formula: see text] (39.7±6.7 vs. 44.5±7.3; P = 0.015) and [Formula: see text] (47.2±4.4 vs. 52.4±6.0; P = 0.009) following SIT, with [Formula: see text] having a greater peak [Formula: see text] both pre (P = 0.02) and post (P = 0.03) training. Quadriceps muscle oxygenation and RPE were not different between groups (all P>0.1). In contrast to [Formula: see text], [Formula: see text] responders are capable of improving submaximal [Formula: see text]-[Formula: see text] in response to SIT via increased SV. However, the increased submaximal exercise [Formula: see text] does not benefit exercising muscle oxygenation.

A whole genome scan of SNP data suggests a lack of abundant hard selective sweeps in the genome of the broad host range plant pathogenic fungus Sclerotinia sclerotiorum.

The pathogenic fungus Sclerotinia sclerotiorum infects over 600 species of plant. It is present in numerous environments throughout the world and causes significant damage to many agricultural crops. Fragmentation and lack of gene flow between populations may lead to population sub-structure. Within discrete recombining populations, positive selection may lead to a 'selective sweep'. This is characterised by an increase in frequency of a favourable allele leading to reduction in genotypic diversity in a localised genomic region due to the phenomenon of genetic hitchhiking. We aimed to assess whether isolates of S. sclerotiorum from around the world formed genotypic clusters associated with geographical origin and to determine whether signatures of population-specific positive selection could be detected. To do this, we sequenced the genomes of 25 isolates of S. sclerotiorum collected from four different continents-Australia, Africa (north and south), Europe and North America (Canada and the northen United States) and conducted SNP based analyses of population structure and selective sweeps. Among the 25 isolates, there was evidence for two major population clusters. One of these consisted of 11 isolates from Canada, the USA and France (population 1), and the other consisted of nine isolates from Australia and one from Morocco (population 2). The rest of the isolates were genotypic outliers. We found that there was evidence of outcrossing in these two populations based on linkage disequilibrium decay. However, only a single candidate selective sweep was observed, and it was present in population 2. This sweep was close to a Major Facilitator Superfamily transporter gene, and we speculate that this gene may have a role in nutrient uptake from the host. The low abundance of selective sweeps in the S. sclerotiorum genome contrasts the numerous examples in the genomes of other fungal pathogens. This may be a result of its slow rate of evolution and low effective recombination rate due to self-fertilisation and vegetative reproduction.

Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack.

BACKGROUND: We aimed to validate two similar existing prognostic scores for early risk of stroke after transient ischaemic attack (TIA) and to derive and validate a unified score optimised for prediction of 2-day stroke risk to inform emergency management. METHODS: The California and ABCD scores were validated in four independent groups of patients (n=2893) diagnosed with TIA in emergency departments and clinics in defined populations in the USA and UK. Prognostic value was quantified with c statistics. The two groups used to derive the original scores (n=1916) were used to derive a new unified score based on logistic regression. FINDINGS: The two existing scores predicted the risk of stroke similarly in each of the four validation cohorts, for stroke risks at 2 days, 7 days, and 90 days (c statistics 0.60-0.81). In both derivation groups, c statistics were improved for a unified score based on five factors (age >or=60 years [1 point]; blood pressure >or=140/90 mm Hg [1]; clinical features: unilateral weakness [2], speech impairment without weakness [1]; duration >or=60 min [2] or 10-59 min [1]; and diabetes [1]). This score, ABCD(2), validated well (c statistics 0.62-0.83); overall, 1012 (21%) of patients were classified as high risk (score 6-7, 8.1% 2-day risk), 2169 (45%) as moderate risk (score 4-5, 4.1%), and 1628 (34%) as low risk (score 0-3, 1.0%). IMPLICATIONS: Existing prognostic scores for stroke risk after TIA validate well on multiple independent cohorts, but the unified ABCD(2) score is likely to be most predictive. Patients at high risk need immediate evaluation to optimise stroke prevention.

Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison.

BACKGROUND: The risk of recurrent stroke is up to 10% in the week after a transient ischaemic attack (TIA) or minor stroke. Modelling studies suggest that urgent use of existing preventive treatments could reduce the risk by 80-90%, but in the absence of evidence many health-care systems make little provision. Our aim was to determine the effect of more rapid treatment after TIA and minor stroke in patients who are not admitted direct to hospital. METHODS: We did a prospective before (phase 1: April 1, 2002, to Sept 30, 2004) versus after (phase 2: Oct 1, 2004, to March 31, 2007) study of the effect on process of care and outcome of more urgent assessment and immediate treatment in clinic, rather than subsequent initiation in primary care, in all patients with TIA or minor stroke not admitted direct to hospital. The study was nested within a rigorous population-based incidence study of all TIA and stroke (Oxford Vascular Study; OXVASC), such that case ascertainment, investigation, and follow-up were complete and identical in both periods. The primary outcome was the risk of stroke within 90 days of first seeking medical attention, with independent blinded (to study period) audit of all events. FINDINGS: Of the 1278 patients in OXVASC who presented with TIA or stroke (634 in phase 1 and 644 in phase 2), 607 were referred or presented direct to hospital, 620 were referred for outpatient assessment, and 51 were not referred to secondary care. 95% (n=591) of all outpatient referrals were to the study clinic. Baseline characteristics and delays in seeking medical attention were similar in both periods, but median delay to assessment in the study clinic fell from 3 (IQR 2-5) days in phase 1 to less than 1 (0-3) day in phase 2 (p<0.0001), and median delay to first prescription of treatment fell from 20 (8-53) days to 1 (0-3) day (p<0.0001). The 90-day risk of recurrent stroke in the patients referred to the study clinic was 10.3% (32/310 patients) in phase 1 and 2.1% (6/281 patients) in phase 2 (adjusted hazard ratio 0.20, 95% CI 0.08-0.49; p=0.0001); there was no significant change in risk in patients treated elsewhere. The reduction in risk was independent of age and sex, and early treatment did not increase the risk of intracerebral haemorrhage or other bleeding. INTERPRETATION: Early initiation of existing treatments after TIA or minor stroke was associated with an 80% reduction in the risk of early recurrent stroke. Further follow-up is required to determine long-term outcome, but these results have immediate implications for service provision and public education about TIA and minor stroke.

Reproducibility of peak oxygen consumption and the impact of test variability on classification of individual training responses in young recreationally active adults.

This study investigated whether VO2 peak is reproducible across repeated tests before (PRE) and after (POST) training, and whether variability across tests impacts how individual responses are classified following 3 weeks of aerobic exercise training (cycle ergometry). Data from 45 young healthy adults (age: 20·1 ± 0·9 years; VO2 peak, 42·0 ± 6·7 ml·min-1 ) from two previously published studies were utilized in the current analysis. Non-responders were classified as individuals who failed to demonstrate an increase or decrease in VO2 peak that was greater than 2·0 times the typical error of measurement (107 ml·min-1 ) away from zero, while responders and adverse responders were above and below this cut-off, respectively. VO2 peak tests at PRE (three total) and POST (three total) were highly reproducible (PRE and POST average and single measures ICCs: range 0·938-0·992), with low coefficients of variation (PRE:4·9 ± 3·1%, POST: 4·8 ± 2·7%). However, a potential learning effect was observed in the VO2 peak tests prior to training, as the initial pretraining test was significantly lower than the third (p = 0·010, PRE 1: 2 946 ± 924 ml·min-1 , PRE 3: 3 042 ± 919 ml·min-1 ). This resulted in fewer individuals classified as adverse responders for Test 3 compared to any combination of tests that included Test 1, suggesting that a single ramp test at baseline may not be sufficient to accurately classify the VO2 peak response in young recreationally active individuals. Thus, it is our recommendation that the initial VO2 peak test be used as a familiarization visit and not included for analysis.

Do interindividual differences in cardiac output during submaximal exercise explain differences in exercising muscle oxygenation and ratings of perceived exertion?

Considerable interindividual differences in the Q˙-V˙O2 relationship during exercise have been documented but implications for submaximal exercise tolerance have not been considered. We tested the hypothesis that these interindividual differences were associated with differences in exercising muscle deoxygenation and ratings of perceived exertion (RPE) across a range of submaximal exercise intensities. A total of 31 (21 ± 3 years) healthy recreationally active males performed an incremental exercise test to exhaustion 24 h following a resting muscle biopsy. Cardiac output (Q˙ L/min; inert gas rebreathe), oxygen uptake (V˙O2 L/min; breath-by-breath pulmonary gas exchange), quadriceps saturation (near infrared spectroscopy) and exercise tolerance (6-20; Borg Scale RPE) were measured. The Q˙-V˙O2 relationship from 40 to 160 W was used to partition individuals post hoc into higher (n = 10; 6.3 ± 0.4) versus lower (n = 10; 3.7 ± 0.4, P < 0.001) responders. The Q˙-V˙O2 difference between responder types was not explained by arterial oxygen content differences (P = 0.5) or peripheral skeletal muscle characteristics (P from 0.1 to 0.8) but was strongly associated with stroke volume (P < 0.05). Despite considerable Q˙-V˙O2 difference between groups, no difference in quadriceps deoxygenation was observed during exercise (all P > 0.4). Lower cardiac responders had greater leg (P = 0.027) and whole body (P = 0.03) RPE only at 185 W, but this represented a higher %peak V˙O2 in lower cardiac responders (87 ± 15% vs. 66 ± 12%, P = 0.005). Substantially lower Q˙-V˙O2 in the lower responder group did not result in altered RPE or exercising muscle deoxygenation. This suggests substantial recruitment of blood flow redistribution in the lower responder group as part of protecting matching of exercising muscle oxygen delivery to demand.