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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Contribution of central and peripheral adaptations to changes in maximal oxygen uptake following 4 weeks of sprint interval training.

The current study examined the contribution of central and peripheral adaptations to changes in maximal oxygen uptake (V̇O2max) following sprint interval training (SIT). Twenty-three males completed 4 weekly SIT sessions (8 × 20-s cycling bouts at ∼170% of work rate at V̇O2max, 10-s recovery) for 4 weeks. Following completion of training, the relationship between changes in V̇O2max and changes in central (cardiac output) and peripheral (arterial-mixed venous oxygen difference (a-vO2diff), muscle capillary density, oxidative capacity, fibre-type distribution) adaptations was determined in all participants using correlation analysis. Participants were then divided into tertiles on the basis of the magnitude of their individual V̇O2max responses, and differences in central and peripheral adaptations were examined in the top (HI; ∼10 mL·kg-1·min-1 increase in V̇O2max, p < 0.05) and bottom (LO; no change in V̇O2max, p > 0.05) tertiles (n = 8 each). Training had no impact on maximal cardiac output, and no differences were observed between the LO group and the HI group (p > 0.05). The a-vO2diff increased in the HI group only (p < 0.05) and correlated significantly (r = 0.71, p < 0.01) with changes in V̇O2max across all participants. Muscle capillary density (p < 0.02) and ß-hydroxyacyl-CoA dehydrogenase maximal activity (p < 0.05) increased in both groups, with no between-group differences (p > 0.05). Citrate synthase maximal activity (p < 0.01) and type IIA fibre composition (p < 0.05) increased in the LO group only. Collectively, although the heterogeneity in the observed V̇O2max response following 4 weeks of SIT appears to be attributable to individual differences in systemic vascular and/or muscular adaptations, the markers examined in the current study were unable to explain the divergent V̇O2max responses in the LO and HI groups.

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.

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.

Population Structure of Sclerotinia subarctica and Sclerotinia sclerotiorum in England, Scotland and Norway.

Sclerotinia species are important fungal pathogens of a wide range of crops and wild host plants. While the biology and population structure of Sclerotinia sclerotiorum has been well-studied, little information is available for the related species S. subarctica. In this study, Sclerotinia isolates were collected from different crop plants and the wild host Ranuculus ficaria (meadow buttercup) in England, Scotland, and Norway to determine the incidence of Sclerotinia subarctica and examine the population structure of this pathogen for the first time. Incidence was very low in England, comprising only 4.3% of isolates while moderate and high incidence of S. subarctica was identified in Scotland and Norway, comprising 18.3 and 48.0% of isolates respectively. Characterization with eight microsatellite markers identified 75 haplotypes within a total of 157 isolates over the three countries with a few haplotypes in Scotland and Norway sampled at a higher frequency than the rest across multiple locations and host plants. In total, eight microsatellite haplotypes were shared between Scotland and Norway while none were shared with England. Bayesian and principal component analyses revealed common ancestry and clustering of Scottish and Norwegian S. subarctica isolates while English isolates were assigned to a separate population cluster and exhibited low diversity indicative of isolation. Population structure was also examined for S. sclerotiorum isolates from England, Scotland, Norway, and Australia using microsatellite data, including some from a previous study in England. In total, 484 haplotypes were identified within 800 S. sclerotiorum isolates with just 15 shared between England and Scotland and none shared between any other countries. Bayesian and principal component analyses revealed a common ancestry and clustering of the English and Scottish isolates while Norwegian and Australian isolates were assigned to separate clusters. Furthermore, sequencing part of the intergenic spacer (IGS) region of the rRNA gene resulted in 26 IGS haplotypes within 870 S. sclerotiorum isolates, nine of which had not been previously identified and two of which were also widely distributed across different countries. S. subarctica therefore has a multiclonal population structure similar to S. sclerotiorum, but has a different ancestry and distribution across England, Scotland, and Norway.

The impact of work-matched interval training on V̇O2peak and V̇O2 kinetics: diminishing returns with increasing intensity.

High-intensity interval training (HIIT) improves peak oxygen uptake (V̇O2peak) and oxygen uptake (V̇O2) kinetics, however, it is unknown whether an optimal intensity of HIIT exists for eliciting improvements in these measures of whole-body oxidative metabolism. The purpose of this study was to (i) investigate the effect of interval intensity on training-induced adaptations in V̇O2peak and V̇O2 kinetics, and (ii) examine the impact of interval intensity on the frequency of nonresponders in V̇O2peak. Thirty-six healthy men and women completed 3 weeks of cycle ergometer HIIT, consisting of intervals targeting 80% (LO), 115% (MID), or 150% (HI) of peak aerobic power. Total work performed per training session was matched across groups. A main effect of training (p < 0.05) and a significant interaction effect was observed for V̇O2peak, with the change in V̇O2peak being greater (p < 0.05) in the MID group than the LO group; however, no differences were observed between the HI group and either the MID or LO groups (ΔV̇O2peak; LO, 2.7 ± 0.7 mL·kg(-1)·min(-1); MID, 5.8 ± 0.7; HI, 4.2 ± 1.0). The greatest proportion of responders was observed in the MID group (LO, 8/12; MID, 12/13; HI, 9/11). A nonsignificant relationship (p = 0.26; r(2) = 0.04) was found between the changes in V̇O2peak and τV̇O2. These results suggest that training at intensities around V̇O2peak may represent a threshold intensity above which further increases in training intensity provide no additional adaptive benefit. The dissociation between changes in V̇O2peak and V̇O2 kinetics also reflects the different underlying mechanisms regulating these adaptations.

Incidence of nonresponse and individual patterns of response following sprint interval training.

The current study sought to explore the incidence of nonresponders for maximal or submaximal performance following a variety of sprint interval training (SIT) protocols. Data from 63 young adults from 5 previously published studies were utilized in the current analysis. Nonresponders were identified using 2 times the typical error (TE) of measurement for peak oxygen uptake (2 × TE = 1.74 mL/(kg·min)), lactate threshold (2 × TE = 15.7 W), or 500 kcal time-to-completion (TTC; 2 × TE = 306 s) trial. TE was determined on separate groups of participants by calculating the test-retest variance for each outcome. The overall rate of nonresponders for peak oxygen uptake across all participants studied was 22% (14/63) with 4 adverse responders observed. No nonresponders for peak oxygen uptake were observed in studies where participants trained 4 times per week (n = 18), while higher rates were observed in most studies requiring training 3 times per week (30%-50%; n = 45). A nonresponse rate of 44% (8/18) and 50% (11/22) was observed for the TTC test and lactate threshold, respectively. No significant correlations were observed between the changes in peak oxygen uptake and TTC (r = 0.014; p = 0.96) or lactate threshold (r = 0.17; p = 0.44). The current analysis demonstrates a significant incidence of nonresponders for peak oxygen uptake and heterogeneity in the individual patterns of response following SIT. Additionally, these data support the importance of training dose and suggest that the incidence of nonresponse may be mitigated by utilizing the optimal dose of SIT.

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.

RApid Primary care Initiation of Drug treatment for Transient Ischaemic Attack (RAPID-TIA): study protocol for a pilot randomised controlled trial.

BACKGROUND: People who have a transient ischaemic attack (TIA) or minor stroke are at high risk of a recurrent stroke, particularly in the first week after the event. Early initiation of secondary prevention drugs is associated with an 80% reduction in risk of stroke recurrence. This raises the question as to whether these drugs should be given before being seen by a specialist--that is, in primary care or in the emergency department. The aims of the RAPID-TIA pilot trial are to determine the feasibility of a randomised controlled trial, to analyse cost effectiveness and to ask: Should general practitioners and emergency doctors (primary care physicians) initiate secondary preventative measures in addition to aspirin in people they see with suspected TIA or minor stroke at the time of referral to a specialist? METHODS/DESIGN: This is a pilot randomised controlled trial with a sub-study of accuracy of primary care physician diagnosis of TIA. In the pilot trial, we aim to recruit 100 patients from 30 general practices (including out-of-hours general practice centres) and 1 emergency department whom the primary care physician diagnoses with TIA or minor stroke and randomly assign them to usual care (that is, initiation of aspirin and referral to a TIA clinic) or usual care plus additional early initiation of secondary prevention drugs (a blood-pressure lowering protocol, simvastatin 40 mg and dipyridamole 200 mg m/r bd). The primary outcome of the main study will be the number of strokes at 90 days. The diagnostic accuracy sub-study will include these 100 patients and an additional 70 patients in whom the primary care physician thinks the diagnosis of TIA is possible, rather than probable. For the pilot trial, we will report recruitment rate, follow-up rate, a preliminary estimate of the primary event rate and occurrence of any adverse events. For the diagnostic study, we will calculate sensitivity and specificity of primary care physician diagnosis using the final TIA clinic diagnosis as the reference standard. DISCUSSION: This pilot study will be used to estimate key parameters that are needed to design the main study and to estimate the accuracy of primary care diagnosis of TIA. The planned follow-on trial will have important implications for the initial management of people with suspected TIA. TRIAL REGISTRATION: ISRCTN62019087.