The TWIST Tool Predicts When Patients Will Recover Independent Walking After Stroke: An Observational Study.

BACKGROUND: The likelihood of regaining independent walking after stroke influences rehabilitation and hospital discharge planning. OBJECTIVE: This study aimed to develop and internally validate a tool to predict whether and when a patient will walk independently in the first 6 months post-stroke. METHODS: Adults with stroke were recruited if they had new lower limb weakness and were unable to walk independently. Clinical assessments were completed one week post-stroke. The primary outcome was time post-stroke by which independent walking (Functional Ambulation Category score ≥ 4) was achieved. Cox hazard regression identified predictors for achieving independent walking by 4, 6, 9, 16, or 26 weeks post-stroke. The cut-off and weighting for each predictor was determined using ß-coefficients. Predictors were assigned a score and summed for a final TWIST score. The probability of achieving independent walking at each time point for each TWIST score was calculated. RESULTS: We included 93 participants (36 women, median age 71 years). Age < 80 years, knee extension strength Medical Research Council grade ≥ 3/5, and Berg Balance Test < 6, 6 to 15, or ≥ 16/56, predicted independent walking and were combined to form the TWIST prediction tool. The TWIST prediction tool was at least 83% accurate for all time points. CONCLUSIONS: The TWIST tool combines routine bedside tests at one week post-stroke to accurately predict the probability of an individual patient achieving independent walking by 4, 6, 9, 16, or 26 weeks post-stroke. If externally validated, the TWIST prediction tool may benefit patients and clinicians by informing rehabilitation decisions and discharge planning.

New Zealand hospital stroke service provision.

AIM: To describe stroke services currently offered in New Zealand hospitals and compare service provision in urban and non-urban settings. METHOD: An online questionnaire was sent to stroke lead clinicians at all New Zealand District Health Boards (DHBs). Questions covered number and location of stroke inpatients, stroke service configuration, use of guidelines/protocols, staffing mix, access to staff education, and culture appropriate care. RESULTS: There were responses from all 20 DHBs. Differences between urban and non-urban hospitals included: access to acute stroke units (55.6% non-urban vs 100% urban; p=0.013), stroke clinical nurse specialists (50% vs 90%; p=0.034), stroke clot retrieval (38.9% vs 80%; p=0.037) and Pacific support services (55.6% vs 100%; p=0.030). There were also differences in carer training (66.7% non-urban vs 100% urban; p=0.039) and goal-specific rehabilitation plans in the community (61.1% vs 100%; p=0.023). Access to TIA services, stroke rehabilitation units, early supported discharge, psychologists, continuing staff education, and culturally responsive stroke care were suboptimal irrespective of hospital location. CONCLUSION: Hospital location is associated with differences in stroke services provision across New Zealand and ongoing work is required to optimise consistent access to best practice care. These results, in conjunction with an ongoing (REGIONS Care) study, will be used to determine whether this affects patient outcomes.

Primary prevention of stroke and cardiovascular disease in the community (PREVENTS): Methodology of a health wellness coaching intervention to reduce stroke and cardiovascular disease risk, a randomized clinical trial.

Rationale Stroke is a major cause of death and disability worldwide, yet 80% of strokes can be prevented through modifications of risk factors and lifestyle and by medication. While management strategies for primary stroke prevention in high cardiovascular disease risk individuals are well established, they are underutilized and existing practice of primary stroke prevention are inadequate. Behavioral interventions are emerging as highly promising strategies to improve cardiovascular disease risk factor management. Health Wellness Coaching is an innovative, patient-focused and cost-effective, multidimensional psychological intervention designed to motivate participants to adhere to recommended medication and lifestyle changes and has been shown to improve health and enhance well-being. Aims and/or hypothesis To determine the effectiveness of Health Wellness Coaching for primary stroke prevention in an ethnically diverse sample including Maori, Pacific Island, New Zealand European and Asian participants. Design A parallel, prospective, randomized, open-treatment, single-blinded end-point trial. Participants include 320 adults with absolute five-year cardiovascular disease risk ≥ 10%, calculated using the PREDICT web-based clinical tool. Randomization will be to Health Wellness Coaching or usual care groups. Participants randomized to Health Wellness Coaching will receive 15 coaching sessions over nine months. Study outcomes A substantial relative risk reduction of five-year cardiovascular disease risk at nine months post-randomization, which is defined as 10% relative risk reduction among those at moderate five-year cardiovascular disease risk (10-15%) and 25% among those at high risk (>15%). Discussion This clinical trial will determine whether Health Wellness Coaching is an effective intervention for reducing modifiable risk factors, and hence decrease the risk of stroke and cardiovascular disease.

Prediction and characterization of enzymatic activities guided by sequence similarity and genome neighborhood networks.

Metabolic pathways in eubacteria and archaea often are encoded by operons and/or gene clusters (genome neighborhoods) that provide important clues for assignment of both enzyme functions and metabolic pathways. We describe a bioinformatic approach (genome neighborhood network; GNN) that enables large scale prediction of the in vitro enzymatic activities and in vivo physiological functions (metabolic pathways) of uncharacterized enzymes in protein families. We demonstrate the utility of the GNN approach by predicting in vitro activities and in vivo functions in the proline racemase superfamily (PRS; InterPro IPR008794). The predictions were verified by measuring in vitro activities for 51 proteins in 12 families in the PRS that represent ∼85% of the sequences; in vitro activities of pathway enzymes, carbon/nitrogen source phenotypes, and/or transcriptomic studies confirmed the predicted pathways. The synergistic use of sequence similarity networks3 and GNNs will facilitate the discovery of the components of novel, uncharacterized metabolic pathways in sequenced genomes.

The Structure-Function Linkage Database.

The Structure-Function Linkage Database (SFLD, http://sfld.rbvi.ucsf.edu/) is a manually curated classification resource describing structure-function relationships for functionally diverse enzyme superfamilies. Members of such superfamilies are diverse in their overall reactions yet share a common ancestor and some conserved active site features associated with conserved functional attributes such as a partial reaction. Thus, despite their different functions, members of these superfamilies 'look alike', making them easy to misannotate. To address this complexity and enable rational transfer of functional features to unknowns only for those members for which we have sufficient functional information, we subdivide superfamily members into subgroups using sequence information, and lastly into families, sets of enzymes known to catalyze the same reaction using the same mechanistic strategy. Browsing and searching options in the SFLD provide access to all of these levels. The SFLD offers manually curated as well as automatically classified superfamily sets, both accompanied by search and download options for all hierarchical levels. Additional information includes multiple sequence alignments, tab-separated files of functional and other attributes, and sequence similarity networks. The latter provide a new and intuitively powerful way to visualize functional trends mapped to the context of sequence similarity.

A multicenter, randomized, controlled study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits with Intra-Arterial therapy (EXTEND-IA).

BACKGROUND AND HYPOTHESIS: Thrombolysis with tissue plasminogen activator is proven to reduce disability when given within 4·5 h of ischemic stroke onset. However, tissue plasminogen activator only succeeds in recanalizing large vessel arterial occlusion in a minority of patients. We hypothesized that anterior circulation ischemic stroke patients, selected with 'dual target' vessel occlusion and evidence of salvageable brain using computed tomography or magnetic resonance imaging 'mismatch' within 4·5 h of onset, would have improved reperfusion and early neurological improvement when treated with intra-arterial clot retrieval after intravenous tissue plasminogen activator compared with intravenous tissue plasminogen activator alone. STUDY DESIGN: EXTEND-IA is an investigator-initiated, phase II, multicenter prospective, randomized, open-label, blinded-endpoint study. Ischemic stroke patients receiving standard 0·9 mg/kg intravenous tissue plasminogen activator within 4·5 h of stroke onset who have good prestroke functional status (modified Rankin Scale <2, no upper age limit) will undergo multimodal computed tomography or magnetic resonance imaging. Patients who also meet dual target imaging criteria: vessel occlusion (internal carotid or middle cerebral artery) and mismatch (perfusion lesion : ischemic core mismatch ratio >1·2, absolute mismatch >10 ml, ischemic core volume <70 ml) will be randomized to either clot retrieval with the Solitaire FR device after full dose intravenous tissue plasminogen activator, or tissue plasminogen activator alone. STUDY OUTCOMES: The coprimary outcome measure will be reperfusion at 24 h and favorable clinical response (reduction in National Institutes of Health Stroke Scale by ≥8 points or reaching 0-1) at day 3. Secondary outcomes include modified Rankin Scale at day 90, death, and symptomatic intracranial hemorrhage.

Differences between self-reported and verified adverse cardiovascular events in a randomised clinical trial.

OBJECTIVES: In clinical trials, adverse events are usually self-reported but may be adjudicated if serious or of particular interest. After adjudicating cardiovascular events for a 5-year calcium supplement trial, we observed discrepancies between self-reported and verified events. We systematically analysed those differences to assess their importance. DESIGN: Secondary analysis of adverse cardiovascular events in a 5-year, randomised, placebo-controlled trial of calcium supplementation (1 g calcium daily) in 1471 postmenopausal women (mean age 74 years). SETTING: Clinical research centre. METHODS: The participant's medical records were reviewed for all self-reported myocardial infarctions (MIs) or strokes, and the event independently adjudicated. Cause of death was obtained from hospital records or death certificates. To identify unreported events, the national hospital discharge database was searched and related hospital records were reviewed. RESULTS: 45 women reported 64 MIs, of which 33 (52%) were verified after adjudication. An additional 25 MIs were identified: 1 during adjudication of other events, 21 from the hospital discharge database, 3 from death certificates. 68 women reported 86 strokes of which 50 (58%) were verified. An additional 13 strokes were identified: 7 during adjudication of reported transient ischaemic attacks, 5 from the hospital discharge database, 1 from death certificates. Therefore, 43% of verified MIs and 21% of verified strokes were not reported to investigators. For non-adjudicated discharge codes, 10% of MIs and 22% of strokes were not verified after adjudication. Nineteen per cent of verified MIs and 27% of verified strokes were not identified in discharge coding or death certificates. Neither the event source nor the level of adjudication altered the relationship between treatment allocation and cardiovascular events. CONCLUSIONS: When adverse event accuracy is critical, researchers should consider adjudicating self-reported events and hospital discharge codes, and attempt to identify unreported events. TRIAL REGISTRATION: Australia New Zealand Clinical Trials registry: ACTRN 012605000242628.

Pythoscape: a framework for generation of large protein similarity networks.

Pythoscape is a framework implemented in Python for processing large protein similarity networks for visualization in other software packages. Protein similarity networks are graphical representations of sequence, structural and other similarities among proteins for which pairwise all-by-all similarity connections have been calculated. Mapping of biological and other information to network nodes or edges enables hypothesis creation about sequence-structure-function relationships across sets of related proteins. Pythoscape provides several options to calculate pairwise similarities for input sequences or structures, applies filters to network edges and defines sets of similar nodes and their associated data as single nodes (termed representative nodes) for compression of network information and output data or formatted files for visualization.

A multicentre, randomized, double-blinded, placebo-controlled Phase III study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND).

BACKGROUND AND HYPOTHESIS: Thrombolytic therapy with tissue plasminogen activator is effective for acute ischaemic stroke within 4·5 h of onset. Patients who wake up with stroke are generally ineligible for stroke thrombolysis. We hypothesized that ischaemic stroke patients with significant penumbral mismatch on either magnetic resonance imaging or computer tomography at three- (or 4·5 depending on local guidelines) to nine-hours from stroke onset, or patients with wake-up stroke within nine-hours from midpoint of sleep duration, would have improved clinical outcomes when given tissue plasminogen activator compared to placebo. STUDY DESIGN: EXtending the time for Thrombolysis in Emergency Neurological Deficits is an investigator-driven, Phase III, randomized, multicentre, double-blind, placebo-controlled study. Ischaemic stroke patients presenting after the three- or 4·5-h treatment window for tissue plasminogen activator and within nine-hours of stroke onset or with wake-up stroke within nine-hours from the midpoint of sleep duration, who fulfil clinical (National Institutes of Health Stroke Score ≥4-26 and prestroke modified Rankin Scale <2) will undergo magnetic resonance imaging or computer tomography. Patients who also meet imaging criteria (infarct core volume <70 ml, perfusion lesion : infarct core mismatch ratio >1·2, and absolute mismatch >10 ml) will be randomized to either tissue plasminogen activator or placebo. STUDY OUTCOME: The primary outcome measure will be modified Rankin Scale 0-1 at day 90. Clinical secondary outcomes include categorical shift in modified Rankin Scale at 90 days, reduction in the National Institutes of Health Stroke Score by 8 or more points or reaching 0-1 at day 90, recurrent stroke, or death. Imaging secondary outcomes will include symptomatic intracranial haemorrhage, reperfusion and or recanalization at 24 h and infarct growth at day 90.

The evolution of function in strictosidine synthase-like proteins.

The exponential growth of sequence data provides abundant information for the discovery of new enzyme reactions. Correctly annotating the functions of highly diverse proteins can be difficult, however, hindering use of this information. Global analysis of large superfamilies of related proteins is a powerful strategy for understanding the evolution of reactions by identifying catalytic commonalities and differences in reaction and substrate specificity, even when only a few members have been biochemically or structurally characterized. A comparison of >2500 sequences sharing the six-bladed ß-propeller fold establishes sequence, structural, and functional links among the three subgroups of the functionally diverse N6P superfamily: the arylesterase-like and senescence marker protein-30/gluconolactonase/luciferin-regenerating enzyme-like (SGL) subgroups, representing enzymes that catalyze lactonase and related hydrolytic reactions, and the so-called strictosidine synthase-like (SSL) subgroup. Metal-coordinating residues were identified as broadly conserved in the active sites of all three subgroups except for a few proteins from the SSL subgroup, which have been experimentally determined to catalyze the quite different strictosidine synthase (SS) reaction, a metal-independent condensation reaction. Despite these differences, comparison of conserved catalytic features of the arylesterase-like and SGL enzymes with the SSs identified similar structural and mechanistic attributes between the hydrolytic reactions catalyzed by the former and the condensation reaction catalyzed by SS. The results also suggest that despite their annotations, the great majority of these >500 SSL sequences do not catalyze the SS reaction; rather, they likely catalyze hydrolytic reactions typical of the other two subgroups instead. This prediction was confirmed experimentally for one of these proteins.

Mid-substance peroneal tendon defects augmented with an acellular dermal matrix allograft.

BACKGROUND: This study evaluated an acellular dermal matrix allograft augmentation for chronic mid-substance peroneous longus and brevis tendon tears. The hypothesis was that acellular dermal matrix allograft augmentation of chronic longitudinal mid-substance or complete tears of both peroneal tendons provides sufficient initial strength to allow a rapid rehabilitation program. MATERIALS AND METHODS: A consecutive series of mid-substance peroneal tendon tears with tissue loss was prospectively evaluated with demographic data, American Orthopaedic Foot and Ankle Society hindfoot-ankle scores, subjective questionnaires, and functional tests as well as physical examination, pre-operative radiographs, and MRIs. Surgical reconstruction consisted of direct tendon repair, fibular sulcus deepening, and ;;gap jumping'' tubular grafting augmentation using an acellular dermal matrix. A rapid rehabilitation protocol was followed. Eleven cases were included (9 females and 2 males). Average age was 46 (range, 29 to 62) years. Followup was 16.9 (range, 12 to 22) months. Two patients had prior surgery for instability, peroneal tendon debridement, and repair. Four patients had previous tenodesis. RESULTS: All showed extensive longitudinal tearing or complete peroneal tendon rupture on MRI. The mean postoperative AOFAS hindfoot score was 93.5 (range, 75 to 100). Four patients had 1 cm of calf atrophy. All patients were able to perform single-heel rise, had painless ankle and foot range of motion bilaterally, and eversion/inversion strength was within one half grade of strength of the contralateral side in all patients. No postoperative hindfoot varus was identified. CONCLUSION: An acellular dermal matrix graft provided an effective ;;gap jumping'' augmentation for repairs of chronic degenerative peroneal tendon tears.

Charge asymmetries in hydration of polar solutes.

We study the solvation of polar molecules in water. The center of water's dipole moment is offset from its steric center. In common water models, the Lennard-Jones center is closer to the negatively charged oxygen than to the positively charged hydrogens. This asymmetry of water's charge sites leads to different hydration free energies of positive versus negative ions of the same size. Here, we explore these hydration effects for some hypothetical neutral solutes, and two real solutes, with molecular dynamics simulations using several different water models. We find that, like ions, polar solutes are solvated differently in water depending on the sign of the partial charges. Solutes having a large negative charge balancing diffuse positive charges are preferentially solvated relative to those having a large positive charge balancing diffuse negative charges. Asymmetries in hydration free energies can be as large as 10 kcal/mol for neutral benzene-sized solutes. These asymmetries are mainly enthalpic, arising primarily from the first solvation shell water structure. Such effects are not readily captured by implicit solvent models, which respond symmetrically with respect to charge.

Changes in stroke care at Auckland Hospital between 1996 and 2001.

AIMS: In 1996, we performed a descriptive audit of stroke care in Auckland Hospital. Since then, a mobile stroke team has been established. We have repeated the 1996 audit to assess changes in stroke management. METHODS: From 1 June to 30 September 2001, information was prospectively recorded for all patients with stroke. RESULTS: There were 177 strokes in 175 patients (92 men, mean age 70.9, standard deviation [SD] 14.9 years). Ninety-seven percent of patients had cerebral imaging (median 4.5 hours; interquartile range [IQR] 2.7-11.6). Acute aspirin was given to 78% of patients in 2001 and 40% in 1996 (p <0.001). Twenty-four percent of patients were kept 'nil by mouth' for at least 24 hours (46% in 1996, p <0.001). At discharge, 73% of patients were taking antiplatelet or anticoagulant therapy (61% in 1996, p <0.001). Only 50% of the patients with elevated discharge blood pressures were taking antihypertensives. There had been a reduction in the mean length of hospital stay to 16 days (21 days in 1996) but no significant change in mortality (14% compared with 17% in 1996). CONCLUSION: A stroke service may increase the attention to the 'processes' of stroke care and use of therapies, which are shown to be of benefit in randomised controlled trials.

Stroke rehabilitation services in New Zealand.

AIMS: To obtain an overall picture of the organisation of stroke rehabilitation services throughout New Zealand and to see if this is consistent with recommendations in evidence-based guidelines. METHODS: A questionnaire was sent to all hospitals in New Zealand. This included questions about access to organised stroke rehabilitation, guidelines for the management of common problems after stroke, and the use of audit. RESULTS: All 48 hospitals surveyed responded, with 37 providing inpatient stroke rehabilitation services. Only one hospital (serving 9% of the population) provided a dedicated, inpatient stroke rehabilitation facility. In the other 36 hospitals, stroke rehabilitation was performed in assessment, treatment and rehabilitation units (25 hospitals, 84%) or general medical wards (8 hospitals, 7%). Only 57% of the population had access to hospitals with a nominated lead clinician for stroke rehabilitation services. Thirty per cent were served by hospitals without a multidisciplinary therapy team expert in stroke care. Guidelines for the management of common problems following stroke were used in most hospitals. Only 8 hospitals (28%) had audited their stroke rehabilitation services. CONCLUSIONS: The organisation and type of rehabilitation services available for people with stroke are not consistent with best practice or accepted guidelines. The development of an organised approach to stroke rehabilitation services in New Zealand must be seen as a priority.