In search of Kipling's six honest serving men in upper limb rehabilitation: within participant case-crossover experiment nested within a web-based questionnaire.

PURPOSE: In search of Kipling's six honest serving men in upper limb rehabilitation after stroke, we sought to investigate clinicians' perspective of when and where to begin therapy, how much and what therapy to provide, and who and why (or not) to provide therapy.Materials & methods: Within-participant case cross-over experiments were nested within an anonymous web-based questionnaire (21 questions, three cases). Graph theory-based voting to produce ranked ordered lists and mixed-effect logistic regression were performed. RESULTS: In total, 225 Australian stroke clinicians responded: 53% occupational therapists, 61% working in acute/inpatient stroke setting. Most respondents indicated they did not have a protocol/expectation regarding when (62%), how much (84%) or what (60%) therapy to provide in their setting. Respondents ranked 24-h to 7-days post-stroke as the optimal time to commence therapy, and 30- to 60-min per day as the optimal dose to provide. Within-participant experiments demonstrated that greater motor recovery as time progressed increased the odds of offering therapy, while lack of motor recovery, shoulder pain, neurological decline and sole therapist reduced the odds. CONCLUSION: We need to develop an evidence base concerning Kipling's six honest serving men and equip clinicians with clinical decision-making skills aligned with this focus.IMPLICATIONS FOR REHABILITATIONMost clinicians did not have access to a protocol / clinical pathway which defines when, how much and what upper limb therapy to provide after stroke, which may be improved by providing individual clinicians with organisational support to make therapy decisions.To improve the personalisation of upper limb rehabilitation in clinical practice, we need to understand when and where after stroke to begin therapy, how much and what therapy to provide, as well as who and why (clinical decision-making) to provide therapy.Clinicians perceive clinical trials as successful if the therapy can demonstrate recovery that is greater than a minimal clinical important difference (MCID).

Thrombolysis and thrombectomy in patients treated with dabigatran with acute ischemic stroke: Expert opinion.

Systemic thrombolysis with rt-PA is contraindicated in patients with acute ischemic stroke anticoagulated with dabigatran. This expert opinion provides guidance on the use of the specific reversal agent idarucizumab followed by rt-PA and/or thrombectomy in patients with ischemic stroke pre-treated with dabigatran. The use of idarucizumab followed by rt-PA is covered by the label of both drugs.

A giant cause of stroke.

An 80 year old man presented subacutely with drowsiness and confusion. Subsequent MRI brain imaging demonstrated multiple posterior circulation infarcts. Extracranial vasculitis was suspected when his ESR was found to be high and vascular imaging showed multifocal irregular narrowing of both vertebral arteries. This was confirmed by targeted temporal artery biopsy, which showed chronic granulomatous inflammation typical of giant cell arteritis (GCA). The patient made a significant recovery following treatment with prednisolone.

The 2010 British Association of Stroke Physicians Survey of interventional treatments for stroke in the United Kingdom.

INTRODUCTION: The UK National Stroke Strategy (Department of Health 2007) states that patients should have access to a stroke service with neurointerventional capacity. This survey was conducted by the Clinical Standards Committee of the British Association of Stroke Physicians to get a snapshot of the availability of interventional treatments for stroke in the United Kingdom. METHODS: Questionnaires covering availability of endovascular treatments for stroke, e.g. intra-arterial thrombolysis and mechanical thrombectomy, were emailed to all British Association of Stroke Physicians members in October 2010. Where more than one response was received from the same hospital, the data were only entered once. If there was a discrepancy between different respondents for the same hospital, details were cross-checked with the respondents to ensure accuracy. RESULTS: Responses were received from 58 hospitals in England, Scotland, Wales, and Northern Ireland. Intra-arterial thrombolysis and/or mechanical thrombectomy were available in 23 hospitals. Of these, three had not performed any procedures in 2010. Twenty centres had conducted a mean (range) of eight (2-20) procedures during the 10-month period. Thirty-five hospitals were not offering endovascular treatments. Sixteen of these were not referring patients to centres which could provide interventional treatments. Hospitals offering endovascular treatments had a mean (range) of 5.2 (2-12) stroke physicians, 2.3 (0-4) interventional neuroradiologists, and 3.6 (0-9) noninterventional neuroradiologists. Only two hospitals providing interventions had four or more interventional neuroradiologists. CONCLUSIONS: Only a small number of hospitals in the United Kingdom provide interventional treatments for stroke. Almost 50% of hospitals not providing interventions had no processes in place for referral to providers.

Current practice of carotid endarterectomy in the UK.

BACKGROUND: Carotid endarterectomy (CEA) reduces the risk of stroke in patients with internal carotid stenosis of 50-99 per cent. This study assessed national surgical practice through audit of CEA procedures and outcomes. METHODS: This was a prospective cohort study of UK surgeons performing CEA, using clinical audit data collected continuously and reported in two rounds, covering operations from December 2005 to December 2007, and January 2008 to September 2009. RESULTS: Some 352 (92·6 per cent) of 380 eligible surgeons contributed data. Of 19,935 CEAs recorded by Hospital Episode Statistics, 12,496 (62·7 per cent) were submitted to the audit. A total of 10,452 operations (83·6 per cent) were performed for symptomatic carotid stenosis; among these patients, the presenting symptoms were transient ischaemic attack in 4507 (43·1 per cent), stroke in 3572 (34·2 per cent) and amaurosis fugax in 1965 (18·8 per cent). The 30-day mortality rate was 1·0 per cent (48 of 4944) in round 1 and 0·8 per cent (50 of 6151) in round 2; the most common cause of death was stroke, followed by myocardial infarction. The rate of death or stroke within 30 days of surgery was 2·5 per cent (124 of 4918) in round 1 and 1·8 per cent (112 of 6135) in round 2. CONCLUSION: CEA is performed less commonly in the UK than in other European countries and probably remains underutilized in the prevention of stroke. Increasing the number of CEAs done in the UK, together with reducing surgical waiting times, could prevent more strokes.

Standardizing the intensity of upper limb treatment in rehabilitation medicine.

OBJECTIVE: To describe a treatment protocol for the upper limb that standardizes intensity of therapy input regardless of the severity of presentation. DESIGN: The protocol is described (Part 1) and feasibility and effect explored (Part 2). SUBJECTS: Participants (n = 11) had a single ischaemic stroke in the middle cerebral artery territory more than one year previously, and had residual weakness of the hand with some extension present at the wrist and the ability to grasp. INTERVENTIONS: Following two baseline assessments, participants attended therapy for 1 hour a day for 10 consecutive working days. Treatment consisted of a combination of strength and functional task training. Outcomes were measured immediately after training, at one month and three months. OUTCOME MEASURES: Intensity was measured with Borg Rating of Perceived Exertion. Secondary outcome measures included Action Research Arm Test (ARAT), nine-hole peg test, and Goal Attainment Scale. RESULTS: Borg scores indicated that the level of intensity was appropriate and similar across all participants despite individual differences in the severity of their initial presentation (median (interquartile range) = 14 (13-15)). The mean ARAT score significantly increased by 6.8 points (chi(2)(3) = 15.618, P<0.001), and was maintained at three-month follow-up (z = - 2.384, P = 0.016). The nine-hole peg test also showed a main effect of time and 88% of goals set were achieved. CONCLUSIONS: The physiotherapy protocol standardized intensity of treatment by grading exercise and task-related practice according to the person's residual ability, rather than simply standardizing treatment times. It was feasible and well tolerated in this group.

Ganciclovir population pharmacokinetics in neonates following intravenous administration of ganciclovir and oral administration of a liquid valganciclovir formulation.

Cytomegalovirus (CMV) is the most common viral congenital infection, producing both sensorineural hearing loss and mental retardation. Our objective was to assess the population pharmacokinetics of a research-grade oral valganciclovir solution in neonates with symptomatic congenital CMV disease. Twenty-four neonates received 6 weeks of antiviral therapy. Ganciclovir and valganciclovir were measured by liquid chromatography/tandem mass spectroscopy. NONMEM version VI beta was used for population analyses. All profiles were consistent with a one-compartment model. Postnatal age, body surface area, and gender did not improve the model fit after body weight was taken into account. The typical value of clearance (l/h), distribution volume (l), and bioavailability of ganciclovir were 0.146 x body weight (WT)(1.68), 1.15 x WT, and 53.6%, respectively. Although these results cannot be extrapolated to extemporaneously compounded valganciclovir preparations, they provide the foundation on which a commercial-grade valganciclovir oral solution may be a viable option for administration to neonates.

Imaging of vertebral artery stenosis: a systematic review.

BACKGROUND AND PURPOSE: Posterior circulation stroke accounts for 20% of ischaemic strokes. Recent data suggest that the early stroke recurrence risk is high and comparable with carotid artery disease. Vertebral artery stenosis accounts for approximately 20% of posterior circulation stroke, and with endovascular treatment available accurate diagnostic imaging is important. We performed a systematic literature review to validate the accuracy of the non-invasive imaging techniques Duplex ultrasound (DUS), magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) in detecting severe vertebral artery stenosis, with intra-arterial angiography (IAA) as the reference standard. METHODS: We identified studies that used non-invasive imaging and IAA as the reference standard to determine vertebral artery stenosis and provided adequate data to calculate sensitivity and specificity. We analysed the quality of these studies, looked for evidence of heterogeneity and performed subgroup analysis for different degrees of stenosis. RESULTS: 11 studies categorised stenosis into 50-99%. The sensitivity of CTA (single study) and pooled sensitivities of contrast enhanced MRA (CE-MRA) and colour duplex were 100% (95% CI 15.8 to 100), 93.9% (79.8 to 99.3) and 70.2% (54.2 to 83.3), respectively. The specificities for CTA, CE-MRA and colour duplex were 95.2% (83.8 to 99.4), 94.8% (91.1 to 97.3) and 97.7% (95.2 to 99.1). However, specificities for CE-MRA and colour duplex demonstrated significant heterogeneity (p = 0.003 and p = 0.002, respectively). CONCLUSIONS: CE-MRA and possibly CTA may be more sensitive in diagnosing vertebral artery stenosis than DUS. However, data are limited and further high quality studies comparing DUS, MRA and CTA with IAA are required.

Temporal expression of inflammatory mediators in brain basilar artery vasculitis and cerebrospinal fluid of rabbits with coccidioidal meningitis.

Strokes due to transmural vasculitis associated with coccidioidal meningitis result in significant morbidity and mortality. The immunological and inflammatory processes responsible are poorly understood. To determine the inflammatory mediators, i.e. cytokines, chemokines, iNOS, matrix metalloproteinase-9 (MMP-9), that possibly contribute to vasculitis, temporal mRNA expression in brain basilar artery samples and MMP-9 protein in the CSF of male NZW rabbits infected intracisternally with 6.5 x 10(4) arthroconidia of Coccidioides immitis were assessed. Five infected and 3 sham-injected rabbits at each time point were euthanized 4, 9, 14 and 20 days post infection. All infected rabbits had neurological abnormalities and severe vasculitis in the basilar arteries on days 9-20. In basilar arteries of infected animals versus controls, mRNAs encoding for IL-6, iNOS, IFN-gamma, IL-2, MCP-1, IL-1beta, IL-10, TNF-alpha, CCR-1, MMP-9, TGF-beta, as well as MMP-9 protein in CSF, were found to be significantly up-regulated. Thus, this study identified inflammatory mediators associated with CNS vasculitis and meningitis due to C. immitis infection. Assessment of the individual contribution of each mediator to vasculitis may offer novel approaches to the treatment of coccidioidal CNS infection. This study also provides unique methodology for immunology studies in a rabbit model.

Invasive fungal infections in low-risk liver transplant recipients: a multi-center prospective observational study.

Prevention of invasive fungal infections (IFIs) in orthotopic liver transplant (OLT) recipients utilizing postoperative systemic antifungal prophylaxis, typically with fluconazole, is justified among those at high risk for IFI. Use of postoperative antifungal prophylaxis for low-risk OLT recipients is widely practiced but not universally accepted nor supported by data. We conducted a prospective observational study among 200 OLT recipients who were at low risk for IFI and did not receive postoperative antifungal prophylaxis. Patients were considered low risk if they had /=units of 40 blood products or return to the operating room for intra-abdominal bleeding; return to the operating room for anastomotic leak or vascular insufficiency; preoperative serum creatinine of >/=2 mg/dL; and perioperative Candida colonization. Patients were followed 100 d post-transplantation for evidence of IFI. Of 193 eligible patients, 7 (4%) developed an IFI. Three (2%) IFIs were due to Candida spp. and potentially preventable by standard fluconazole prophylaxis. Three patients developed invasive aspergillosis; one developed late onset disseminated cryptococcosis. Liver transplant recipients at low risk for IFI can be identified utilizing pre-determined criteria, and post-transplantation antifungal prophylaxis can be routinely withheld in these patients.

Serial MRI of a mycotic aneurysm of the cavernous carotid artery.

Cerebral mycotic or infective aneurysms are a rare complication of infectious illness, and such aneurysms of the intracavernous portion of the internal carotid artery are rare. They have been described as a consequence of cavernous sinus infection in an immunocompromised host, but not previously in a renal transplant recipient. We present such a case with serial MRI showing progression from arterial narrowing to aneurysm formation. Transcranial Doppler sonography of the middle cerebral artery showed distal asymptomatic embolisation from the aneurysm.

Vertebral artery origin angioplasty and primary stenting: safety and restenosis rates in a prospective series.

OBJECTIVES: To report a single centre ongoing experience of endovascular treatment for atherosclerotic vertebral artery origin stenosis in a series of symptomatic patients, with follow up imaging to determine the incidence of restenosis. METHODS: 14 patients with vertebral artery origin stenosis on catheter angiography were treated. Angioplasty without stenting was undertaken in the first four patients, all of whom had follow up catheter angiography at one year. Subsequently, patients were treated by primary stenting and followed up with colour Doppler ultrasound examination. RESULTS: The procedure was technically successful in all treated arteries, with no immediate complications. The degree of stenosis was reduced from (mean (SD)) 73 (18)% before treatment to 21 (26)% immediately after treatment in the angioplasty alone group (p = 0.059). In the primary stenting patients, the severity of stenosis was reduced from 82 (8)% to 13 (13)% immediately after treatment (p < 0.001). Restenosis to 70% or greater occurred at one year in all four patients initially treated by angioplasty without stenting. One patient subsequently developed further symptoms and was retreated by stenting. One of the 10 patients treated by primary stenting developed restenosis. None of the remaining patients had further posterior circulation ischaemic symptoms during a mean follow up period of 33.6 months (range 1 to 72 months). CONCLUSIONS: Restenosis occurs often after vertebral artery origin balloon angioplasty without stenting but is uncommon after stenting. Primary stenting is therefore recommended to maintain patency at this site, and had a low complication rate in this series.

Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy.

We conducted a case study of human immunodeficiency virus (HIV)-negative patients with cryptococcosis at 15 United States medical centers from 1990 through 1996 to understand the demographics, therapeutic approach, and factors associated with poor prognosis in this population. Of 306 patients with cryptococcosis, there were 109 with pulmonary involvement, 157 with central nervous system (CNS) involvement, and 40 with involvement at other sites. Seventy-nine percent had a significant underlying condition. Patients with pulmonary disease were usually treated initially with fluconazole (63%); patients with CNS disease generally received amphotericin B (92%). Fluconazole was administered to approximately two-thirds of patients with CNS disease for consolidation therapy. Therapy was successful for 74% of patients. Significant predictors of mortality in multivariate analysis included age > or =60 years, hematologic malignancy, and organ failure. Overall mortality was 30%, and mortality attributable to cryptococcosis was 12%. Cryptococcosis continues to be an important infection in HIV-negative patients and is associated with substantial overall and cause-specific mortality.

Clearance of fungal burden during treatment of disseminated histoplasmosis with liposomal amphotericin B versus itraconazole.

Animal studies have shown that fungal burden correlates with survival during treatment with new antifungal therapies for histoplasmosis. The purpose of this report is to compare the clearance of fungal burden in patients with histoplasmosis treated with liposomal amphotericin B versus itraconazole. In two separate closed clinical trials that evaluated the efficacy of liposomal amphotericin B and itraconazole treatment of disseminated histoplasmosis in patients with AIDS, blood was cultured for fungus and blood and urine were tested for Histoplasma antigen. The clinical response rates were similar; 86% with liposomal amphotericin B (n = 51) versus 85% with itraconazole (n = 59). Of the patients with positive blood cultures at enrollment, after 2 weeks of therapy cultures were negative in over 85% of the liposomal amphotericin B group versus 53% of the itraconazole group (P = 0.0008). Furthermore, after 2 weeks, median antigen levels in serum fell by 1.6 U in the liposomal amphotericin B group versus 0.1 U in the itraconazole group (P = 0.02), and those in urine fell by 2.1 U in the liposomal amphotericin B group and 0.2 U in the itraconazole group (P = 0.0005). The more rapid clearance of fungemia supports the use of liposomal amphotericin B rather than itraconazole for initial treatment of moderately severe or severe histoplasmosis.

Need for alternative trial designs and evaluation strategies for therapeutic studies of invasive mycoses.

Studies of invasive fungal infections have been and remain difficult to implement. Randomized clinical trials of fungal infections are especially slow and expensive to perform because it is difficult to identify eligible patients in a timely fashion, to prove the presence of the fungal infection in an unequivocal fashion, and to evaluate outcome in a convincing fashion. Because of these challenges, licensing decisions for antifungal agents have to date depended heavily on historical control comparisons and secondary advantages of the new agent. Although the availability of newer and potentially more effective agents makes these approaches less desirable, the fundamental difficulties of trials of invasive fungal infections have not changed. Therefore, there is a need for alternative trial designs and evaluation strategies for therapeutic studies of invasive mycoses, and this article summarizes the possible strategies in this area.

DNA fingerprinting of serial Candida albicans isolates obtained during itraconazole prophylaxis in patients with AIDS.

During a randomized double-blind placebo-controlled study testing the efficacy of itraconazole for prophylaxis of systemic and mucosal fungal infections in patients with acquired immune deficiency syndrome, 298 patients were enrolled with 295 evaluable. Of those, 46 patients were considered prophylaxis failures because of recurrent oral or esophageal candidiasis. Oropharyngeal fungal cultures were taken at the time of suspected thrush or Candida esophagitis, but not at baseline. All of the Candida spp. isolates were cultured on CHROMagar Candida medium then identified using API 20 AUX strips. Antifungal susceptibility testing was performed following the National Committee for Clinical Laboratory Standards M-27A guidelines. Sequential isolates were genotyped using randomly amplified polymorphic DNA. Polymerase chain reaction fingerprints were generated using two repetitive sequence primers, (GGA)7 and (GACA)4. The study group consisted of 23 patients, nine from the itraconazole arm and 14 from the placebo arm, who were prophylaxis failures and had more than two C. albicans isolates. Five of 23 had isolates showing a > or =4-fold reduction in susceptibility; four of these patients were in the itraconazole prophylaxis arm and one was in the placebo arm. Three of the five had yeast isolations showing changes in banding patterns over time. Such changes may indicate genetic changes in the same strain that could be linked to acquired resistance to itraconazole, or acquisition of a new strain, or emergence of a previously minor component of the original population.

Photoelastic stress analysis of strain patterns in equine hooves after four-point trimming.

OBJECTIVE: To evaluate changes in strain patterns in normal equine hooves following 4-point trimming, using photoelastic stress analysis. SAMPLE POPULATION: 15 equine front limbs with normal hoof configuration. PROCEDURE: Limbs were disarticulated at the carpometacarpal joint. Weight-bearing surfaces of each hoof were trimmed level to ensure 100% ground contact. Hoof walls were coated with a custom-made strain-sensitive plastic, and limbs were loaded to a third of body weight. Using a polariscope, strain distribution, magnitudes, and directions were evaluated in level hooves as well as before and after standardized 4-point trimming. Repeated-measures ANOVA was used to compare strain magnitudes and directions before and after trimming. RESULTS: In leveled specimens, strain fields were symmetrically distributed above the heels and at quarter-toe junctions along a line between the middle and distal thirds of the hoof wall. After 4-point trimming, strain epicenters localized above the contact points, whereas strain magnitudes significantly increased by approximately 50%. Decreasing contact area by 50% resulted in an additional significant increase (32%) in strain magnitude. Trimming did not have a significant effect on strain orientations. CONCLUSION AND CLINICAL RELEVANCE: This study documents that 4-point trimming results in strain concentration above the hoof contact points and that strain magnitude is dependent on contact area.