Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS. METHODS: The lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with ALS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31. FINDINGS: Between May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54 (50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log-rank χ(2) on 1 df=1·64; p=0·20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0·71 (95% CI 0·40-1·24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event. INTERPRETATION: We found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments. FUNDING: The Motor Neurone Disease Association of Great Britain and Northern Ireland.

Contrasting effects of physical wear on elution of two antibiotics from orthopedic cement.

The use of antibiotics as a supplement to bone cement for the purposes of providing a local release of antibiotics is common practice in arthroplasty surgery and the kinetics of elution of the antibiotics in such systems have been investigated previously. However, in these previous studies no account was taken of the potential effects that wear may have on the elution kinetics of the antibiotic. Here, we have modified an existing wear testing rig to allow the simultaneous study of the elution kinetics of bone cement samples containing antibiotics being subjected to immersion only and immersion and conjoint wear. The results show contrasting effects with two commonly used antibiotics. Bone cement containing daptomycin showed no substantial change in antibiotic elution due to wear, while cement containing gentamicin (the most commonly used antibiotic in this application) in contrast demonstrated a substantial reduction in the rate of antibiotic elution when wear was applied. Scanning electron microscopy revealed a possible explanation for these diverse results, due to wear-induced "sealing" of the surface in conjunction with the crystal morphology of the antibiotic.

Fentanyl HCl iontophoretic transdermal system versus morphine IV-PCA for postoperative pain management: survey of healthcare provider opinion.

OBJECTIVE: This survey estimated differences in staff time requirements between fentanyl HCl iontophoretic transdermal system (fentanyl ITS) and intravenous patient-controlled analgesia (IV-PCA) in post-operative pain management. RESEARCH DESIGN AND METHODS: European Delphi panels of nurses and anaesthesiologists, who had practical experience with both fentanyl ITS and IV-PCA, were provided a task list, developed from a previous clinical trial, associated with each modality. The panellists were asked to estimate time spent on each task. Estimates were calculated by multiplying the estimated patient proportion for whom the task was performed by the expected frequency of task performance, by the estimated task time. RESULTS: Data is presented as mean minutes (standard deviation). Fentanyl ITS use was estimated to save an average of 68.7 min total staff time per patient per treatment period compared to IV-PCA (86.5 (20.3)) vs. 156.4 (55.2); respectively; p < 0.001), the largest amount of savings being in the 'Setup' category (19.4 (6.7) vs. 47.8 (17.5), respectively; p < 0.001), and mostly due to IV-PCA task elimination. Significant time savings were estimated using fentanyl ITS over IV-PCA in the 'Discontinuation' category (4.8 (2.4) vs. 20.6 (3.3), respectively; p < 0.001). Panellists agreed that fentanyl ITS use would decrease staff assistance time required for helping patients during self-care routines and it may also decrease the patient's time to ambulation. Survey limitations included: possible recall bias due to the observational nature of the data; task list descriptions resulting in possible double-counting of data; no sensitivity analyses; and the declarative nature of the responses possibly leading to a dilution of survey findings. CONCLUSIONS: Fentanyl ITS use was estimated, by expert opinion, to require 44% less staff time than IV-PCA use.

Ultrasound surveillance of ectatic abdominal aortas.

INTRODUCTION: Some studies have considered abdominal aortas of 2.6-2.9 cm diameter (ectatic aortas) at age 65 years as being abnormal and have recommended surveillance, whereas others have considered these normal and surveillance unnecessary. It is, therefore, not clear how to manage patients with an initial aortic diameter between 2.6-2.9 cm detected at screening. The aim of this study was to evaluate growth rates of ectatic aortas detected on initial ultrasound screening to determine if any developed into clinically significant abdominal aortic aneurysms (AAAs; > 5.0 cm) and clarify the appropriate surveillance intervals for these patients. PATIENTS AND METHODS: Data were obtained from a prospective AAA screening programme which commenced in 1992. The group of patients with initial aortic diameters of 2.6-2.9 cm with a minimum of 1-year follow-up were included in this study (Group 2). This was further divided into two subgroups (Groups 3a and 3b) based on a minimum follow-up interval obtained from outcome analysis. Mean growth rate was calculated as change in aortic diameter with time. The comparison of growth rates in Groups 3a and 3b was performed using the t-test. The number and proportion of AAAs that expanded to >or= 3.0 cm and >or= 5.0 cm in diameter were also calculated. RESULTS: Out of 999 patients with AAA >or= 2.6 cm with minimum 1-year follow-up, 358 (36%) were classified as ectatic aortas (2.6-2.9 cm) at initial ultrasound screening with the mean growth rate of 1.69 mm/year (95% CI, 1.56-1.82 mm/year) with a mean follow-up of 5.4 years. Of these 358 ectatic aortas, 314 (88%) expanded into >or= 3.0 cm, 45 (13%) expanded to >or= 5.0 cm and only 8 (2%) expanded to >or= 5.5 cm over a mean follow-up of 5.4 years (range, 1-14 years). No ectatic aortas expanded to >or= 5.0 cm within the first 4 years of surveillance. Therefore, the minimum follow-up interval was set at 4 years and this threshold was then used for further analysis. The mean growth rate in Group 3a (< 5.0 cm at last scan) was 1.33 mm/year (95% CI, 1.23-1.44 mm/year) with a mean follow-up of 7 years compared to Group 3b (>or= 5.0 cm at last scan) with the mean growth rate of 3.33 mm/year (95% CI 3.05-3.61 mm/year) and a mean follow-up of 8 years. The comparison of mean growth rates between Groups 3a and 3b is statistically significant (t-test; T = 13.00; P < 0.001). CONCLUSIONS: One-third of patients undergoing AAA screening will have ectatic aortas (2.6-2.9 cm) and at least 13% of these will expand to a size of >or= 5.0 cm over a follow-up of 4-14 years. A threshold diameter of 2.6 cm for defining AAAs in a screening programme is recommended and ectatic aortas detected at age 65 years can be re-screened at 4 years after the initial scan. A statistically significant difference was found in the growth rates of ectatic aortas with minimum 4 years follow-up, expanding to >or= 5.0 cm compared to those less than 5.0 cm at last surveillance scan. Further studies are required to test the hypothesis of whether growth rate over the first 4 years of surveillance will identify those who are most likely to expand to a clinically significant size (> 5.0 cm).

Predictive value of common symptom combinations in diagnosing colorectal cancer.

BACKGROUND: This study compared the diagnostic values of age and single symptoms of colorectal cancer with those of age and symptom combinations. METHODS: Consecutive patients with lower gastrointestinal symptoms referred to a surgical clinic over a 12-year period were studied prospectively. The diagnostic value of age and common symptoms of bowel cancer, individually and in combination, was determined by measuring positive predictive value, sensitivity and specificity. RESULTS: In total, 467 (5.5 per cent) of 8529 patients had colorectal cancer. Symptom combination analyses showed that patients presenting with rectal bleeding and change in bowel habit without anal symptoms had the highest risk of cancer. Those with rectal bleeding and perianal symptoms without change in bowel habit were at the lowest risk of having cancer. Symptom subgroups defined by age had positive predictive values for cancer that varied from less than 1 to 35 per cent. CONCLUSION: Symptom combinations defined by age have greater diagnostic value than single symptoms alone.

A study of the routine use of venous photoplethysmography in a one-stop vascular surgery clinic.

INTRODUCTION: The decision to offer surgical treatment for varicose veins should be based on objective evidence of venous dysfunction and not only the subjective appearance or the reported symptoms. Special tests are required to identify the sub-group of patients with functional superficial venous reflux accurately. The initial test should be simple, cheap, objective, sensitive and easy to perform by a wide range of staff in order to screen out patients without reflux. The final test should be anatomically specific to identify the appropriate surgical procedure. The aim of this study was to test the feasibility of using photoplethysmography (PPG) as the initial test as part of a one-stop vascular clinic assessment protocol. PATIENTS AND METHODS: All patients referred to one consultant over a 68-week period were assessed using standard practice for the first 22 weeks and with an objective assessment protocol based on PPG for the subsequent 46 weeks. RESULTS: A total of 347 out-patient appointments for patients with venous disease were booked: 239 (69%) were new referrals. Of the new patients, 59% were CEAP C2/3 and 23% were CEAP C4-6. The introduction of the objective assessment protocol was associated with a reduction in patients offered surgery from 39% to 24% overall and 51% to 28% in new patients with CEAP C2. There was a corresponding increase in the number of patients discharged back to the GP from 19% to 29% overall and 17% to 32%, respectively. The number of patients referred for duplex ultrasound fell slightly from 26% to 22%. Overall, there was a significant change in practice between the two periods (chi(2) = 13.3; df = 3; P = 0.004). CONCLUSIONS: The introduction of an objective assessment protocol based on PPG as the initial objective test reduces the number of patients offered surgery based on objective evidence of venous dysfunction.

Use of ulcer size and initial responses to treatment to predict the healing time of leg ulcers.

OBJECTIVE: To test the following two hypotheses: the initial healing profiles of individual leg ulcers determine the longer-term outcome; healing time can be predicted from an initial ulcer size measurement and a sequence of further measurements recorded after treatment has started. METHOD: Twenty-three patients with venous leg ulcers were studied (10 male, 13 female). Digital images of the ulcers were taken at weekly intervals; ulcer size was measured electronically and the information stored in an electronic patient record. The healing profile for each ulcer was analysed by linear regression using the correlation coefficient (r) to indicate linearity. For [r] > 0.85 ([r] = modulus of r, [where r is negative], that is good linearity and hence wound healing), the predicted healing time was calculated from the initial size (cm2) and initial healing rate (cm2/week), and was compared with the actual healing time. RESULTS: The majority of ulcers (17/23) healed with linearity ([r] > 0.85). For these ulcers there was agreement between the predicted healing time and the actual healing time (correlation coefficient 0.95). CONCLUSION: Venous ulcers that respond to treatment appear to heal at a near constant rate. The initial response to treatment can be used to reliably estimate the healing time.

Measuring sub-bandage pressure: comparing the use of pressure monitors and pulse oximeters.

OBJECTIVE: To test the use of low-cost sub-bandage pressure monitors and pulse oximeters as part of a quality-control measure for graduated compression bandaging in leg ulcer clinics. METHOD: Twenty-five healthy volunteers (mean age 40 years) providing 50 limbs were bandaged with a four-layer compression bandaging system. The ankle systolic pressure (ASP) was measured using a pulse oximeter (Nellcor NBP-40) before applying the graduated compression bandages. Interface pressure was measured by placing pressure sensors on the skin at three points (2cm above the medial malleolus; the widest part of the calf; and a point midway between them) in the supine and standing positions. The ASP was measured again with the pulse oximeter after the bandage had been applied, and the effect of the bandage on the ASP was recorded. The actual pressure created by the bandage was compared with the required pressure profile. RESULTS: Interface pressures varied with change of position and movement. With the operator blinded to the pressure monitors while applying the bandages, the target pressure of 35-40mmHg at the ankle was achieved in only 36% of limbs ([mean +/- 95% confidence interval]; 32.3 +/- 1.6mmHg [supine]; 38.4 +/- 2.4mmHg [standing position]). With the help of the pressure monitors, the target pressure was achieved in 78% of the limbs. There was no correlation between the pressure monitors and pulse oximeter pressures, demonstrating that the pulse oximeter is not a useful tool for measuring sub-bandage pressures. CONCLUSION: The results suggest a tool (interface pressure monitors) that is easy to operate should be available as part of quality assurance for treatment, training of care providers and education.

Gender, ageing, and injustice: social and political contexts of bioethics.

There has been considerable work in bioethics addressing injustice and gender oppression in the provision of healthcare services, in the interaction between client and healthcare professional, and in allocation of healthcare services within a particular hospital or health service. There remain several sites of continued injustice that can only be addressed adequately from a broader analytical perspective, one that attends to the social and political contexts framing healthcare policy and practice. Feminist bioethicists have a strong track record in providing this kind of analysis. Using current Australian aged care and welfare policy this paper demonstrates some of the ways in which issues of gender, age, and social inequity shape bioethical debate, policy, and practice in the areas of aged care and welfare provision. The author develops an argument that demonstrates the gender injustice underlying health care and welfare policy. This argument recognises the inevitability of human dependency relations, and questions the adequacy of current political theories to address the requirements for full and equal citizenship. The author shows that an adequate analysis of the ethics of aged healthcare depends on sufficient consideration of the social and political context within which healthcare policy is framed and an adequate understanding of human dependency.

Evaluation of simple criteria to predict successful weaning from mechanical ventilation in intensive care patients.

BACKGROUND: There is increasing evidence that weaning protocols improve outcome from mechanical ventilation, but it is unclear how best to implement such protocols in large intensive care units. We evaluated a checklist of simple bedside criteria to determine whether it could be used reliably to predict successful discontinuation of mechanical ventilation. METHODS: We carried out a prospective observational cohort study in a 12-bedded general intensive care unit (ICU). We developed a checklist of metabolic, cardiorespiratory and neurological criteria that suggested that patients should start the weaning process. We performed daily assessments throughout ICU stay and recorded whether the criteria were met. Ultimate ventilator independence was used as the reference standard. RESULTS: We studied 325 sequential admissions to the ICU. Data were available for 98% of patients; 97% of admissions were mechanically ventilated on admission to ICU. Overall, 205 of the 308 ventilated patients (67%) achieved ventilator independence during ICU admission; the other patients died or were transferred ventilated to other ICUs. Eighty-three per cent of the patients who achieved ventilator independence met the set criteria. Fulfilling the criteria was a moderately strong predictor of ultimate ventilator independence: specificity 89%, positive predictive value 94%, positive likelihood ratio (LR) 7.6. When we analysed data by the day from admission on which patients were examined, the test was a strong predictor of subsequent ventilator independence when criteria were met by day 1 (LR 11.1) or day 2 (LR 6.9), but weaker when met by more than/equal to 4 days (LR <3). Patients who met criteria after more than/equal to 4 days often had prolonged weaning and a high incidence of re-intubation. Patients who achieved ventilator independence without fulfilling the criteria (n=35) had a short duration of mechanical ventilation (median 2 days, interquartile range 1-3 days). The most frequent reason for failing criteria before ventilator independence was a Pa(O(2))/FI(O(2)) ratio less than 24 kPa (49% of cases). CONCLUSIONS: A simple checklist can assist nurse assessment of suitability for weaning and could be used as a trigger to commence a weaning protocol. The day on which criteria are met is a useful way of stratifying patients for likely patterns of weaning.

The haemodynamics of multiple sequential stenoses and the criteria for a critical stenosis.

INTRODUCTION: Occlusive arterial disease is usually multi-focal but the cumulative functional effect of multiple arterial stenoses is not fully understood. We tested the hypothesis that a non-linear pressure/flow model (DeltaP=k1Q+k2Q2) that has been validated for single stenoses is also valid for multiple stenoses arranged in series. METHOD: The pressure/flow characteristics of three dissimilar modelled stenoses were measured individually and in different combinations using a hydraulic flow rig. RESULTS: The combined effect of multiple stenoses fitted the non-linear model accurately (R2=0.99) and approximated to the sum of the k1 and k2 parameters for each individual stenosis. For multiple stenoses the cumulative k1 was less than the predicted and the series order of the individual stenoses consistently altered the combined effect. CONCLUSIONS: A sequence of multiple stenoses is functionally equivalent to a single equivalent stenosis of greater functional severity and can be represented by a single viscous (k1) and inertial (k2) pressure loss coefficient. This finding allows the term 'critical stenosis' to be defined precisely in terms of the functional effect rather than the anatomical appearance, particularly where disease is multi-focal.

Clinical evaluation of a continuous oxygen consumption monitor in mechanically ventilated patients.

We measured oxygen consumption using a new noninvasive modular metabolic monitor, M-COVX trade mark, in ventilated critically ill patients. Oxygen consumption was measured continuously as part of routine monitoring for up to 24 h following mechanical ventilation in 27 patients admitted to a general intensive care unit. We explored several possible sources of error. Most errors related to inaccurate tidal volume measurement, which resulted in rejection of a median 14% (interquartile range 8-34%) of data. Water accumulation in the pneumotachograph was responsible and occurred more frequently with water bath humidifiers. After manual removal of erroneous data mean oxygen consumption values were virtually identical to calculated values in 24 of 27 patients. We conclude that in most ventilated patients averaging of continuous oxygen consumption data with the M-COVX module results in small errors.

The haemodynamics of asymmetric stenoses.

OBJECTIVE: Occlusive arterial disease is usually irregular with both symmetric (concentric) and asymmetric (eccentric) stenoses. Knowledge of the effect of stenosis geometry on stenosis haemodynamics is necessary to correctly interpret tests that measure stenosis severity anatomically. The independent haemodynamic effect of stenosis asymmetry has not been described. DESIGN: In vitro flow-rig measurement of the steady pressure/flow behaviour of rigid, 20mm long, square-ended symmetric and asymmetric stenoses in a 6.7-mm diameter tube using a blood analogue (40% glycerol). RESULTS: All stenoses, irrespective of geometry, had a linear resistance (R) to flow (Q) relationship such that R=k(1)+ k(2)Q where k(1) and k(2) are constants (corr>0.99, p<0.05). Asymmetry was found to have a significant haemodynamic effect if the stenosis severity is expressed as a diameter reduction but no effect if stenosis severity is expressed as an area reduction. The maximum flow for an inflow pressure of 90mmHg (Q(90)) fell from 2050 to 280ml/min as stenosis area reduction increased from 80% to 96%. CONCLUSIONS: Arterial stenoses exhibit flow-dependent resistance irrespective of their geometry. The effect of stenosis asymmetry can only be ignored if anatomical severity is expressed as a percentage area reduction. A clinically useful measure of stenosis severity is the maximum flow for a given inflow pressure.

Digital imaging versus conventional contact tracing for the objective measurement of venous leg ulcers.

OBJECTIVE: This study aimed to compare the accuracy and inter-observer reproducibility of leg ulcer measurements made using digital images and conventional contact tracing. METHOD: The accuracy of measurements made with these two methods by four observers of 11 shapes with a known area was assessed. The time taken to do this was also measured. Following this, the accuracy and inter-observer reproducibility of the two methods was measured for patients with leg ulcers presenting to the vascular clinic, with contact tracing as the reference. RESULTS: For the reference shapes, both methods had a mean error of less than 5%. Contact tracing significantly underestimated the area by 3.9% (p < 0.05), while digital tracing showed no significant error. Digital tracing was quicker than contact tracing, especially for larger shapes (p < 0.05). For leg ulcers, there was no significant difference between area measurements made by the two methods. Inter-observer variation of digital tracing was greater for the ulcers than the reference shapes. This was due to differences in subjective interpretation and technical problems in recording some images. CONCLUSION: Measurement of leg ulcer area using computer-aided tracing of digital camera images is more accurate and quicker than contact tracing provided that appropriate care is taken when taking the pictures. Digital images offer considerable advantages in the shared hospital-community care of patients with leg ulcers.

Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice.

Endothelial cell progenitors, angioblasts, have been detected in the peripheral blood of adult humans, mice, and rabbits. These cells have been shown to incorporate into the endothelium of newly forming blood vessels in pathological and nonpathological conditions. Here we investigated the possibility that the CD34-expressing leukocytes (CD34(+) cells) that appear to be enriched for angioblasts could be used to accelerate the rate of blood-flow restoration in nondiabetic and diabetic mice undergoing neovascularization due to hindlimb ischemia. CD34(+) cells did not accelerate the restoration of flow in nondiabetic mice, but dramatically increased it in diabetic mice. Furthermore, CD34(+) cells derived from type 1 diabetics produced fewer differentiated endothelial cells in culture than did their type 2 diabetic- or nondiabetic-derived counterparts. In vitro experiments suggest that hyperglycemia per se does not alter the ability of angioblasts to differentiate or of angioblast-derived endothelial cells to proliferate. In contrast, hyperinsulinemia may enhance angioblast differentiation but impair angioblast-derived endothelial cell survival or proliferation. Our findings suggest that CD34(+) cells may be a useful tool for therapeutic angiogenesis in diabetics.

Integrating mental health services into primary care for HIV-infected pregnant and non-pregnant women: Whole Life--a theoretically derived model for clinical care and outcomes assessment.

Poor women of color who are disproportionately both infected and affected by HIV/AIDS also face multiple lifestyle and psychosocial burdens that complicate effective delivery of health care, thereby contributing to their poorer prognosis. Addressing these factors within the context of HIV/AIDS primary care for women is the aim of Whole Life, a program to integrate mental health services into primary care for HIV-infected pregnant and non-pregnant women. Whole Life utilizes a theoretically derived clinical services model that provides data for both clinical care and patient outcomes research within the constraints of a clinical setting. During a woman's first two clinic visits, data are gathered in structured interviews with standardized instruments-adapted for relevance to the population-that meet clinical and service needs, as well as measure components of the Whole Life model. Interviews are conducted by existing front-line staff who have been trained in using these instruments to gather information typically recorded in clinical notes. The implementation of Whole Life to date clearly demonstrates the feasibility of mental health-primary care services integration in a publicly funded HIV primary care clinic serving poor women of color.

Negative regulation of selected bHLH proteins by eHAND.

The bHLH protein eHAND plays an important role in the development of extraembryonic, mesodermal, and cardiac cell lineages, presumably through heterodimerization with other HLH proteins and DNA binding. In this study, we have identified a novel transcriptional activity of eHAND. In transient transfection assays, eHAND is a potent inhibitor of activation by some but not all bHLH proteins. eHAND can prevent E-box DNA binding by these bHLH proteins. Interestingly, eHAND can also strongly inhibit transactivation activity by a MyoD approximately E47 tethered dimer, which suggests a distinct mechanism of action. eHAND also inhibits MyoD-dependent skeletal muscle cell differentiation and expression of the muscle-specific myosin heavy chain protein. In addition, we show that eHAND can repress activity of the natural p75LNGFR promoter, whose expression overlaps that of eHAND and dHAND. The inhibitory activity of eHAND may be attributed to multiple mechanisms, such as the ability to act as a corepressor, the presence of a repression domain, and its ability to sequester E proteins in an inactive complex. Based upon its inhibitory effect on bHLH proteins and cellular differentiation, we propose that eHAND may function by several mechanisms to promote placental giant cell proliferation by negatively regulating the activities of the bHLH protein MASH-2.