Differences in body sway can be identified in Huntington's disease using a practical balance assessment device.

INTRODUCTION: Huntington's disease (HD) is a progressive neurodegenerative disorder with motor, cognitive, and psychiatric symptoms that typically manifest in middle adulthood. Balance assessments may be useful for predicting disease onset and progression, but studies are limited. We aimed to enhance estimates of HD onset using an inexpensive and practical body sway assessment device [i.e., Wii Balance Board (WBB)]. METHODS: We assessed total body sway (TBS) on 64 HD gene carriers [Presymptomatic HD (PsHD; n = 16); Prodromal HD (ProHD; n = 16); HD (n = 32)] and 21 demographically similar normal controls (NC) employing a WBB and custom-designed laptop software. Participants completed balance test trials that included combinations of eyes open or closed while standing on a stable versus unstable surface. Non-parametric analyses were conducted to assess group differences in TBS conditions. RESULTS: The HD group had significantly higher TBS in most balance conditions relative to NC, PsHD, and ProHD groups (ps < .05). Importantly, the ProHD group demonstrated higher TBS relative to NC in all balance conditions (ps < .05) with medium to large effect size ranges (r≥ 0.40). No differences in TBS were exhibited between NC and PsHD groups (ps > .05). CONCLUSIONS: Increased body sway, easily evaluated using a brief, objective balance assessment, may serve as an important functional marker in patients with, and during the transition to, HD. Further studies are needed to confirm and extend these findings.

Lamotrigine versus levetiracetam or zonisamide for focal epilepsy and valproate versus levetiracetam for generalised and unclassified epilepsy: two SANAD II non-inferiority RCTs.

BACKGROUND: Levetiracetam (Keppra®, UCB Pharma Ltd, Slough, UK) and zonisamide (Zonegran®, Eisai Co. Ltd, Tokyo, Japan) are licensed as monotherapy for focal epilepsy, and levetiracetam is increasingly used as a first-line treatment for generalised epilepsy, particularly for women of childbearing age. However, there is uncertainty as to whether or not they should be recommended as first-line treatments owing to a lack of evidence of clinical effectiveness and cost-effectiveness. OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of lamotrigine (Lamictal®, GlaxoSmithKline plc, Brentford, UK) (standard treatment) with levetiracetam and zonisamide (new treatments) for focal epilepsy, and to compare valproate (Epilim®, Sanofi SA, Paris, France) (standard treatment) with levetiracetam (new treatment) for generalised and unclassified epilepsy. DESIGN: Two pragmatic randomised unblinded non-inferiority trials run in parallel. SETTING: Outpatient services in NHS hospitals throughout the UK. PARTICIPANTS: Those aged ≥ 5 years with two or more spontaneous seizures that require anti-seizure medication. INTERVENTIONS: Participants with focal epilepsy were randomised to receive lamotrigine, levetiracetam or zonisamide. Participants with generalised or unclassifiable epilepsy were randomised to receive valproate or levetiracetam. The randomisation method was minimisation using a web-based program. MAIN OUTCOME MEASURES: The primary outcome was time to 12-month remission from seizures. For this outcome, and all other time-to-event outcomes, we report hazard ratios for the standard treatment compared with the new treatment. For the focal epilepsy trial, the non-inferiority limit (lamotrigine vs. new treatments) was 1.329. For the generalised and unclassified epilepsy trial, the non-inferiority limit (valproate vs. new treatments) was 1.314. Secondary outcomes included time to treatment failure, time to first seizure, time to 24-month remission, adverse reactions, quality of life and cost-effectiveness. RESULTS: Focal epilepsy. A total of 990 participants were recruited, of whom 330 were randomised to receive lamotrigine, 332 were randomised to receive levetiracetam and 328 were randomised to receive zonisamide. Levetiracetam did not meet the criteria for non-inferiority (hazard ratio 1.329) in the primary intention-to-treat analysis of time to 12-month remission (hazard ratio vs. lamotrigine 1.18, 97.5% confidence interval 0.95 to 1.47), but zonisamide did meet the criteria (hazard ratio vs. lamotrigine 1.03, 97.5% confidence interval 0.83 to 1.28). In the per-protocol analysis, lamotrigine was superior to both levetiracetam (hazard ratio 1.32, 95% confidence interval 1.05 to 1.66) and zonisamide (hazard ratio 1.37, 95% confidence interval 1.08 to 1.73). For time to treatment failure, lamotrigine was superior to levetiracetam (hazard ratio 0.60, 95% confidence interval 0.46 to 0.77) and zonisamide (hazard ratio 0.46, 95% confidence interval 0.36 to 0.60). Adverse reactions were reported by 33% of participants starting lamotrigine, 44% starting levetiracetam and 45% starting zonisamide. In the economic analysis, both levetiracetam and zonisamide were more costly and less effective than lamotrigine and were therefore dominated. Generalised and unclassifiable epilepsy. Of 520 patients recruited, 260 were randomised to receive valproate and 260 were randomised to receive to levetiracetam. A total of 397 patients had generalised epilepsy and 123 had unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the primary intention-to-treat analysis of time to 12-month remission (hazard ratio 1.19, 95% confidence interval 0.96 to 1.47; non-inferiority margin 1.314). In the per-protocol analysis of time to 12-month remission, valproate was superior to levetiracetam (hazard ratio 1.68, 95% confidence interval 1.30 to 2.15). Valproate was superior to levetiracetam for time to treatment failure (hazard ratio 0.65, 95% confidence interval 0.50 to 0.83). Adverse reactions were reported by 37.4% of participants receiving valproate and 41.5% of those receiving levetiracetam. Levetiracetam was both more costly (incremental cost of £104, 95% central range -£587 to £1234) and less effective (incremental quality-adjusted life-year of -0.035, 95% central range -0.137 to 0.032) than valproate, and was therefore dominated. At a cost-effectiveness threshold of £20,000 per quality-adjusted life-year, levetiracetam was associated with a probability of 0.17 of being cost-effective. LIMITATIONS: The SANAD II trial was unblinded, which could have biased results by influencing decisions about dosing, treatment failure and the attribution of adverse reactions. FUTURE WORK: SANAD II data could now be included in an individual participant meta-analysis of similar trials, and future similar trials are required to assess the clinical effectiveness and cost-effectiveness of other new treatments, including lacosamide and perampanel. CONCLUSIONS: Focal epilepsy - The SANAD II findings do not support the use of levetiracetam or zonisamide as first-line treatments in focal epilepsy. Generalised and unclassifiable epilepsy - The SANAD II findings do not support the use of levetiracetam as a first-line treatment for newly diagnosed generalised epilepsy. For women of childbearing potential, these results inform discussions about the benefit (lower teratogenicity) and harm (worse seizure outcomes and higher treatment failure rate) of levetiracetam compared with valproate. TRIAL REGISTRATION: Current Controlled Trials ISRCTN30294119 and EudraCT 2012-001884-64. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 75. See the NIHR Journals Library website for further project information.

BACKGROUND AND METHODS: The SANAD II trial was a clinical trial designed to identify the most clinically effective and cost-effective treatment for adults and children aged > 5 years with newly diagnosed epilepsy. There are two main epilepsy types: focal and generalised. In focal epilepsy, seizures start at a single place in the brain (a focus), whereas in generalised epilepsy seizures start in both sides of the brain at the same time. Anti-seizure medications are the main treatment. For people with newly diagnosed epilepsy, the first anti-seizure medication should control the seizures as quickly as possible while avoiding side effects. The first-choice treatments are lamotrigine (Lamictal®, GlaxoSmithKline plc, Brentford, UK) for focal epilepsy and valproate (Epilim®, Sanofi SA, Paris, France) for generalised epilepsy (however, the latter should be avoided in women who could become pregnant). A number of newer anti-seizure medications have been approved for NHS use, but it is unclear whether or not they should be used as first-line treatments. The SANAD II trial focused on the new medicines levetiracetam (Keppra®, UCB Pharma Ltd, Slough, UK) and zonisamide (Zonegran®, Eisai Co. Ltd, Tokyo, Japan). We recruited 1510 people aged ≥ 5 years with newly diagnosed epilepsy: 990 with focal epilepsy and 520 with generalised or unclassified epilepsy. FINDINGS: FOCAL EPILEPSY: People starting treatment with levetiracetam or zonisamide were significantly less likely to have a 12-month remission from seizures than people starting treatment with lamotrigine, unless they were changed to another anti-seizure medication. Side effects that were thought to be caused by anti-seizure medications were reported by 33% of participants starting lamotrigine, 44% of those starting levetiracetam and 45% of those starting zonisamide. The cost-effectiveness analyses showed that neither levetiracetam nor zonisamide is value for money for the NHS when compared with lamotrigine. The SANAD II findings do not support the use of levetiracetam or zonisamide as first-line treatments in focal epilepsy. FINDINGS: GENERALISED AND UNCLASSIFIABLE EPILEPSY: People starting treatment with levetiracetam were significantly less likely to have a 12-month remission from seizures than people starting valproate, unless they were changed to another anti-seizure medication. Side effects that were thought to be caused by anti-seizure medications were reported by 37% of participants starting valproate and 42% of participants starting levetiracetam. The cost-effectiveness analyses showed that levetiracetam is not good value for money for the NHS when compared with valproate. The SANAD II findings do not support the use of levetiracetam as a first-line treatment for newly diagnosed generalised epilepsy. Importantly, our results will inform treatment decisions for women, who may choose a less effective treatment that is safer in pregnancy.

The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial.

BACKGROUND: Levetiracetam and zonisamide are licensed as monotherapy for patients with focal epilepsy, but there is uncertainty as to whether they should be recommended as first-line treatments because of insufficient evidence of clinical effectiveness and cost-effectiveness. We aimed to assess the long-term clinical effectiveness and cost-effectiveness of levetiracetam and zonisamide compared with lamotrigine in people with newly diagnosed focal epilepsy. METHODS: This randomised, open-label, controlled trial compared levetiracetam and zonisamide with lamotrigine as first-line treatment for patients with newly diagnosed focal epilepsy. Adult and paediatric neurology services across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked focal seizures. Participants were randomly allocated (1:1:1) using a minimisation programme with a random element utilising factor to receive lamotrigine, levetiracetam, or zonisamide. Participants and investigators were not masked and were aware of treatment allocation. SANAD II was designed to assess non-inferiority of both levetiracetam and zonisamide to lamotrigine for the primary outcome of time to 12-month remission. Anti-seizure medications were taken orally and for participants aged 12 years or older the initial advised maintenance doses were lamotrigine 50 mg (morning) and 100 mg (evening), levetiracetam 500 mg twice per day, and zonisamide 100 mg twice per day. For children aged between 5 and 12 years the initial daily maintenance doses advised were lamotrigine 1·5 mg/kg twice per day, levetiracetam 20 mg/kg twice per day, and zonisamide 2·5 mg/kg twice per day. All participants were included in the intention-to-treat (ITT) analysis. The per-protocol (PP) analysis excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analysis included all participants who received one dose of any study drug. The non-inferiority limit was a hazard ratio (HR) of 1·329, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on lamotrigine. The trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). FINDINGS: 990 participants were recruited between May 2, 2013, and June 20, 2017, and followed up for a further 2 years. Patients were randomly assigned to receive lamotrigine (n=330), levetiracetam (n=332), or zonisamide (n=328). The ITT analysis included all participants and the PP analysis included 324 participants randomly assigned to lamotrigine, 320 participants randomly assigned to levetiracetam, and 315 participants randomly assigned to zonisamide. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission versus lamotrigine (HR 1·18; 97·5% CI 0·95-1·47) but zonisamide did meet the criteria for non-inferiority in the ITT analysis versus lamotrigine (1·03; 0·83-1·28). The PP analysis showed that 12-month remission was superior with lamotrigine than both levetiracetam (HR 1·32 [97·5% CI 1·05 to 1·66]) and zonisamide (HR 1·37 [1·08-1·73]). There were 37 deaths during the trial. Adverse reactions were reported by 108 (33%) participants who started lamotrigine, 144 (44%) participants who started levetiracetam, and 146 (45%) participants who started zonisamide. Lamotrigine was superior in the cost-utility analysis, with a higher net health benefit of 1·403 QALYs (97·5% central range 1·319-1·458) compared with 1·222 (1·110-1·283) for levetiracetam and 1·232 (1·112, 1·307) for zonisamide at a cost-effectiveness threshold of £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs. INTERPRETATION: These findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy. Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials. FUNDING: National Institute for Health Research Health Technology Assessment programme.

The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial.

BACKGROUND: Valproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy. METHODS: We did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5-12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). FINDINGS: 520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0-94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 [95% CI 0·96-1·47]); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of -0·040 (95% central range -0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of £20 000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years. INTERPRETATION: Compared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

Is a shortened length of stay and increased rate of discharge to home associated with a low readmission rate and cost-effectiveness after primary total knee arthroplasty?

BACKGROUND: It is controversial whether shortening the average length of hospital stay and increasing discharge from a rehabilitation facility to home with either health care or outpatient physical therapy is safe and cost-effective. METHODS: We computed the average length of hospital stay; the rate of discharge to a rehabilitation facility, home with health care, or home with outpatient physical therapy; the all-cause readmission rate within 30 days of discharge per year; and cost savings for 2328 consecutive patients treated with a unilateral primary total knee replacement between 2009 and 2014. RESULTS: The average length of hospital stay per year shortened from 2.0 to 1.3 days (P < .0001); the rate of discharge per year to a rehabilitation facility decreased from 41% to 1% and increased from 9% to 53% to home with outpatient physical therapy (P < .0001); and the rate of readmission within 30 days per year did not change (P = .38). The cost savings averaged $3245 per patient. CONCLUSIONS: A shorter length of hospital stay and an increased rate of discharge to home was not associated with an increased rate of readmission within 30 days and was cost-effective. LEVEL OF EVIDENCE: Level IV, Therapeutic study.

Constraints of philanthropy on determining the distribution of biodiversity conservation funding.

Caught between ongoing habitat destruction and funding shortfalls, conservation organizations are using systematic planning approaches to identify places that offer the highest biodiversity return per dollar invested. However, available tools do not account for the landscape of funding for conservation or quantify the constraints this landscape imposes on conservation outcomes. Using state-level data on philanthropic giving to and investments in land conservation by a large nonprofit organization, we applied linear regression to evaluate whether the spatial distribution of conservation philanthropy better explained expenditures on conservation than maps of biodiversity priorities, which were derived from a planning process internal to the organization and return on investment (ROI) analyses based on data on species richness, land costs, and existing protected areas. Philanthropic fund raising accounted for considerably more spatial variation in conservation spending (r(2) = 0.64) than either of the 2 systematic conservation planning approaches (r(2) = 0.08-0.21). We used results of one of the ROI analyses to evaluate whether increases in flexibility to reallocate funding across space provides conservation gains. Small but plausible "tax" increments of 1-10% on states redistributed to the optimal funding allocation from the ROI analysis could result in gains in endemic species protected of 8.5-80.2%. When such increases in spatial flexibility are not possible, conservation organizations should seek to cultivate increased support for conservation in priority locations. We used lagged correlations of giving to and spending by the organization to evaluate whether investments in habitat protection stimulate future giving to conservation. The most common outcome at the state level was that conservation spending quarters correlated significantly and positively with lagged fund raising quarters. In effect, periods of high fund raising for biodiversity followed (rather than preceded) periods of high expenditure on land conservation projects, identifying one mechanism conservation organizations could explore to seed greater activity in priority locations. Our results demonstrate how limitations on the ability of conservation organizations to reallocate their funding across space can impede organizational effectiveness and elucidate ways conservation planning tools could be more useful if they quantified and incorporated these constraints.

Accuracy evaluation of a lower-cost and four higher-cost laser scanners.

Knowing the accuracy of laser scanners is imperative to select the best scanner to generate bone models. However, errors stated by manufacturers may not apply to bones. The three objectives of this study were to determine: 1) whether the overall error stated by the manufacturers of five laser scanners was different from the root mean squared error (RMSE) computed by scanning a gage block; 2) the repeatability of 3D models generated by the laser scanners when scanning a complex freeform surface such as a distal femur and whether this differed from the repeatability when scanning a gage block; 3) whether the errors for one lower-cost laser scanner are comparable to those of four higher-cost laser scanners. The RMSEs in scanning the gage block were 2 to 52µm lower than the overall errors stated by the manufacturers. The repeatability in scanning the bovine femur 10 times was significantly worse than that in scanning the gage block 10 times. The precision of the lower-cost laser scanner was comparable to that of the higher-cost laser scanners, but the bias was an order of magnitude greater. The contributions of this study are that 1) the overall errors stated by the manufacturers are an upper bound when simple geometric objects like a gage block are scanned, 2) the repeatability is worse on average three times when scanning a complex freeform surface compared to scanning the gage block, and 3) the main difference between the lower-cost and the higher-cost laser scanners is the bias.

Some Challenges Posed by Coal Bed Methane Regional Assessment Modeling.

Coal measures (coal bearing rock strata) can contain large reserves of methane. These reserves are being exploited at a rapidly increasing rate in many parts of the world. To extract coal seam gas, thousands of wells are drilled at relatively small spacing to depressurize coal seams to induce desorption and allow subsequent capture of the gas. To manage this process effectively, the effect of coal bed methane (CBM) extraction on regional aquifer systems must be properly understood and managed. Groundwater modeling is an integral part of this management process. However, modeling of CBM impacts presents some unique challenges, as processes that are operative at two very different scales must be adequately represented in the models. The impacts of large-scale gas extraction may be felt over a large area, yet despite the significant upscaling that accompanies construction of a regional model, near-well conditions and processes cannot be ignored. These include the highly heterogeneous nature of many coal measures, and the dual-phase flow of water and gas that is induced by coal seam depressurization. To understand these challenges, a fine-scale model was constructed incorporating a detailed representation of lithological heterogeneity to ensure that near-well processes and conditions could be examined. The detail of this heterogeneity was at a level not previously employed in models built to assess groundwater impacts arising from CBM extraction. A dual-phase reservoir simulator was used to examine depressurization and water desaturation processes in the vicinity of an extractive wellfield within this fine-scale model. A single-phase simulator was then employed so that depressurization errors incurred by neglecting near-well, dual-phase flow could be explored. Two models with fewer lithological details were then constructed in order to examine the nature of depressurization errors incurred by upscaling and to assess the interaction of the upscaling process with the requirement for adequate representation of near-source, dual-phase processes.

Evidence of no benefit from knee surgery for osteoarthritis led to coverage changes and is linked to decline in procedures.

Patients and physicians may be reluctant to abandon widely used treatments that have been found to be ineffective. In 2002 and 2008 the New England Journal of Medicine published the results of clinical trials showing that arthroscopic debridement and lavage--surgical treatments to remove damaged tissue and debris--do not benefit patients with osteoarthritis of the knee. To determine whether the trials' publication was associated with changes in practice patterns, we examined ambulatory surgery data from Florida and found that the number of debridement and lavage procedures per 100,000 adults declined 47 percent between 2001 and 2010. The reduction translates into national savings of $82-$138 million annually. These reductions may be offset by increases in the use of other procedures. The results indicate that clinical trials of widely used therapies can lead to cost-saving changes in practice patterns.

Assessment of the radii of the medial and lateral femoral condyles in varus and valgus knees with osteoarthritis.

BACKGROUND: Understanding the relationship between the radii of the medial and lateral femoral condyles in varus and valgus knees is important for aligning the femoral component and for restoring kinematics in total knee arthroplasty. The purpose of this study was to test the hypothesis that the asymmetry between the radii of the medial and lateral femoral condyles in varus and valgus knees with osteoarthritis is small enough to be clinically unimportant. METHODS: A magnetic resonance imaging scan was obtained with use of a biplanar, rotational alignment protocol in a consecutive series of subjects with end-stage osteoarthritis prior to total knee arthroplasty. The alignment protocol oriented the scanning plane so that both condyles were imaged in a plane perpendicular to the primary femoral axis of the knee about which the tibia flexes and extends. The study included 155 varus knees and forty-four valgus knees. Radii were calculated from the area of the best-fit circle overlaid from 10 degrees to 160 degrees on the subchondral corticocancellous bone interface of the medial and lateral femoral condyles. The radius of a condyle was the average of the radii on four adjacent images that showed the femoral condyle with the largest curvature. RESULTS: In the 155 varus knees, the radius of the lateral condyle was an average of 0.1 mm larger than that of the medial condyle (p = 0.003). In the forty-four valgus knees, the radius of the lateral condyle was an average of 0.2 mm larger than that of the medial condyle (p < 0.006). There was a strong association between the radii of the medial and lateral femoral condyles in both the varus (r(2) = 0.9210) and the valgus (r(2) = 0.9129) knees. CONCLUSIONS: As determined by imaging of the femoral condyles perpendicular to the primary femoral axis of the knee, the asymmetry between the radii of the medial and lateral femoral condyles in varus and valgus knees with end-stage osteoarthritis was < or =0.2 mm, which is small enough to be considered clinically unimportant when aligning a total knee prosthesis.

The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.

BACKGROUND: Carbamazepine is widely accepted as a drug of first choice for patients with partial onset seizures. Several newer drugs possess efficacy against these seizure types but previous randomised controlled trials have failed to inform a choice between these drugs. We aimed to assess efficacy with regards to longer-term outcomes, quality of life, and health economic outcomes. METHODS: SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm A recruited 1721 patients for whom carbamazepine was deemed to be standard treatment, and they were randomly assigned to receive carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate. Primary outcomes were time to treatment failure, and time to 12-months remission, and assessment was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. FINDINGS: For time to treatment failure, lamotrigine was significantly better than carbamazepine (hazard ratio [HR] 0.78 [95% CI 0.63-0.97]), gabapentin (0.65 [0.52-0.80]), and topiramate (0.64 [0.52-0.79]), and had a non-significant advantage compared with oxcarbazepine (1.15 [0.86-1.54]). For time to 12-month remission carbamazepine was significantly better than gabapentin (0.75 [0.63-0.90]), and estimates suggest a non-significant advantage for carbamazepine against lamotrigine (0.91 [0.77-1.09]), topiramate (0.86 [0.72-1.03]), and oxcarbazepine (0.92 [0.73-1.18]). In a per-protocol analysis, at 2 and 4 years the difference (95% CI) in the proportion achieving a 12-month remission (lamotrigine-carbamazepine) is 0 (-8 to 7) and 5 (-3 to 12), suggesting non-inferiority of lamotrigine compared with carbamazepine. INTERPRETATION: Lamotrigine is clinically better than carbamazepine, the standard drug treatment, for time to treatment failure outcomes and is therefore a cost-effective alternative for patients diagnosed with partial onset seizures.

The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial.

BACKGROUND: Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. METHODS: SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. FINDINGS: For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1.57 [95% CI 1.19-2.08]), but there was no significant difference between valproate and lamotrigine (1.25 [0.94-1.68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1.55 [1.07-2.24] and topiramate (1.89 [1.32-2.70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0.76 [0.62-0.94]), and for the subgroup with an idiopathic generalised epilepsy 0.68 (0.53-0.89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. INTERPRETATION: Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.