Radiation Oncology Opinions and Practice on Cardiotoxicity in Lung Cancer: A Cross-sectional Study by the International Cardio-oncology Society.

AIMS: Symptomatic radiation cardiotoxicity affects up to 30% patients with lung cancer and several heart substructure doses are associated with reduced overall survival. A greater focus on minimising cardiotoxicity is now possible due to advancements in radiotherapy technology and the new discipline of cardio-oncology, but uptake of emerging data has not been ascertained. A global cross-sectional analysis of Radiation Oncologists who treat lung cancer was therefore conducted by the International Cardio-Oncology Society in order to establish the impact of recently published literature and guidelines on practice. MATERIALS AND METHODS: A bespoke questionnaire was designed following an extensive review of the literature and from recurring relevant themes presented at Radiation Oncology and Cardio-Oncology research meetings. Six question domains were retained following consensus discussions among the investigators, comprising 55 multiple choice stems: guidelines, cardiovascular assessment, cardiology investigations, radiotherapy planning strategies, primary prevention prescribing and local cardio-oncology service access. An invitation was sent to all Radiation Oncologists registered with ICOS and to Radiation Oncology colleagues of the investigators. RESULTS: In total 118 participants were recruited and 92% were consultant physicians. The ICOS 2021 expert consensus statement was rated as the most useful position paper, followed by the joint ESC-ESTRO 2022 guideline. The majority (80%) of participants indicated that a detailed cardiovascular history was advisable. Although 69% of respondents deemed the availability of cardiac substructure auto-segmentation to be very/quite important, it was implemented by only a few, with the most common being the left anterior descending coronary artery V15. A distinct cardio-oncology service was available to 39% participants, while the remainder utilised general cardiology services. CONCLUSION: The uptake of recent guidelines on cardiovascular optimisation is good, but access to cardiology investigations and consultations, and auto-segmentation, represent barriers to modifying radiotherapy practices in lung cancer to reduce the risk of radiation cardiotoxicity.

Risk profiles and incidence of cardiovascular events across different cancer types.

BACKGROUND: Cancer survivors are at increased risk for cardiovascular (CV) disease, although additional data are needed to better understand the incidence of CV events across different malignancies. This study sought to characterize the incidence of major adverse CV events [myocardial infarction, stroke, unstable angina (MACE), or heart failure (HF)] across multiple cancer types after cancer diagnosis. PATIENTS AND METHODS: Patients were identified from a USA-based administrative claims database who had index cancer diagnoses of breast, lung, prostate, melanoma, myeloma, kidney, colorectal, leukemia, or lymphoma between 2011 and 2019, with continuous enrollment for ≥12 months before diagnosis. Baseline CV risk factors and incidence rates of CV events post-index were identified for each cancer. Multivariable Cox hazards models assessed the cumulative incidence of MACE, accounting for baseline risk factors. RESULTS: Among 839 934 patients across nine cancer types, CV risk factors were prevalent. The cumulative incidence of MACE was highest in lung cancer and myeloma, and lowest in breast cancer, prostate cancer, and melanoma. MACE cumulative incidence for lung cancer was 26% by 4 years (2.7-fold higher relative to breast cancer). The incidence of stroke was especially pronounced in lung cancer, while HF was highest in myeloma and lung cancer. CONCLUSIONS: CV events were especially increased following certain cancer diagnoses, even after accounting for baseline risk factors. Understanding the variable patient characteristics and associated CV events across different cancers can help target appropriate CV risk factor modification and develop strategies to minimize adverse CV events and improve patient outcomes.

Shark depredation: future directions in research and management.

Shark depredation is a complex social-ecological issue that affects a range of fisheries worldwide. Increasing concern about the impacts of shark depredation, and how it intersects with the broader context of fisheries management, has driven recent research in this area, especially in Australia and the United States. This review synthesises these recent advances and provides strategic guidance for researchers aiming to characterise the occurrence of depredation, identify the shark species responsible, and test deterrent and management approaches to reduce its impacts. Specifically, the review covers the application of social science approaches, as well as advances in video camera and genetic methods for identifying depredating species. The practicalities and considerations for testing magnetic, electrical, and acoustic deterrent devices are discussed in light of recent research. Key concepts for the management of shark depredation are reviewed, with recommendations made to guide future research and policy development. Specific management responses to address shark depredation are lacking, and this review emphasizes that a "silver bullet" approach for mitigating depredation does not yet exist. Rather, future efforts to manage shark depredation must rely on a diverse range of integrated approaches involving those in the fishery (fishers, scientists and fishery managers), social scientists, educators, and other stakeholders.

Quantifying the impact of environmental variables upon catch per unit effort of the blue shark Prionace glauca in the western English Channel.

The effect of environmental variables on blue shark Prionace glauca catch per unit effort (CPUE) in a recreational fishery in the western English Channel, between June and September 1998-2011, was quantified using generalized additive models (GAMs). Sea surface temperature (SST) explained 1·4% of GAM deviance, and highest CPUE occurred at 16·7° C, reflecting the optimal thermal preferences of this species. Surface chlorophyll a concentration (CHL) significantly affected CPUE and caused 27·5% of GAM deviance. Additionally, increasing CHL led to rising CPUE, probably due to higher productivity supporting greater prey biomass. The density of shelf-sea tidal mixing fronts explained 5% of GAM deviance, but was non-significant, with increasing front density negatively affecting CPUE. Time-lagged frontal density significantly affected CPUE, however, causing 12·6% of the deviance in a second GAM and displayed a positive correlation. This outcome suggested a delay between the evolution of frontal features and the subsequent accumulation of productivity and attraction of higher trophic level predators, such as P. glauca.

The liver to abdominal area ratio (LAAR): a novel imaging score for prognostication in cirrhosis.

BACKGROUND: Anecdotally, liver size is important in determining prognosis in patients with end-stage liver disease (ESLD). AIMS: To assess if a ratio of liver area and abdominal area on cross-sectional imaging could accurately predict mortality in ESLD. METHODS: A retrospective-prospective cohort study was performed on patients with ESLD in a training set. The censor point used was date of patient death or liver transplant (LT). The liver to abdominal area ratio (LAAR) was calculated using the formula {LAAR = [liver area (cm(2))/abdominal area (cm(2))] × 100}. A validation set was collected from a different institution. RESULTS: Three hundred and sixteen patients were identified. Complete imaging and survival data were available in 158 subjects, 100 male (63%). The LAAR score detected progression to death/LT in our cohort (P < 0.003). Its prognostic accuracy at 90, 360 and 720 days, using the optimal cut-off (32.1), from baseline CT date to death/LT using the log-rank test was P = 0.28, P = 0.06 (OR 1.347, 95% CI 0.94-1.94) and P < 0.0001 (OR 1.89, 95% CI 1.25-2.85) respectively. On multivariate analysis, LAAR (P = 0.008), MELD (P = 0.004) and MELD-Na (P = 0.03) were independently associated with the primary study outcome measurement at 720 days. The validation set of 52 patients confirmed the utility of the LAAR to determine risk of death or need for LT, AUROC 0.89 (0.78-0.97), and P < 0.0001. CONCLUSIONS: The liver to abdominal area ratio (LAAR) score offers a new paradigm in disease modelling in end-stage liver disease (ESLD) and offers prognostic accuracy at 2 years from computer tomography (CT) imaging.

The Preoperative Assessment of Hepatic Tumours: Evaluation of UK Regional Multidisciplinary Team Performance.

Introduction. In the UK, patients where liver resection is contemplated are discussed at hepatobiliary multidisciplinary team (MDT) meetings. The aim was to assess MDT performance by identification of patients where radiological and pathological diagnoses differed. Materials and Methods. A retrospective review of a prospectively maintained database of all cases undergoing liver resection from March 2006 to January 2012 was performed. The presumed diagnosis as a result of radiological investigation and MDT discussion is recorded at the time of surgery. Imaging was reviewed by specialist gastrointestinal radiologists, and resultswereagreedonby consensus. Results. Four hundred and thirty-eight patients were studied. There was a significant increase in the use of preoperative imaging modalities (P ≤ 0.01) but no change in the rate of discrepant diagnosis over time. Forty-two individuals were identified whose final histological diagnosis was different to that following MDT discussion (9.6%). These included 30% of patients diagnosed preoperatively with hepatocellular carcinoma and 25% with cholangiocarcinoma of a major duct. Discussion. MDT assessment of patients preoperatively is accurate in terms of diagnosis. The highest rate of discrepancies occurred in patients with focal lesions without chronic liver disease or primary cancer, where hepatocellular carcinoma was overdiagnosed and peripheral cholangiocarcinoma underdiagnosed, where particular care should be taken. Additional care should be taken in these groups and preoperative multimodality imaging considered.

Recombinant human insulin-like growth factor I (rhIGF-I) for the treatment of amyotrophic lateral sclerosis/motor neuron disease.

BACKGROUND: Recombinant human insulin-like growth factor I (rhIGF-I) is a possible disease modifying therapy for amyotrophic lateral sclerosis (ALS, which is also known as motor neuron disease (MND)). OBJECTIVES: To examine the efficacy of rhIGF-I in affecting disease progression, impact on measures of functional health status, prolonging survival and delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival in ALS. Occurrence of adverse events was also reviewed. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (21 November 2011), CENTRAL (2011, Issue 4), MEDLINE (January 1966 to November 2011) and EMBASE (January 1980 to November 2011) and sought information from the authors of randomised clinical trials and manufacturers of rhIGF-I. SELECTION CRITERIA: We considered all randomised controlled clinical trials involving rhIGF-I treatment of adults with definite or probable ALS according to the El Escorial Criteria. The primary outcome measure was change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score after nine months of treatment and secondary outcome measures were change in AALSRS at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events. DATA COLLECTION AND ANALYSIS: Each author independently graded the risk of bias in the included studies. The lead author extracted data and the other authors checked them. We generated some missing data by making ruler measurements of data in published graphs. We collected data about adverse events from the included trials. MAIN RESULTS: We identified three randomised controlled trials (RCTs) of rhIGF-I, involving 779 participants, for inclusion in the analysis. In a European trial (183 participants) the mean difference (MD) in change in AALSRS total score after nine months was -3.30 (95% confidence interval (CI) -8.68 to 2.08). In a North American trial (266 participants), the MD after nine months was -6.00 (95% CI -10.99 to -1.01). The combined analysis from both RCTs showed a MD after nine months of -4.75 (95% CI -8.41 to -1.09), a significant difference in favour of the treated group. The secondary outcome measures showed non-significant trends favouring rhIGF-I. There was an increased risk of injection site reactions with rhIGF-I (risk ratio 1.26, 95% CI 1.04 to 1.54). . A second North American trial (330 participants) used a novel primary end point involving manual muscle strength testing. No differences were demonstrated between the treated and placebo groups in this study. All three trials were at high risk of bias. AUTHORS' CONCLUSIONS: Meta-analysis revealed a significant difference in favour of rhIGF-I treatment; however, the quality of the evidence from the two included trials was low. A third study showed no difference between treatment and placebo. There is no evidence for increase in survival with IGF1. All three included trials were at high risk of bias.

Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).

BACKGROUND: Riluzole is approved for the treatment of amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest efficacy. OBJECTIVES: To examine the efficacy of riluzole in prolonging survival and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival, and to assess the effect of riluzole upon functional health. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (20 April 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2), MEDLINE (1966 to April 2011), EMBASE (1980 to May 2011) and made enquiries of authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. SELECTION CRITERIA: Types of studies: randomized controlled trials TYPES OF PARTICIPANTS: adults with a diagnosis of amyotrophic lateral sclerosis Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality with riluzole 50 mg, 100 mg and 200 mg; neurologic function, muscle strength and adverse events. DATA COLLECTION AND ANALYSIS: One author performed data extraction and two other authors checked them. One author checked the data and entered them into the computer. The other authors verified the data entry. We obtained missing data from the trial authors whenever possible. MAIN RESULTS: The four trials examining tracheostomy-free survival included a total of 974 riluzole-treated patients and 503 placebo-treated patients. No new randomized controlled trials were found when we updated the searches for this update in 2011. The methodological quality was acceptable and three trials were easily comparable, although one trial (169 participants) included older patients in more advanced stages of amyotrophic lateral sclerosis and one (195 participants) had multiple primary endpoints. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (hazard ratio (HR) 0.80, 95% confidence internal (CI) 0.64 to 0.99, P= 0.042) and there was no evidence of heterogeneity (P = 0.33). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P < 0.0001) and the overall treatment effect was reduced but still significant (HR 0.84, 95% CI 0.698 to 0.997, P= 0.046). This represented a 9% gain in the probability of surviving one year (49% in the placebo and 58% in the riluzole group), and increased median survival from 11.8 to 14.8 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A three-fold increase in serum alanine transferase was more frequent in riluzole-treated patients than controls (mean difference 2.62, 95% CI 1.59 to 4.31). AUTHORS' CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.

A simple reminder system improves venous thromboembolism prophylaxis rates and reduces thrombotic events for hospitalized patients1.

BACKGROUND: Compliance with venous thromboembolism (VTE) prophylaxis is poor. OBJECTIVES: We sought to determine whether a simple electronic reminder applicable to all hospitalized patients would increase prophylaxis rates and reduce VTE rates. METHODS: An electronic reminder was added to the electronic medical record admission note used by all services in our hospital. Prophylaxis, VTE and bleeding rates before and after implementation were compared. Data were analyzed with sas version 9.1. RESULTS: Among all adult medical and surgical patients admitted to our hospital during the time periods studied, 42.8% (1236/2888) before and 60.0% (1410/2350) after the reminder was added received appropriate prophylaxis as per American College of Chest Physicians (ACCP) guidelines (P < 0.001). The difference reached significance for both medical (51.0% vs. 68.9%; P < 0.001) and surgical (48.0% vs. 61.0%; P < 0.001) services. Fewer patients were diagnosed with VTE after our reminder was added (1.1% vs. 0.3%; P = 0.001), and there was a trend towards fewer bleeds (1.1% vs. 0.6%; P = 0.09). The presence of the reminder was an independent predictor for prophylaxis being given (odds ratio [OR] 1.92, 95% confidence interval [CI] 1.70-2.18; P < 0.001), and was independently associated with a decreased risk for VTE (OR 0.30, 95% CI 0.14-0.64; P = 0.003) after adjustment for other VTE risk factors. CONCLUSION: Adding an electronic reminder to the admission note improved prophylaxis rates and reduced VTE rates across services. The system is easily reproducible and applicable to other facilities. The improvement obtained was modest, so additional measures will probably be needed to optimize prophylaxis rates.

Emerging pharmacology and physiology of neuromedin U and the structurally related peptide neuromedin S.

Neuromedin U (NMU) has been paired with the G-protein-coupled receptors (GPRs) NMU(1) (formerly designated as the orphan GPR66 or FM-3) and NMU(2) (FM-4 or hTGR-1). Recently, a structurally related peptide, neuromedin S (NMS), which shares an amidated C-terminal heptapeptide motif, has been identified in both rat and human, and has been proposed as a second ligand for these receptors. Messenger RNA encoding NMU receptor subtypes shows differential expression: NMU(1) is predominantly expressed in peripheral tissues, particularly the gastrointestinal tract, whereas NMU(2) is abundant within the brain and spinal cord. NMU peptide parallels receptor distribution with highest expression in the gastrointestinal tract and specific structures within the brain, reflecting its major role in the regulation of energy balance. The NMU knockout mouse has an obese phenotype and, in agreement, the Arg165Trp amino acid variant of NMU-25 in humans, which is functionally inactive, co-segregated with childhood-onset obesity. Emerging physiological roles for NMU include vasoconstriction mediated predominantly via NMU(1) with nociception and bone remodelling via NMU(2). The NMU system has also been implicated in the pathogenesis of septic shock and cancers including bladder carcinoma and acute myeloid leukaemia. Intriguingly, NMS is more potent at NMU(2) receptors in vivo where it has similar central actions in suppression of feeding and regulation of circadian rhythms to NMU. Taken together with its vascular actions, NMU may be a functional link between energy balance and the cardiovascular system and may provide a future target for therapies directed against the disorders that comprise metabolic syndrome.

Leber's hereditary optic neuropathy associated with multiple sclerosis: Harding's syndrome.

We describe a 32-year-old woman with sequential, severe, painless visual loss in one eye and then the other, and three temporally distinct episodes of neurological disturbance suggestive of demyelination in the spinal cord. She was positive for the T14484C mutation in the mitochondrial genome, one of three common mutations causing Leber's hereditary optic neuropathy. In addition, MRI identified areas of demyelination within the periventricular white matter of the brain and within the spinal cord. The coexistence of multiple sclerosis and Leber's hereditary optic neuropathy (Harding's syndrome) is known to occur more often than would be expected by chance; therefore, screening for the Leber's mutations in multiple sclerosis patients with severe visual loss should be considered because this has important prognostic and genetic implications.

Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues.

Amyotrophic lateral sclerosis (ALS) is a relatively rare disease with a reported population incidence of between 1.5 and 2.5 per 100,000 per year. Over the past 10 years, the design of ALS epidemiological studies has evolved to focus on a prospective, population based methodology, employing the El Escorial criteria and multiple sources of data to ensure complete case ascertainment. Five such studies, based in Europe and North America, have been published and show remarkably consistent incidence figures among their respective Caucasian populations. Population based studies have been useful in defining clinical characteristics and prognostic indicators in ALS. However, many epidemiological questions remain that cannot be resolved by any of the existing population based datasets. The working hypotheses is that ALS, like other chronic diseases, is a complex genetic condition, and the relative contributions of individual environmental and genetic factors are likely to be relatively small. Larger studies are required to characterise risks and identify subpopulations that might be suitable for further study. This current paper outlines the contribution of the various population based registers, identifies the limitations of the existing datasets and proposes a mechanism to improve the future design and output of descriptive epidemiological studies.

Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease.

BACKGROUND: Trophic factors, including recombinant human insulin-like growth factor I (rhIGF-I) are possible disease modifying therapies for amyotrophic lateral sclerosis. OBJECTIVES: To examine the efficacy of recombinant human insulin-like growth factor I in amyotrophic lateral sclerosis. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (March 2006), MEDLINE (January 1966 to March 2006) and EMBASE (January 1980 to March 2006) and asked the authors of randomised clinical trials and manufacturers of recombinant human insulin-like growth factor I. SELECTION CRITERIA: We considered all randomised controlled clinical trials involving rhIGF-I treatment of amyotrophic lateral sclerosis in adults with a clinical diagnosis of definite or probable amyotrophic lateral sclerosis according to the El Escorial Criteria. The primary outcome measure was change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score after nine months treatment and secondary outcome measures were change in AALSRS at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events. DATA COLLECTION AND ANALYSIS: We identified three randomised clinical trials. Only two were included in the analysis. Each author graded the studies for methodological quality. Data were extracted and entered by the lead author and checked by the other two. Some missing data had to be regenerated by calculations based on ruler measurements of data presented in published graphs. MAIN RESULTS: In a European trial with 59 participants on placebo and 124 on rhIGF-I, 0.1 mg/kg/day the mean difference (MD) in change in AALSRS total score after nine months was -3.30 (95% confidence interval (CI) -8.68 to 2.08), non-significantly less in the treated than the placebo group. In a North American trial, in which 90 participants on placebo were compared with 89 on recombinant human insulin-like growth factor I 0.05 mg/kg/day, and 87 participants on 0.1 mg/kg/day, the MD after nine months was -6.00 (95%CI -10.99 to -1.01), significantly less on treatment. The combined analysis from both randomised clinical trials showed a weighted mean difference after nine months of -4.75 (95% CI -8.41 to -1.09), a significant difference in favour of the treated group. The secondary outcome measures showed non-significant trends favouring rhIGF-I. Similarly the data with the 0.05 mg/kg/day dose showed trends favouring rhIGF-I at all time points but did not reach significance at the five per cent level at any point. There was an increased risk of injection site reactions with rhIGF-I (relative risk 2.53, 95% CI 1.40 to 4.59). AUTHORS' CONCLUSIONS: The available randomised placebo controlled trials do not permit a definitive assessment of the clinical efficacy of rhIGF-I on ALS. More research is needed and one trial is in progress. Future trials should include survival as an outcome measure.

Amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (known in the UK as motor neuron disease) is a devastating illness with uncertain pathogenesis. In this Seminar, we review its natural history, clinical features, diagnostic criteria, variant and mimic syndromes, genetic forms, and epidemiology. Several hypotheses about causes of the disorder are discussed, such as excitotoxicity and oxidant stress, and we review past and present putative disease-modifying treatments. Disease-management strategies, from telling the patient about their illness to end-of-life decisions and palliative care, are presented. We review options for control of the main symptoms of amyotrophic lateral sclerosis--including dysphagia, dysarthria, respiratory distress, pain, and psychological disorders--and care in the terminal phase. The need for good psychosocial and spiritual care of patients and families is emphasised. We conclude with an overview of some current major issues and future prospects, ranging from the search for disease markers to challenging developments such as stem-cell and gene therapy.

Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).

BACKGROUND: Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest efficacy. OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Register for randomized trials in December 2004 and made enquiries of authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. We searched MEDLINE (January 1966 to August 25 2006) and EMBASE (January 1980 to September 30th 2006). SELECTION CRITERIA: Types of studies: randomized trials. TYPES OF PARTICIPANTS: adults with a diagnosis of amyotrophic lateral sclerosis. Types of interventions: treatment with riluzole or placebo. Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality with riluzole 50, 100 and 200 mg; neurologic function, muscle strength and adverse events. DATA COLLECTION AND ANALYSIS: We identified four eligible randomized trials. MAIN RESULTS: The four trials examining tracheostomy-free survival included a total of 974 riluzole treated patients and 503 placebo treated patients. The methodological quality was acceptable and three trials were easily comparable, although one trial included older patients in more advanced stages of amyotrophic lateral sclerosis and one had multiple primary endpoints. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (P value = 0.042, hazard ratio 0.80, 95% confidence interval 0.64 to 0.99) and there was no evidence of heterogeneity (P value = 0.33). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P value < 0.0001) and the random effects model, which takes this into account, resulted in the overall treatment effect estimate falling just short of significance (P value = 0.056, hazard ratio 0.84, 95% confidence interval 0.70 to 1.01). This represented a 9% gain in the probability of surviving one year (57% in the placebo and 66% in the riluzole group). There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (weighted mean difference 2.62, 95% confidence interval 1.59 to 4.31). AUTHORS' CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.