ObjectiveTo determine whether a multicomponent intervention based on physical activity with technological support and nutritional counselling prevents mobility disability in older adults with physical frailty and sarcopenia.DesignEvaluator blinded, randomised controlled trial.Setting16 clinical sites across 11 European countries, January 2016 to 31 October 2019.Participants1519 community dwelling men and women aged 70 years or older with physical frailty and sarcopenia, operationalised as the co-occurrence of low functional status, defined as a short physical performance battery (SPPB) score of 3 to 9, low appendicular lean mass, and ability to independently walk 400 m. 760 participants were randomised to a multicomponent intervention and 759 received education on healthy ageing (controls).InterventionsThe multicomponent intervention comprised moderate intensity physical activity twice weekly at a centre and up to four times weekly at home. Actimetry data were used to tailor the intervention. Participants also received personalised nutritional counselling. Control participants received education on healthy ageing once a month. Interventions and follow-up lasted for up to 36 months.Main outcome measuresThe primary outcome was mobility disability (inability to independently walk 400 m in <15 minutes). Persistent mobility disability (inability to walk 400 m on two consecutive occasions) and changes from baseline to 24 and 36 months in physical performance, muscle strength, and appendicular lean mass were analysed as pre-planned secondary outcomes. Primary comparisons were conducted in participants with baseline SPPB scores of 3-7 (n=1205). Those with SPPB scores of 8 or 9 (n=314) were analysed separately for exploratory purposes.ResultsMean age of the 1519 participants (1088 women) was 78.9 (standard deviation 5.8) years. The average follow-up was 26.4 (SD 9.5) months. Among participants with SPPB scores of 3-7, mobility disability occurred in 283/605 (46.8%) assigned to the multicomponent intervention and 316/600 (52.7%) controls (hazard ratio 0.78, 95% confidence interval 0.67 to 0.92; P=0.005). Persistent mobility disability occurred in 127/605 (21.0%) participants assigned to the multicomponent intervention and 150/600 (25.0%) controls (0.79, 0.62 to 1.01; P=0.06). The between group difference in SPPB score was 0.8 points (95% confidence interval 0.5 to 1.1 points; P<0.001) and 1.0 point (95% confidence interval 0.5 to 1.6 points; P<0.001) in favour of the multicomponent intervention at 24 and 36 months, respectively. The decline in handgrip strength at 24 months was smaller in women assigned to the multicomponent intervention than to control (0.9 kg, 95% confidence interval 0.1 to 1.6 kg; P=0.028). Women in the multicomponent intervention arm lost 0.24 kg and 0.49 kg less appendicular lean mass than controls at 24 months (95% confidence interval 0.10 to 0.39 kg; P<0.001) and 36 months (0.26 to 0.73 kg; P<0.001), respectively. Serious adverse events occurred in 237/605 (39.2%) participants assigned to the multicomponent intervention and 216/600 (36.0%) controls (risk ratio 1.09, 95% confidence interval 0.94 to 1.26). In participants with SPPB scores of 8 or 9, mobility disability occurred in 46/155 (29.7%) in the multicomponent intervention and 38/159 (23.9%) controls (hazard ratio 1.25, 95% confidence interval 0.79 to 1.95; P=0.34).ConclusionsA multicomponent intervention was associated with a reduction in the incidence of mobility disability in older adults with physical frailty and sarcopenia and SPPB scores of 3-7. Physical frailty and sarcopenia may be targeted to preserve mobility in vulnerable older people.Trial registrationClinicalTrials.gov NCT02582138.

To investigate the hypothesis that early treatment of a migraine attack with sumatriptan, while pain is still mild, results in higher pain free rates in comparison to delayed treatment, when pain is at least moderate, we performed a prospective, controlled and open label study. Migraineurs with or without aura who fulfilled the diagnostic criteria recommended by the International Headache Society were enrolled in the study and randomly assigned to either 'early' or 'late' treatment with sumatriptan 100 mg tablets. In the early treatment group significantly more patients were pain free at all times measured during two hours after dosing than in the late treatment group. Furthermore, patients in the early treatment group became pain free significantly sooner after dosing than patients who delayed treatment. It is concluded that migraineurs, who are able to differentiate between a migraine attack and other forms of headache, benefit from early intervention with sumatriptan 100 mg tablets.

Free radical-mediated inflammatory processes account for a great portion of morbidity and mortality in critically ill patients. The purpose of this study was to determine two plasma peroxidation markers and three volatile markers related to lipid peroxidation, metabolic activity and cholesterol metabolism, and to explore relationships between the different markers and patients' clinical status. Substances were analyzed in whole blood and in exhaled air in patients with head injury, acute respiratory distress syndrome (ARDS) and in those being at risk of developing ARDS. These results were compared with the baseline measurements in healthy individuals. Additionally, patients were assessed according to their inflammatory status. Concentrations of malondialdehyde and thiobarbituric acid-reactive substances in plasma as well as pentane concentrations in breath increased with increasing inflammatory status. Although these compounds are generated through peroxidation of fatty acids, concentrations of these markers were significantly different in patient groups. Isoprene concentrations were lowest in the ARDS group. Acetone concentrations were not different between patient groups. We conclude that for the assessment of lipid peroxidation and other inflammatory reactions a set of parameters has to be defined. More detailed insights into inflammatory processes can be obtained when the volatile markers and the serum markers are considered together.

IntroductionRemifentanil is an opioid with a unique pharmacokinetic profile. Its organ-independent elimination and short context-sensitive half time of 3 to 4 minutes lead to a highly predictable offset of action. We tested the hypothesis that with an analgesia-based sedation regimen with remifentanil and propofol, patients after cardiac surgery reach predefined criteria for discharge from the intensive care unit (ICU) sooner, resulting in shorter duration of time spent in the ICU, compared to a conventional regimen consisting of midazolam and fentanyl. In addition, the two regimens were compared regarding their costs. MethodsIn this prospective, open-label, randomised, singlecentre study, a total of 80 patients (18 to 75 years old), who had undergone cardiac surgery, were postoperatively assigned to one of two treatment regimens for sedation in the ICU for 12 to 72 hours. Patients in the remifentanil/propofol group received remifentanil (6-max. 60 µg kg -1 h -1 ; dose exceeds recommended labelling). Propofol (0.5 to 4.0 mg kg -1 h -1 ) was supplemented only in the case of insufficient sedation at maximal remifentanil dose. Patients in the midazolam/fentanyl group received midazolam (0.02 to 0.2 mg kg -1 h -1 ) and fentanyl (1.0 to 7.0 µg kg -1 h -1 ). For treatment of pain after extubation, both groups received morphine and/or non-opioid analgesics. ResultsThe time intervals (mean values ± standard deviation) from arrival at the ICU until extubation (20.7 ± 5.2 hours versus 24.2 h ± 7.0 hours) and from arrival until eligible discharge from the ICU (46.1 ± 22.0 hours versus 62.4 ± 27.2 hours) were significantly (p < 0.05) shorter in the remifentanil/propofol group. Overall costs of the ICU stay per patient were equal (approximately €1,700 on average). ConclusionCompared with midazolam/fentanyl, a remifentanilbased regimen for analgesia and sedation supplemented with propofol significantly reduced the time on mechanical ventilation and allowed earlier discharge from the ICU, at equal overall costs.

LEP algesimetry is sensitive to analgesics with different modes of action and may enable the effects of novel analgesics to be assessed during early clinical development.

The role of lipid peroxidation after brain injury is still not completely understood, and results of different studies have been equivocal. In this study, three proposed peroxidation markers were determined in patients early after isolated head injury and results compared to healthy controls. Malondialdehyde (MDA) and thiobarbituric acid-reactive substances (TBARS) were measured in plasma, and n-pentane was determined in patients' exhaled air. For MDA and TBARS no significant differences could be shown (0.267 vs. 0.358 ng/mL, and 0.896 vs. 0.814 ng/mL in patients vs. healthy volunteers, respectively). n-Pentane, however, was significantly increased in the expired air of patients (0.471 vs. 0.118 nmol/L in healthy volunteers). Similar results for n-pentane were obtained when only male patients and volunteers were considered (0.510 vs. 0.113 nmol/L). Stratification according to clinical outcome showed significantly higher values for n-pentane in male patients with poor outcome (0.656 nmol/L) in comparison with healthy male volunteers (0.113 nmol/L). No difference was found when patients were stratified according to the presence or absence of subarachnoid hemorrhage. It is concluded that, only in a sub-population of patients with brain injury, lipid-peroxidation is a crucial mechanism. n-Pentane seems to be a valuable marker to detect lipid peroxidation early after brain trauma. Malondialdehyde may be of value only later in the course of the disease. TBARS are not a specific marker and should therefore not be used.

There is an obvious need to improve clinical trial designs with respect to efficiency, duration and the number of patients recruited. Adaptive (flexible) designs may be valuable in this respect. We simulated the properties of a two-stage adaptive proof-of-concept and dose-finding trial design in adult migraine patients with moderate to severe headache, with or without aura. We also assessed the usefulness of a combined Bayesian and frequentist approach in the estimation of the probability of success of subsequent Phase III studies. Applying such an innovative approach would result in a reduction of the required sample size by 30 patients and no prolongation of the trial duration. The probability of success in Phase III is > 81%. An innovative adaptive design can facilitate testing of investigational migraine medications by reducing patient numbers and improving predictivity of success in Phase III.

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