Mechanistic studies of isomeric [2]rotaxanes consisting of two different tetrathiafulvalene units reveal that the movement of cyclobis(paraquat-p-phenylene) can be controlled.

Controlling the movement in artificial molecular machines is a key challenge that needs to be solved before their full potential can be harnessed. In this study, two isomeric tri-stable [2]rotaxanes 1·4PF6 and 2·4PF6 incorporating both a tetrathiafulvalene (TTF) and a monopyrrolotetrathiafulvalene (MPTTF) unit in the dumbbell component have been synthesised to measure the energy barriers when the tetracationic cyclobis(paraquat-p-phenylene) (CBPQT4+) ring moves across either a TTF2+ or an MPTTF2+ dication. By strategically exchanging one of the thiomethyl barriers on either the TTF unit or the MPTTF unit with the bulkier thioethyl group, the movement of the CBPQT4+ ring in 14+ and 24+ can be controlled to take place in only one direction upon tetra-oxidation. Cyclic voltammetry and 1H NMR spectroscopy were used to investigate the switching mechanism and it was found that upon tetra-oxidation of 14+ and 24+, the CBPQT4+ ring moves first to a position where it is located between the TTF2+ and MPTTF2+ dications producing high-energy co-conformations which slowly interconvert into thermodynamically more stable co-conformations. The kinetics of the movement occurring in the tetra-oxidised [2]rotaxanes 18+ and 28+ were studied at different temperatures allowing the free energy of the transition state, when CBPQT4+ moves across TTF2+ (21.5 kcal mol-1) and MPTTF2+ (20.3 kcal mol-1) at 298 K, to be determined. These results demonstrate for the first time that the combination of a TTF and an MPTTF unit can be used to induce directional movement of the CBPQT4+ ring in molecular machines with a 90% efficiency.

Evaluating the energy landscape of an out-of-equilibrium bistable [2]rotaxane containing monopyrrolotetrathiafulvalene.

The unique redox properties of monopyrrolotetrathiafulvalene can be used to induce directional movement in interlocked molecules. In this study, the kinetics for the directional movement of cyclobis(paraquat-p-phenylene) across the dioxidised monopyrrolotetrathiafulvalene in a [2]rotaxane is quantified by time-resolved 1H NMR spectroscopy.

Efficacy and safety of emapalumab in macrophage activation syndrome.

OBJECTIVES: Macrophage activation syndrome (MAS) is a severe, life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD). The objective of this study was to confirm the adequacy of an emapalumab dosing regimen in relation to interferon-γ (IFNγ) activity by assessing efficacy and safety. The efficacy outcome was MAS remission by week 8, based on clinical and laboratory criteria. METHODS: We studied emapalumab, a human anti-IFNγ antibody, administered with background glucocorticoids, in a prospective single-arm trial involving patients who had MAS secondary to sJIA or AOSD and had previously failed high-dose glucocorticoids, with or without anakinra and/or ciclosporin. The study foresaw 4-week treatment that could be shortened or prolonged based on investigator's assessment of response. Patients entered a long-term (12 months) follow-up study. RESULTS: Fourteen patients received emapalumab. All patients completed the trial, entered the long-term follow-up and were alive at the end of follow-up. The investigated dosing regimen, based on an initial loading dose followed by maintenance doses, was appropriate, as shown by rapid neutralisation of IFNγ activity, demonstrated by a prompt decrease in serum C-X-C motif chemokine ligand 9 (CXCL9) levels. By week 8, MAS remission was achieved in 13 of the 14 patients at a median time of 25 days. Viral infections and positive viral tests were observed. CONCLUSIONS: Neutralisation of IFNγ with emapalumab was efficacious in inducing remission of MAS secondary to sJIA or AOSD in patients who had failed high-dose glucocorticoids. Screening for viral infections should be performed, particularly for cytomegalovirus. TRIAL REGISTRATION NUMBER: NCT02069899 and NCT03311854.

Health-related quality of life, anxiety and depression in the diagnostic phase of suspected cancer, and the influence of diagnosis.

BACKGROUND: Undergoing diagnostic evaluation for cancer has been associated with a high prevalence of anxiety and depression and affected health-related quality of life (HRQoL). The aims of this study were to assess HRQoL, anxiety, and depression pre- and post-diagnosis in patients undergoing diagnostic evaluations for cancer due to non-specific symptoms; to examine changes over time in relation to final diagnosis (cancer yes/no); and to assess the predictive value of pre-diagnostic psychological, socio-demographic and clinical factors. METHODS: A prospective, multicenter survey study of patients suspected to have cancer based on non-specific symptoms was performed. Participants completed the EORTC-QLQ-C30 quality of life scale, HADS, SOC-13 and self-rated health before and after completing diagnostic evaluations. Intra- and inter-group differences between patients diagnosed with cancer versus patients with non-cancer diagnoses were calculated. The impact of baseline psychological, socio-demographic, and medical factors on HRQoL, anxiety and depression at follow-up was explored by bootstrapped multivariate linear regression analyses and logistic regression analyses. RESULTS: A total of 838 patients participated in this study; 679 (81 %) completed the follow-up. Twenty-two percent of the patients received a cancer diagnosis at the end of the follow-up. Patients presented initially with a high burden of symptoms and affected role and emotional functioning and global health/QL, irrespective of diagnosis. The prevalence of clinical anxiety prior to knowledge of the diagnosis was 32 % in patients with cancer and 35 % in patients who received a non-cancer diagnosis. HRQoL and anxiety improved after diagnosis, and a larger improvement was seen in patients who received a non-cancer diagnosis. There were no intra- or inter-group differences in the depression scores. The strongest predictors of global QL, anxiety, and depression after a known diagnosis were baseline scores, co-morbidity and poor self-rated health. CONCLUSIONS: Patients undergoing diagnostic evaluations for cancer based on non-specific symptoms experience a high prevalence of anxiety and affected quality of life prior to knowledge of the diagnosis. The predictive value of the baseline scores is important when assessing the psychological impact of undergoing diagnostic evaluations for cancer.

Effect of weight maintenance on symptoms of knee osteoarthritis in obese patients: a twelve-month randomized controlled trial.

OBJECTIVE: To compare results of obese patients with knee osteoarthritis (OA) who, after an intensive weight loss regimen, received 1 year of either dietary support (D), a knee-exercise program (E), or "no attention" (C; control group). METHODS: We conducted a randomized, 2-phase, parallel-group trial. A total of 192 obese participants with knee OA were enrolled; the mean age was 62.5 years and 81% were women with a mean entry weight of 103.2 kg. In phase 1, all participants were randomly assigned to 1 of 3 groups and began a dietary regimen of 400-810 and 1,250 kcal/day for 16 weeks (2 8-week phases) to achieve a major weight loss. Phase 2 consisted of 52 weeks' maintenance in either group D, E, or C. Outcomes were changes from randomization in pain on a 100-mm visual analog scale, weight, and response according to the Outcome Measures in Rheumatology-Osteoarthritis Research Society International criteria. RESULTS: Mean weight loss for phase 1 was 12.8 kg. After 1 year on maintenance therapy, the D group sustained a lower weight (11.0 kg, 95% confidence interval [95% CI] 9.0, 12.8 kg) than those in the E (6.2, 95% CI 4.4, 8.1 kg) and C (8.2, 95% CI 6.4, 10.1 kg) groups (P = 0.002 by analysis of covariance [ANCOVA]). Adherence was low in the E group. All groups had statistically significant pain reduction (D: 6.1; E: 5.6; and C: 5.5 mm) with no difference between groups (P = 0.98 by ANCOVA). In each group 32 (50%), 26 (41%), and 33 (52%) participants responded to treatment in the D, E, and C groups, respectively, with no statistically significant difference in the number of responders (P = 0.41). CONCLUSION: A significant weight reduction with a 1-year maintenance program improves knee OA symptoms irrespective of maintenance program.

Comparison of three weight maintenance programs on cardiovascular risk, bone and vitamins in sedentary older adults.

OBJECTIVE: Obese patients with knee osteoarthritis (OA) are encouraged to lose weight to obtain symptomatic relief. Risk of vascular events is higher in people with OA compared to people without arthritis. Our aim in this randomized trial was to compare changes in cardiovascular disease (CVD) risk-factors, nutritional health, and body composition after 1-year weight-loss maintenance achieved by [D]diet, [E]knee-exercise, or [C]control, following weight loss by low-energy-diet. DESIGN AND METHODS: Obese individuals (n = 192, >50 years) with knee OA, 63 years (SD 6), weight 103.2 kg (15.0), body-mass index 37.3 kg/m(2) (4.8), were enrolled into a 68-week weight-loss trial. RESULTS: Mean changes in weight, in D, E, and C were -11.0, -6.3, and -8.3 kg (P = 0.002). Reduction in waist circumference in D, E, and C were -8.4, -4.6, and -7.0 cm (P = 0.007). D reduced waist circumference significantly more than E: -3.8 cm (95%CI -6.2 to -1.4; P = 0.0024). There was no difference between the groups in changes in CVD risk factors; blood pressure, triglycerides, and cholesterol. Nutritional health was improved in all groups. For markers of bone, no statistical difference was found between the groups. CONCLUSIONS: Dietary support, or control, maintained improvements in cardiovascular risk factors to the same extent and none of the interventions had a detrimental effect on bone.