Effectiveness of an intervention to reduce sedentary behaviour as a personalised secondary prevention strategy for patients with coronary artery disease: main outcomes of the SIT LESS randomised clinical trial.

BACKGROUND: A high sedentary time is associated with increased mortality risk. Previous studies indicate that replacement of sedentary time with light- and moderate-to-vigorous physical activity attenuates the risk for adverse outcomes and improves cardiovascular risk factors. Patients with cardiovascular disease are more sedentary compared to the general population, while daily time spent sedentary remains high following contemporary cardiac rehabilitation programmes. This clinical trial investigated the effectiveness of a sedentary behaviour intervention as a personalised secondary prevention strategy (SIT LESS) on changes in sedentary time among patients with coronary artery disease participating in cardiac rehabilitation. METHODS: Patients were randomised to usual care (n = 104) or SIT LESS (n = 108). Both groups received a comprehensive 12-week centre-based cardiac rehabilitation programme with face-to-face consultations and supervised exercise sessions, whereas SIT LESS participants additionally received a 12-week, nurse-delivered, hybrid behaviour change intervention in combination with a pocket-worn activity tracker connected to a smartphone application to continuously monitor sedentary time. Primary outcome was the change in device-based sedentary time between pre- to post-rehabilitation. Changes in sedentary time characteristics (prevalence of prolonged sedentary bouts and proportion of patients with sedentary time ≥ 9.5 h/day); time spent in light-intensity and moderate-to-vigorous physical activity; step count; quality of life; competencies for self-management; and cardiovascular risk score were assessed as secondary outcomes. RESULTS: Patients (77% male) were 63 ± 10 years and primarily diagnosed with myocardial infarction (78%). Sedentary time decreased in SIT LESS (- 1.6 [- 2.1 to - 1.1] hours/day) and controls (- 1.2 [ ─1.7 to - 0.8]), but between group differences did not reach statistical significance (─0.4 [─1.0 to 0.3]) hours/day). The post-rehabilitation proportion of patients with a sedentary time above the upper limit of normal (≥ 9.5 h/day) was significantly lower in SIT LESS versus controls (48% versus 72%, baseline-adjusted odds-ratio 0.4 (0.2-0.8)). No differences were observed in the other predefined secondary outcomes. CONCLUSIONS: Among patients with coronary artery disease participating in cardiac rehabilitation, SIT LESS did not induce significantly greater reductions in sedentary time compared to controls, but delivery was feasible and a reduced odds of a sedentary time ≥ 9.5 h/day was observed. TRIAL REGISTRATION: Netherlands Trial Register: NL9263. Outcomes of the SIT LESS trial: changes in device-based sedentary time from pre-to post-cardiac rehabilitation (control group) and cardiac rehabilitation + SIT LESS (intervention group). SIT LESS reduced the odds of patients having a sedentary time >9.5 hours/day (upper limit of normal), although the absolute decrease in sedentary time did not significantly differ from controls. SIT LESS appears to be feasible, acceptable and potentially beneficial, but a larger cluster randomised trial is warranted to provide a more accurate estimate of its effects on sedentary time and clinical outcomes. CR: cardiac rehabilitation.

Sedentary Behaviour Intervention as a Personalised Secondary Prevention Strategy (SIT LESS) for patients with coronary artery disease participating in cardiac rehabilitation: rationale and design of the SIT LESS randomised clinical trial.

Patients with coronary artery disease (CAD) are more sedentary compared with the general population, but contemporary cardiac rehabilitation (CR) programmes do not specifically target sedentary behaviour (SB). We developed a 12-week, hybrid (centre-based+home-based) Sedentary behaviour IntervenTion as a personaLisEd Secondary prevention Strategy (SIT LESS). The SIT LESS programme is tailored to the needs of patients with CAD, using evidence-based behavioural change methods and an activity tracker connected to an online dashboard to enable self-monitoring and remote coaching. Following the intervention mapping principles, we first identified determinants of SB from literature to adapt theory-based methods and practical applications to target SB and then evaluated the intervention in advisory board meetings with patients and nurse specialists. This resulted in four core components of SIT LESS: (1) patient education, (2) goal setting, (3) motivational interviewing with coping planning, and (4) (tele)monitoring using a pocket-worn activity tracker connected to a smartphone application and providing vibrotactile feedback after prolonged sedentary bouts. We hypothesise that adding SIT LESS to contemporary CR will reduce SB in patients with CAD to a greater extent compared with usual care. Therefore, 212 patients with CAD will be recruited from two Dutch hospitals and randomised to CR (control) or CR+SIT LESS (intervention). Patients will be assessed prior to, immediately after and 3 months after CR. The primary comparison relates to the pre-CR versus post-CR difference in SB (objectively assessed in min/day) between the control and intervention groups. Secondary outcomes include between-group differences in SB characteristics (eg, number of sedentary bouts); change in SB 3 months after CR; changes in light-intensity and moderate-to-vigorous-intensity physical activity; quality of life; and patients' competencies for self-management. Outcomes of the SIT LESS randomised clinical trial will provide novel insight into the effectiveness of a structured, hybrid and personalised behaviour change intervention to attenuate SB in patients with CAD participating in CR. Trial registration number NL9263.

The state of the art in beyond 5G distributed massive multiple-input multiple-output communication system solutions.

Beyond fifth generation (5G) communication systems aim towards data rates in the tera bits per second range, with improved and flexible coverage options, introducing many new technological challenges in the fields of network architecture, signal pro- cessing, and radio frequency front-ends. One option is to move towards cell-free, or distributed massive Multiple-Input Multiple-Output (MIMO) network architectures and highly integrated front-end solutions. This paper presents an outlook on be- yond 5G distributed massive MIMO communication systems, the signal processing, characterisation and simulation challenges, and an overview of the state of the art in millimetre wave antennas and electronics.

Element Specificity of Transient Extreme Ultraviolet Magnetic Dichroism.

In this work we combine theory and experiment to study transient magnetic circular dichroism (TRMCD) in the extreme ultraviolet spectral range in bulk Co and CoPt. We use the ab initio method of real-time time-dependent density functional theory to simulate the magnetization dynamics in the presence of short laser pulses. From this we demonstrate how TRMCD may be calculated using an approximation to the excited-state linear response. We apply this approximation to Co and CoPt and show computationally that element-specific dynamics of the local spin moments can be extracted from the TRMCD in the extreme ultraviolet energy range, as is commonly assumed. We then compare our theoretical prediction for the TRMCD for CoPt with experimental measurement and find excellent agreement at many different frequencies including the M_{23} edge of Co and N_{67} and O_{23} edges of Pt.

Magneto-Optical Functions at the 3p Resonances of Fe, Co, and Ni: Ab initio Description and Experiment.

We present experimental data and a complete theoretical description of the magneto-optical contributions to the complex refractive index in the extreme ultraviolet (XUV) range covering the 3p resonances of Fe, Co, and Ni. The direct comparison of the two allows us to conclude that many-body corrections to the ground state and local field effects are crucial for an accurate description of M-edge spectra. Our results are relevant for investigation of static magnetization, via XUV spectroscopy of multielement systems, as well as the dynamics of magnetization, as needed in the study of femtomagnetism and spintronics.

Addition of heart score to high-sensitivity troponin T versus conventional troponin T in risk stratification of patients with chest pain at the coronary emergency rooms.

Patients with chest pain have a large impact on available resources in coronary emergency rooms (CER). Clinical judgement, ECG, risk scores and biomarkers guide in risk stratification. We investigated if high-sensitivity troponin T (HsT) and the HEART Score could contribute to risk stratification at the CER. All patients with chest pain, without elevated conventional troponin levels at presentation, were included. HsT levels were determined at admission (T1), at 4-6 h (T2) and 8-10 h after symptom onset (T3). The HEART Score was calculated as risk score for the occurrence of a major adverse cardiac event (MACE). Thirty days after discharge, occurrence of MACE was registered. Eighty-nine patients were included (overall mean age 61 years (range 20-90)). At presentation, 68 patients (76 %) had a HsT below cut-off value of 14 ng/l (mean HEART Score 3.7, range 1-9). Thirty-one of these 68 patients had a HEART Score between 1-3, no MACE occurred in this group. For 3 patients (4 %) HsT levels increased above 14 ng/l. These 3 patients had a HEART Score between 4-6. The majority of patients with chest pain can be safely discharged within 4-6 h after onset of symptoms using HsT and the HEART Score. In contrast, patients with initially normal HsT but a high HEART Score need longer follow-up and repeat HsT determination.

Routine versus aggressive upstream rhythm control for prevention of early atrial fibrillation in heart failure: background, aims and design of the RACE 3 study.

BACKGROUND: Rhythm control for atrial fibrillation (AF) is cumbersome because of its progressive nature caused by structural remodelling. Upstream therapy refers to therapeutic interventions aiming to modify the atrial substrate, leading to prevention of AF. OBJECTIVE: The Routine versus Aggressive upstream rhythm Control for prevention of Early AF in heart failure (RACE 3) study hypothesises that aggressive upstream rhythm control increases persistence of sinus rhythm compared with conventional rhythm control in patients with early AF and mild-to-moderate early systolic or diastolic heart failure undergoing electrical cardioversion. DESIGN: RACE 3 is a prospective, randomised, open, multinational, multicenter trial. Upstream rhythm control consists of angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers, mineralocorticoid receptor antagonists, statins, cardiac rehabilitation therapy, and intensive counselling on dietary restrictions, exercise maintenance, and drug adherence. Conventional rhythm control consists of routine rhythm control therapy without cardiac rehabilitation therapy and intensive counselling. In both arms, every effort is made to keep patients in the rhythm control strategy, and ion channel antiarrhythmic drugs or pulmonary vein ablation may be instituted if AF relapses. Total inclusion will be 250 patients. If upstream therapy proves to be effective in improving maintenance of sinus rhythm, it could become a new approach to rhythm control supporting conventional pharmacological and non-pharmacological rhythm control.

[Brant goose colonies near snowy owls: internest distances in relation to lemming and arctic fox abundance].

Brant goose colonies around snowy owl nests have been studied near Meduza Bay (73 degrees 21' N, 80 degrees 32' E) and in the lower reaches of the Uboinaya River (73 degrees 37' N, 82 degrees 10' E), the northwestern Taimyr Peninsula, from 1999 to 2006. All brant nests within 680 m from an owl nest have been regarded as an individual colony. The results show that the area of the colony is always larger than the guarded area around the owl nest. In years of high abundance of lemmings, brant geese nest generally closer to the owl nest than in years of high abundance. When arctic foxes are abundant, however, brant geese nest significantly closer to owls than when the foxes are scarce, irrespective of lemming abundance. The mechanism of brant colony formation around owl nests is based on a number of stimuli.

Cumulative metal leaching from utilisation of secondary building materials in river engineering.

The present paper estimates the utilisation of bulky wastes (minestone, steel slag, phosphorus slag and demolition waste) in hydraulic engineering structures in Dutch parts of the rivers Rhine, Meuse and Scheldt over the period 1980-2025. Although they offer several economic, technical and environmental benefits, these secondary building materials contain various metals that may leach into river water. A leaching model was used to predict annual emissions of arsenic, cadmium, copper, chromium, lead, mercury, nickel and zinc. Under the current utilisation and model assumptions, the contribution of secondary building materials to metal pollution in Dutch surface waters is expected to be relatively low compared to other sources (less than 0.1% and 0.2% in the years 2000 and 2025, respectively). However, continued and widespread large-scale applications of secondary building materials will increase pollutant leaching and may require further cuts to be made in emissions from other sources to meet emission reduction targets and water quality standards. It is recommended to validate available leaching models under various field conditions. Complete registration of secondary building materials will be required to improve input data for leaching models.

OM197-MP-AC induces the maturation of human dendritic cells and promotes a primary T cell response.

Dendritic cell (DC) maturation is critical for the induction of antigen-specific T lymphocyte responses and may be essential for the development of human vaccines relying on T cell immunity. We investigated the effects on human DC of OM-197, a synthetic pseudodipeptide derived from amino acids, linked to three fatty acid chains and devoid of endotoxin properties. OM-197 upregulated the expression of HLA-DR, CD80, CD86, CD83, CD40 and CD54 at the surface of myeloid DC naturally present in blood as well as of DC generated in vitro from monocytes using IL-4 and GM-CSF. OM-197 also induced the release of IL-12 and TNF-alpha from DC. Finally, DC incubated with OM-197 after pulsing with hepatitis B surface antigen (HBs Ag) induced in vitro expansion of IFN-gamma-secreting HBs Ag-specific CD4(+) T lymphocytes from naive individuals. Taken together, these data identify OM-197 as a potential vaccine adjuvant for the induction of Th1-type responses.

[Anti-tumor immunotherapy based on dendritic cells]. / L'immunothérapie anti-tumorale à base de cellules dendritiques.

In cancer immunotherapy, the use of dendritic cells (DC) loaded with tumor-associated antigens (TAA) emerged as a promising strategy. We initiated 3 pilot clinical trials with immunological endpoints using TAA loaded autologous DC. These trials showed that this approach was safe and associated with the induction of potent TAA specific IFN-gamma responses, which were transient despite the providing a further help through KLH presentation. Subcutaneous (s.c.) IL-2 administration was associated with long-lasting TAA specific IL-5 production. Clinical responses were observed in about 1/3 of the patients. Further improvements will take advantage of the use of a new type of DC cells (IL-3/IFN-beta DC) and of tumor cell-DC hybrids.

Tumoricidal activity of monocyte-derived dendritic cells: evidence for a caspase-8-dependent, Fas-associated death domain-independent mechanism.

Monocyte-derived dendritic cells (DC) were found to be cytotoxic for several tumor cell lines including Jurkat cells, which were killed through a calcium-independent pathway. K562 cells were resistant, excluding a NK cell-like activity. DC-mediated apoptosis did not involve classical death receptors because it was not reversed by blocking TNF/TNFR, CD95/CD95 ligand, or TNF-related apoptosis-inducing ligand/TNF-related apoptosis-inducing ligand receptor interactions. Fas-associated death domain-deficient, but not caspase-8 deficient, Jurkat cells were killed by DC. Indeed, caspase-8 cleavage was demonstrated in Jurkat cells cocultured with DC, and the use of specific caspase inhibitors confirmed that apoptosis triggered by DC was caspase-8 dependent. Furthermore, the involvement of Bcl-2 family members in the control of DC-mediated apoptosis was demonstrated by Bid cleavage in Jurkat cells cocultured with DC and resistance of Jurkat cells overexpressing Bcl-2 to DC-mediated cytotoxicity. Overall, these data indicate that monocyte-derived DC exert a caspase-8-dependent, Fas associated death domain-independent tumoricidal activity, a finding that could be relevant to their therapeutic use in cancer.

Human monocyte-derived dendritic cells produce bioactive gelatinase B: inhibition by IFN-beta.

We studied the secretion of gelatinase B by dendritic cells (DC) generated by culturing human peripheral blood monocytes in granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). First, we found the intracellular expression of gelatinase B on sections of fixed DC pellets. Zymography analysis of the supernatants of DC cultured for 72 h demonstrated the presence of gelatinase B. To determine if DC produce net enzymatic activity, bioactive gelatinase, a novel sensitive fluorescent-activated substrate conversion (FASC) assay was used to complement the zymography data. Culture media of unstimulated DC demonstrated reproducible net gelatinolytic activity. Tumor necrosis factor-alpha (TNF-alpha) IL-1beta but not lipopolysaccharide (LPS) stimulation caused a significant increase in gelatinase B production in zymography analysis. Both types of stimulation failed to increase net gelatinase activity in FASC assay. Interestingly, interferon-beta (IFN-beta) significantly diminished both the total zymolytic production and the net bioactive gelatinase produced by DC in a dose-dependent manner. We conclude that human monocyte-derived DC secrete bioactive gelatinase B and that IFN-beta inhibits this production.

Deficient IL-12(p35) gene expression by dendritic cells derived from neonatal monocytes.

To gain insight into the defects responsible for impaired Th1 responses in human newborns, we analyzed the production of cytokines by dendritic cells (DC) derived from cord blood monocytes. We observed that neonatal DC generated from adherent cord blood mononuclear cells cultured for 6 days in the presence of IL-4 and GM-CSF show a phenotype similar to adult DC generated from adherent PBMC, although they express lower levels of HLA-DR, CD80, and CD40. Measurement of cytokine levels produced by neonatal DC upon stimulation by LPS, CD40 ligation, or poly(I:C) indicated a selective defect in the synthesis of IL-12. Determination of IL-12(p40) and IL-12(p35) mRNA levels by real-time RT-PCR revealed that IL-12(p35) gene expression is highly repressed in stimulated neonatal DC whereas their IL-12(p40) gene expression is not altered. The addition of rIFN-gamma to LPS-stimulated newborn DC restored their expression of IL-12(p35) and their synthesis of IL-12 (p70) up to adult levels. Moreover, we observed that neonatal DC are less efficient than adult DC to induce IFN-gamma production by allogenic adult CD4(+) T cells. This defect was corrected by the addition of rIL-12. We conclude that neonatal DC are characterized by a severe defect in IL-12(p35) gene expression which is responsible for an impaired ability to elicit IFN-gamma production by T cells.

Medical abortion as an alternative to vacuum aspiration: first experiences with the 'abortion pill' in The Netherlands.

OBJECTIVE: To establish to what extent medical abortion is desired as a supplement to existing care provision in The Netherlands and to establish the (dis)advantages of medical abortion versus surgical vacuum aspiration. METHODS: The research project began in November 1999 and ended in September 2000. In two abortion clinics, the clients were asked to answer some questions about their expectations (before treatment) and their experiences with the treatment (at the post-treatment check-up). At the post-treatment check-up, the clients were also asked to fill out the Hopkin's Symptom Checklist (HSCL) which is an objective measure for the psychological and physical well-being of the clients during the previous week. RESULTS: One hundred and thirty-one clients who chose medical abortion and 131 clients who chose surgical vacuum aspiration participated in the study. The failure rate was 3.3% for medical abortion and 1.5% for surgical vacuum aspiration. Of the medical abortion clients, 80.2% reported they were satisfied with this treatment and 68.1% said they would choose the same treatment procedure in the future. For vacuum aspiration, these figures were 92.9% and 83.2%, respectively. The most reported advantage of medical abortion was the fact that it was a pill, and no surgical procedures were necessary. The most reported disadvantages of medical abortion were the amount of blood loss and insecurity concerning the time of abortion. CONCLUSIONS: Medical abortion seems to be a good supplement to the existing care provision in The Netherlands and should be offered in other clinics.

Role and expression of CD40 on human retinal pigment epithelial cells.

PURPOSE: To examine the CD40 costimulatory molecule expression on normal resting or activated adult human retinal pigment epithelium (hRPE) cells and to evaluate its role as an activation molecule considering the potential antigen presentation functions of hRPE cells. METHODS: Expression of HLA-DR and costimulatory (CD40, B7.1, B7.2, CD54, and CD58) molecules on hRPE cells was analyzed by flow cytometry. CD40 triggering was performed using soluble CD40L or cocultures with CD40L transfected fibroblasts. Interleukin (IL)-6, -8, -10, and -12 secretions were measured by enzyme-linked immunosorbent assay. Antigen presentation function of hRPE cells was assessed by coculturing hRPE cells with allogeneic T cells. T-cell proliferation was measured by [(3)H]-thymidine incorporation, and T-cell apoptosis by measurement of caspase-3 activity. RESULTS: Interferon (IFN)gamma-activated hRPE cells expressed CD40, but not B7.1 or B7.2. Although interferongamma enhanced IL-6 and IL-8 production, CD40 triggering of IFNgamma-activated hRPE cells did not induce IL-12 secretion. hRPE cells did not stimulate allogeneic resting T cells and downregulated phytohemagglutinin-activated allogeneic T cells via a cell-to-cell contact-dependent mechanism. Some induction of apoptosis was detected. CONCLUSIONS: CD40 is expressed on IFNgamma-activated hRPE cells. Its ligation leads to an increased production of IL-6 and IL-8 but fails to induce B7.1 or B7. 2 expression, or to induce IL-12 secretion. Accordingly, hRPE cells do not activate allogenic T cells but inhibit T-cell proliferation, partly through induction of apoptosis. These results suggest that hRPE cells could be implicated more in a deviant antigen presentation. If the exact molecular mechanisms are unclear, it is likely that CD40-CD40L interaction could play a role in this process.

Electrocardiography in primary care; is it useful?

UNLABELLED: Little is known about the value of electrocardiography in primary care. AIMS: To assess whether electrocardiography (ECG) is a useful instrument, in addition to history taking and physical examination, in that it changes the general practitioner's management of patients with suspected cardiovascular symptoms or disease. METHODS AND RESULTS: We performed a prospective study in a group practice of eight general practitioners in The Netherlands. During 2 years all ECGs that were recorded in these practices were studied. Two questionnaires were filled out by the general practitioners, one before and one after the ECG recording, to determine indication for electrocardiography, the general practitioner's anticipated management before and after ECG results, and the subjective usefulness according to the applying doctor. All ECGs were reviewed by an experienced general practitioner working in the group practice and later on by a cardiologist. In addition, all clinical information, including the 6 months follow-up period, was scrutinised by both the cardiologist and general practitioner to establish the patients' prognosis. A total of 301 ECGs was included in the analysis. Main indications for electrocardiography were chest pain (57%), and collapse or palpitation (30%). In 92 (30.6%; 95% CI 25.4-35.8) patients a change in management by the general practitioner occurred following the ECG results. Most prevalent changes were non-referral to a cardiologist, while referral was anticipated before the ECG results (34%), referral while the patient would not have been referred without ECG results (20%), and change in cardiovascular therapy (40%). In one of these cases only, this change could be considered unfavourable, since a subendocardial infarction, not detectable on the ECG, was missed. In patients with chest pain, a normal ECG (likelihood ratio (LR) 0.06) and an abnormal ECG (LR 13.3) were very useful to distinguish between patients likely or unlikely to experience cardiac events in the near future. The mean subjective usefulness, on a scale of 0-100, of the ECG evaluation according to the applying general practitioner was 77. 5 (S.D. 14.4). There was good agreement in ECG interpretation between the experienced general practitioner, the cardiologist and a second general practitioner. CONCLUSION: Electrocardiography in addition to history taking and physical examination, may be an important tool in primary care. It can reduce considerably the number of unnecessary referrals.

Expression of c-FLIP(L) and resistance to CD95-mediated apoptosis of monocyte-derived dendritic cells: inhibition by bisindolylmaleimide.

To gain insight into the mechanisms controlling apoptosis of dendritic cells (DC), human monocyte-derived DC were analyzed for their expression of CD95 (Fas/Apo-1) and their response to CD95 ligation. Although DC expressed the CD95 molecule on their membrane, they did not undergo apoptosis on CD95 ligation unless sensitized by cycloheximide. In parallel, DC synthesized c-FLIP(L), an inhibitor of the CD95-mediated death-signaling cascade. We also demonstrated that bisindolylmaleimide down-regulates c-FLIP(L) expression in DC and, in parallel, allows CD95-mediated apoptosis in these cells. In contrast, Bcl-2, Bcl-x(L), and Bax levels were not affected by bisindolylmaleimide. We conclude that DC resist CD95- mediated apoptosis in association with c-FLIP(L) expression and that the immunosuppressive potential of bisindolylmaleimide previously observed at the T-cell level also involves facilitation of CD95-mediated DC apoptosis.