Associations Between Adherence to the Physical Activity and Exercise Program Applied in the LAST Study and Functional Recovery After Stroke

ObjectiveTo investigate the associations between participants’ adherence to a physical activity and exercise program after stroke and functional recovery 18 months after inclusion.DesignSecondary analyses of the intervention arm in the multisite randomized controlled trial Life After Stroke (LAST).SettingPrimary health care services in 3 Norwegian municipalities.ParticipantsOf the participants enrolled (N=380), 186 (48.9%) were randomized to the intervention. The study sample comprised community dwelling individuals included 3 months after stroke, with mean age of 71.7 ± 11.9 years and 82 (44.1%) women. According to the National Institutes of Health Stroke Scale, 97.3% were diagnosed as having mild (National Institutes of Health Stroke Scale<8) and 2.7% with moderate (8-16 on the National Institutes of Health Stroke Scale) stroke.InterventionMonthly coaching by physiotherapists encouraging participants to adhere to 30 minutes of daily physical activity and 45-60 minutes of weekly exercise.Main Outcome MeasuresThe primary outcome was Motor Assessment Scale (MAS). Secondary outcome measures were 6-minute walk test, Timed Up and Go (TUG), Berg Balance Scale (BBS), and the physical domains of the Stroke Impact Scale (SIS). Adherence was assessed by combining participants’ training diaries and physiotherapists’ reports.ResultsThe relationship between adherence and functional recovery was analyzed with simple and multiple linear regression models. Adjusted for age, sex, dependency, and cognition, results showed statistically significant associations between adherence and functional outcomes after 18 months, as measured by MAS, TUG, BBS, and SIS (P≤.026).ConclusionsIncreased adherence to physical activity and exercise was associated with improved functional recovery after mild to moderate stroke. This emphasizes the importance of developing adherence-enhancing interventions. Dose-response studies are recommended for future research.     

Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells

Cluster of differentiation 1c (CD1c)-dependent self-reactive T cells are abundant in human blood, but self-antigens presented by CD1c to the T-cell receptors of these cells are poorly understood. Here we present a crystal structure of CD1c determined at 2.4 Å revealing an extended ligand binding potential of the antigen groove and a substantially different conformation compared with known CD1c structures. Computational simulations exploring different occupancy states of the groove reenacted these different CD1c conformations and suggested cholesteryl esters (CE) and acylated steryl glycosides (ASG) as new ligand classes for CD1c. Confirming this, we show that binding of CE and ASG to CD1c enables the binding of human CD1c self-reactive T-cell receptors. Hence, human CD1c adopts different conformations dependent on ligand occupancy of its groove, with CE and ASG stabilizing CD1c conformations that provide a footprint for binding of CD1c self-reactive T-cell receptors.Cluster of differentiation 1 (CD1) proteins are a family of MHC class I-like glycoproteins that present lipid antigens to T cells. CD1 restricted T cells are abundant in humans and play important roles in host defense and immune regulation. Human CD1 proteins comprise five CD1 isoforms, CD1a, CD1b, CD1c, CD1d, and CD1e, which exhibit different intracellular trafficking behaviors and ligand binding preferences (1). Structurally, the main differences between these CD1 isoforms lie in the architecture of their lipophilic ligand binding grooves. Whereas all CD1 isoforms share a highly conserved A′ channel (or pocket) for binding C18–C26 acyl chains, specialization is provided by further connecting channels (2–7). In CD1a, the A′ channel is “fused” to a wide and shallow F′ channel, enabling binding of lipopeptides such as mycobacterial didehydroxymycobactin (DDM) (8). CD1b features a unique T′ tunnel that connects A′ and F′, thereby forming a “superchannel” for accommodating very long acyl chains (e.g., mycobacterial mycolates) (2, 4). CD1d, the only isoform also conserved in rodents, exhibits a two-branched ligand binding groove with two linear channels A′ and F′ connected near the main portal into the groove, known as the F′ portal. A similar two-branched arrangement of A′ and F′ is seen in CD1e, the only CD1 isoform not expressed on the cell surface. Compared with CD1d, CD1a, and CD1b, the portal into the groove in CD1e is widely exposed, consistent with its known role in lipid transfer processes inside lysosomes (6).CD1c presents foreign- (9, 10) as well as self-lipid antigens to T cells (11). Two recent crystal structures of human CD1c revealed a two-branched design similar to that of CD1d and CD1e, with two channels A′ and F′ connecting near the groove portal. In these structures, a mycobacterial phosphomycoketide (PM) or mannosyl-β1-phosphomycoketide (MPM) occupied the A′ channel, whereas an undefined short ligand was present in the F′ channel (7, 12). The spatial arrangement of these ligands in the CD1c groove was very similar to and virtually overlapping in 3D comparisons with that of alpha-galactosylceramide (αGC) in human CD1d (Fig. S1 A and B). Because CD1c and CD1d are known to traffic to the same intracellular compartments for antigen sampling (13), these CD1c-PM and CD1c-MPM structures did not readily explain how CD1c and CD1d could functionally differentiate. Furthermore, the F′ channel in both CD1c-PM and CD1c-MPM was widely open to solvent, which was strikingly different from known structures of CD1a, CD1b, and CD1d and reminiscent of CD1e (7, 12). Based on these facts we hypothesized that human CD1c might undergo substantial conformational transformations in the F′ channel region upon binding of more optimal ligands, with relevance for T-cell receptor binding.Open in a separate windowFig. S1.Published CD1d-αGC and CD1c-MPM structures show a similar arrangement of their bound ligands in both the A′ and F′ channel. (A) Comparison of the configurations of bound ligands in CD1d-αGC (PDB ID code 1ZT4), CD1c-MPM (PDB ID code 3OV6), and CD1c-SL (PDB ID code 5C9J). (B) Ligands bound to CD1d (PDB ID code 1ZT4) (αGC; shown in yellow) and CD1c (PDB ID code 3OV6) (MPM; shown in blue, and spacer lipid shown in cyan) are superimposed and shown in two different orientations.     

Aortic valve stenosis: fatal natural history despite normal left ventricular function and low invasive peak-to-peak pressure gradients

For many years, the severity of valvular aortic stenosis (AS) was evaluated mainly on the basis of cardiac catheterization. In many centers, the handy peak-to-peak transvalvular pressure difference or 'peak-to-peak gradient' in relation to left ventricular function was used as a crucial feature in taking a decision regarding valve substitution. In a prospective study during the period 1994-1997, 150 consecutive patients with AS were examined systematically using cardiac catherization as well as transthoracic (TTE) and transesophageal echocardiography. The study was performed in order to compare the diagnostic accuracy and reproducibility of the three modalities with the purpose of improving our evaluation strategy. We found that the three methods were able to determine the aortic valve area with similar accuracy and reproducibility. The data thus support earlier papers and the currently recommended strategy of managing most patients on the basis of TTE since this approach is more rapid and gentle to the patients. In accordance with the past policy of our department, however, considerable weight was put on the invasive data during the study period. Thus, 12 patients with invasive peak-to-peak gradient <50 mm Hg and no severe depression of left ventricular function were not offered valve replacement, despite symptoms and significant valve area reductions. At 2.5 years of follow-up, 6 had died, 3 of severe heart failure, 2 while awaiting scheduled valve replacement, and 1 during aortocoronary bypass surgery. Another 3 patients later experienced further symptom progression and underwent successful aortic valve replacement. In the remaining 3 patients, all free from coronary stenoses and other valvular heart disease than AS, heart failure symptoms had worsened considerably during continued medical therapy. In conclusion, we do not recommend consideration of the peak-to-peak gradient in the process of deciding whether or not AS patients should receive valve replacement. A low peak-to-peak gradient does not exclude severe AS, even in the presence of preserved left ventricular function.     

Association of aortic stiffness with biomarkers of myocardial wall stress after myocardial infarction

Background

Aortic pulse wave velocity (PWV) was linked to LV-geometry and -function in patients with kidney disease and non-ischemic cardiomyopathy. The role of aortic compliance after acute STEMI is so far unknown. In the present study, we prospectively investigated the relationship of increased aortic stiffness with biomarkers of myocardial wall stress 4 months after STEMI.

Methods

48 STEMI patients who were reperfused by primary coronary angioplasty underwent cardiovascular magnetic resonance (CMR) at baseline and at 4-month follow-up. The CMR protocol comprised cine-CMR as well as gadolinium contrast-enhanced CMR. Aortic PWV was determined by velocity-encoded, phase-contrast CMR. Blood samples were routinely drawn at baseline and follow-up to determine N-terminal pro-B-type natriuretic peptide (NT-proBNP). In a subgroup of patients, mid-regional pro-adrenomedullin (MR-proADM) and mid-regional pro-A-type natriuretic peptide (MR-proANP) levels were determined.

Results

Patients with a PWV above median (> 7.0 m/s) had significantly higher NT-proBNP, MR-proADM and MR-proANP concentrations at 4-month follow-up than patients with a PWV below median (all p < 0.02). PWV showed moderate to good correlation with NT-proBNP, MR-proAMD and MR-proANP levels 4 months after STEMI (all p < 0.05). Multivariate analysis revealed PWV, beside myocardial infarct size, as an independent predictor of 4-month NT-proBNP levels after correction for age, creatinine and LV ejection fraction (model r: 0.781, p < 0.001).

Conclusion

Aortic stiffness is directly associated with biomarkers of myocardial wall stress 4 months after reperfused STEMI, suggesting a role for aortic stiffness in chronic LV-remodelling.     

Promoting head CT exams in the emergency department triage using a machine learning model

Neuroradiology - In this study, we aimed to develop a novel prediction model to identify patients in need of a non-contrast head CT exam during emergency department (ED) triage. We collected data...     

Higher-Order Structure Characterization of Pharmaceutical Proteins by 2D Nuclear Magnetic Resonance Methyl Fingerprinting

A key challenge in the analytical assessment of therapeutic proteins is the comprehensive characterization of their higher-order structure (HOS). To directly assess HOS, a new type of assay is warranted. The most sensitive and detailed method for characterizing HOS is unquestionably nuclear magnetic resonance (NMR) spectroscopy. NMR spectroscopy provides direct information about the HOS at an atomic level, and with modern NMR spectrometers and improved pulse sequences, this has become feasible even on unlabeled proteins. Hence, NMR spectroscopy could be a very powerful tool for control of HOS following, for example, process changes resulting in structural changes, oxidation, degradation, or chemical modifications. We present a method for characterizing the HOS of therapeutic proteins by monitoring their methyl groups using 2D H, C-correlated NMR. We use a statistical model that compares the NMR spectrum of a given sample to a reference and results in one output value describing how similar the HOS of the samples are. This makes the overall result easy to interpret even for non-NMR experts. We show that the method is applicable to proteins of varying size and complexity (here up to ～30 kDa) and that it is sufficiently sensitive for the detection of small changes in both primary and HOS.     

Risk factors for urinary incontinence 1 year after the first vaginal delivery in a cohort of primiparous Danish women

Introduction and hypothesis

The objective was to examine the relationship between maternal and perinatal factors and the occurrence of stress (SUI) or mixed (MUI) urinary incontinence (UI) 1 year after the first vaginal delivery in primiparous women.

Methods

Participants in this prospective cohort were recruited consecutively from June 2003 to July 2005 from all eligible women who delivered in the department. A validated questionnaire, the International Consultation of Incontinence Questionnaire Short Form (ICIQ-SF) was completed by all participants 2–3 days after delivery, and a similar second questionnaire was filled out 1 year later. Additional data were obtained from the medical records. The first questionnaire was completed by 1,018 women (63 %) and the second by 859 women (84 %). The study group comprised the 575 women without any UI before the pregnancy and who had a vaginal delivery. The primary analysis comprised 117 women with either SUI or MUI 1 year after the vaginal delivery and 403 women without any UI.

Results

In univariate analyses, the following factors were associated with SUI or MUI: prepregnancy body mass index (BMI)?≥?30 (p?<?0.05), UI during the pregnancy (p?<?0.05), perineal lesions (p?<?0.05), and anal sphincter tears (p?=?0.05). Logistic regression analysis showed that SUI or MUI was strongly associated with UI during the pregnancy [adjusted odds ratio (OR) 4.7, 95 % confidence interval (CI) 2.9–7.7) and inversely associated with oxytocin augmentation (adjusted OR 0.5, 95 % CI 0.3–0.9).

Conclusions

SUI or MUI 1 year after the first vaginal delivery was strongly associated with UI during the pregnancy and inversely associated with oxytocin augmentation.     

A Phase Ib/II,open-label,multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma

Journal of Neuro-Oncology - To estimate the maximum tolerated dose (MTD) and/or identify the recommended Phase II dose (RP2D) for combined INC280 and buparlisib in patients with recurrent...