The effects of an aerobic training intervention on cognition, grey matter volumes and white matter microstructure

While there is strong evidence from observational studies that physical activity is associated with reduced risk of cognitive decline and dementia, the extent to which aerobic training interventions impact on cognitive health and brain structure remains subject to debate. In a pilot study of 46 healthy older adults (66.6 years ± 5.2 years, 63% female), we compared the effects of a twelve-week aerobic training programme to a waitlist control condition on cardiorespiratory fitness, cognition and magnetic resonance imaging (MRI) outcomes. Cardiorespiratory fitness was assessed by VO2 max testing. Cognitive assessments spanned executive function, memory and processing speed. Structural MRI analysis included examination of hippocampal volume, and voxel-wise assessment of grey matter volumes using voxel-based morphometry. Diffusion tensor imaging analysis of fractional anisotropy, axial diffusivity and radial diffusivity was performed using tract-based spatial statistics. While the intervention successfully increased cardiorespiratory fitness, there was no evidence that the aerobic training programme led to changes in cognitive functioning or measures of brain structure in older adults. Interventions that are longer lasting, multi-factorial, or targeted at specific high-risk populations, may yield more encouraging results

A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease

Prognostic Utility of Calcium Scoring as an Adjunct to Stress Myocardial Perfusion Scintigraphy in End-Stage Renal Disease

Coronary artery calcium score (CACS) is a strong predictor of adverse cardiovascular events in the general population. Recent data confirm the prognostic utility of single-photon emission computed tomographic (SPECT) imaging in end-stage renal disease, but whether performing CACS as part of hybrid imaging improves risk prediction in this population is unclear. Consecutive patients (n = 284) were identified after referral to a university hospital for cardiovascular risk stratification in assessment for renal transplantation. Participants underwent technetium-99m SPECT imaging after exercise or standard adenosine stress in those unable to achieve 85% maximal heart rate; multislice CACS was also performed (Siemens Symbia T16, Siemens, Erlangen, Germany). Subjects with known coronary artery disease (n = 88) and those who underwent early revascularization (n = 2) were excluded. The primary outcome was a composite of death or first myocardial infarction. An abnormal SPECT perfusion result was seen in 22% (43 of 194) of subjects, whereas 45% (87 of 194) had at least moderate CACS (>100 U). The frequency of abnormal perfusion (summed stress score ≥4) increased with increasing CACS severity (p = 0.049). There were a total of 15 events (8 deaths, and 7 myocardial infarctions) after a median duration of 18 months (maximum follow-up 3.4 years). Univariate analysis showed diabetes mellitus (Hazard ratio [HR] 3.30, 95% CI 1.14 to 9.54; p = 0.028), abnormal perfusion on SPECT (HR 5.32, 95% CI 1.84 to 15.35; p = 0.002), and moderate-to-severe CACS (HR 3.55, 95% CI 1.11 to 11.35; p = 0.032) were all associated with the primary outcome. In a multivariate model, abnormal perfusion on SPECT (HR 4.18, 95% CI 1.43 to 12.27; p = 0.009), but not moderate-to-severe CACS (HR 2.50, 95% CI 0.76 to 8.20; p = 0.130), independently predicted all-cause death or myocardial infarction. The prognostic value of CACS was not incremental to clinical and SPECT perfusion data (global chi-square change = 2.52, p = 0.112). In conclusion, a perfusion defect on SPECT is an independent predictor of adverse outcome in potential renal transplant candidates regardless of the CACS. The use of CACS as an adjunct to SPECT perfusion data does not provide incremental prognostic utility for the prediction of mortality and nonfatal myocardial infarction in end-stage renal disease

Playing Games with Tito:Designing Hybrid Museum Experiences for Critical Play

This article brings together two distinct, but related perspectives on playful museum experiences: Critical play and hybrid design. The article explores the challenges involved in combining these two perspectives, through the design of two hybrid museum experiences that aimed to facilitate critical play with/in the collections of the Museum of Yugoslavia and the highly contested heritage they represent. Based on reflections from the design process as well as feedback from test users, we describe a series of challenges: Challenging the norms of visitor behaviour, challenging the role of the artefact, and challenging the curatorial authority. In conclusion, we outline some possible design strategies to address these challenges

Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma

ImportancePatients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited. ObjectiveTo evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma. Design, Setting, and ParticipantsThe TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to >= 23.0 months). Data were collected from April 15, 2016, through September 4, 2018, with September 4, 2018, as a data cutoff, and analyzed from September 4, 2018, through January 30, 2019. InterventionsThe recommended phase 2 dose (RP2D) was 200 mg of oral niraparib once daily and 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. Main Outcomes and MeasuresThe primary objectives of phase 1 were to evaluate dose-limiting toxic effects and establish the RP2D and dosing schedule. The primary objective of phase 2 was to assess objective response rate (ORR; complete plus partial responses). Results from the phase 1 ovarian carcinoma and TNBC cohorts and phase 2 ovarian carcinoma cohort are reported. Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis. ResultsFourteen patients (9 with ovarian carcinoma and 5 with TNBC) in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, 46-83 years]). In the integrated efficacy phases 1 and 2 ovarian carcinoma population (60 of 62 evaluable patients), ORR was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, 28 (47%) with stable disease, and 20 (33%) with progressive disease. The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status. Median duration of response was not reached (range, 4.2 to >= 14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment. Conclusions and RelevanceNiraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab. Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy. Trial RegistrationClinicalTrials.gov identifier: NCT02657889Peer reviewe

T1 Mapping for the Diagnosis of Acute Myocarditis Using CMR: Comparison to T2-Weighted and Late Gadolinium Enhanced Imaging

Objectives This study sought to test the diagnostic performance of native T1 mapping in acute myocarditis compared with cardiac magnetic resonance (CMR) techniques such as dark-blood T2-weighted (T2W)-CMR, bright-blood T2W-CMR, and late gadolinium enhancement (LGE) imaging. Background The diagnosis of acute myocarditis on CMR often requires multiple techniques, including T2W, early gadolinium enhancement, and LGE imaging. Novel techniques such as T1 mapping and bright-blood T2W-CMR are also sensitive to changes in free water content. We hypothesized that these techniques can serve as new and potentially superior diagnostic criteria for myocarditis. Methods We investigated 50 patients with suspected acute myocarditis (age 42 ± 16 years; 22% women) and 45 controls (age 42 ± 14 years; 22% women). CMR at 1.5-T (median 3 days from presentation) included: 1) dark-blood T2W-CMR (short-tau inversion recovery); 2) bright-blood T2W-CMR (acquisition for cardiac unified T2 edema); 3) native T1 mapping (shortened modified look-locker inversion recovery); and 4) LGE. Image analysis included: 1) global T2 signal intensity ratio of myocardium compared with skeletal muscle; 2) myocardial T1 relaxation times; and 3) areas of LGE. Results Compared with controls, patients had significantly higher global T2 signal intensity ratios by dark-blood T2W-CMR (1.73 ± 0.27 vs. 1.56 ± 0.15, p < 0.01), bright-blood T2W-CMR (2.02 ± 0.33 vs. 1.84 ± 0.17, p < 0.01), and mean myocardial T1 (1,010 ± 65 ms vs. 941 ± 18 ms, p < 0.01). Receiver-operating characteristic analysis showed clear differences in diagnostic performance. The areas under the curve for each method were: T1 mapping (0.95), LGE (0.96), dark-blood T2 (0.78), and bright-blood T2 (0.76). A T1 cutoff of 990 ms had a sensitivity, specificity, and diagnostic accuracy of 90%, 91%, and 91%, respectively. Conclusions Native T1 mapping as a novel criterion for the detection of acute myocarditis showed excellent and superior diagnostic performance compared with T2W-CMR. It also has a higher sensitivity compared with T2W and LGE techniques, which may be especially useful in detecting subtle focal disease and when gadolinium contrast imaging is not feasible