Diet quality in late midlife is associated with faster walking speed in later life in women, but not men: findings from a prospective British birth cohort

Healthy diet has been linked to better age-related physical functioning, but evidence on the relationship of overall diet quality in late midlife and clinically relevant measures of physical functioning in later life is limited. Research on potential sex differences in this relationship is scarce. The aim was to investigate the prospective association between overall diet quality, as assessed by the Healthy Eating Index-2015 at age 60-64y and measures of walking speed seven years later, among men and women from the Insight46, a neuroscience sub-study of the Medical Research Council National Survey of Health and Development. Diet was assessed at age 60-64y using five-day food diaries, from which total HEI-2015 was calculated. At age 69-71y, walking speed was estimated during four 10-meter walks at self-selected pace, using inertial measurement units. Multivariable linear regression models with sex as modifier, controlling for age, follow-up, lifestyle, health, social variables and physical performance were used. The final sample was 164 women and 167 men (n=331). Women had higher HEI-2015 scores and slower walking speed than men. A 10 point increase in HEI-2015 was associated with faster walking speed seven years later among women (B: 0.024, 95% CI: 0.006, 0.043), but not men. The association remained significant in the multivariable model (B: 0.021, 95% CI: 0.003, 0.040). In women in late midlife higher diet quality is associated with faster walking speed. A healthy diet in late midlife is likely to contribute towards better age-related physical capability and sex differences are likely to affect this relationship

Exercise response in Parkinson’s Disease : insights from a cross-sectional comparison with sedentary controls and a per protocol analysis of a randomised controlled trial

Objectives: To investigate the acute and adaptation cardiovascular and metabolic training responses in people with Parkinson’s (pwP). Design: 1) A cross sectional study of exercise response of pwP compared to sedentary controls,2) an interventional study of exercise training in pwP. Setting: Community leisure facilities. Participants: pwP (n=83) & sedentary controls (n=55) Interventions: Study (1) included participants from a two arm parallel single blind phase II Randomised Controlled Trial (RCT), that undertook a baseline maximal incremental exercise test and study (2) included those randomised to the exercise group in the RCT, who completed a six-month weekly exercise programme (n=37). The intervention (study (2) was a prescribed exercise program consisting of sessions lasting 60 minutes, twice a week over a six-month period. The control group followed the same protocol which derived the same cardio respiratory parameters, except the they were instructed to aim for a cadence of ~60rpm and the unloaded phase lasted 3minutes with an initial step of 25watts. Primary and secondary outcome measures: Stepwise incremental exercise test to volitional exhaustion was the primary outcome measure. Results: Study (1) showed higher maximum values for heart rate, VO2l.min-1, VCO2l.min-1 and Ventilation l.min-1 for the control group; Respiratory Exchange Ratio (RER), perceived exertion and O2 Pulse (VO2l.min-1/ HR) did not differ between groups. In study (2), for pwP who adhered to training (n=37), RER increased significantly and although there was no significant change in aerobic capacity or heart rate response, reduced blood pressure was found. Conclusions: An abnormal cardiovascular response to exercise was observed in pwP compared to controls. After the exercise programme, metabolic deficiencies remained for pwP. These observations add to the pathogenic understanding of PD, acknowledge an underling metabolic contribution and support that certain cardiovascular symptoms may improve as a result of this type of exercise Trial registration: ClinicalTrials.Gov (NCT01439022)

Cryoglobulinemic vasculitis in primary Sj\uf6gren's Syndrome: Clinical presentation, association with lymphoma and comparison with Hepatitis C-related disease

Objective: To describe the clinical spectrum of cryoglobulinemic vasculitis (CV) in primary Sj\uf6gren's syndrome (pSS), investigate its relation to lymphoma and identify the differences with hepatitis C virus (HCV) related CV. Methods: From a multicentre study population of consecutive pSS patients, those who had been evaluated for cryoglobulins and fulfilled the 2011 classification criteria for CV were identified retrospectively. pSS-CV patients were matched with pSS patients without cryoglobulins (1:2) and HCV-CV patients (1:1). Clinical, laboratory and outcome features were analyzed. A data driven logistic regression model was applied for pSS-CV patients and their pSS cryoglobulin negative controls to identify independent features associated with lymphoma. Results: 1083 pSS patients were tested for cryoglobulins. 115 (10.6%) had cryoglobulinemia and 71 (6.5%) fulfilled the classification criteria for CV. pSS-CV patients had higher frequency of extraglandular manifestations and lymphoma (OR=9.87, 95% CI: 4.7\u201320.9) compared to pSS patients without cryoglobulins. Purpura was the commonest vasculitic manifestation (90%), presenting at disease onset in 39% of patients. One third of pSS-CV patients developed B-cell lymphoma within the first 5 years of CV course, with cryoglobulinemia being the strongest independent lymphoma associated feature. Compared to HCV-CV patients, pSS-CV individuals displayed more frequently lymphadenopathy, type II IgMk cryoglobulins and lymphoma (OR = 6.12, 95% CI: 2.7\u201314.4) and less frequently C4 hypocomplementemia and peripheral neuropathy. Conclusion: pSS-CV has a severe clinical course, overshadowing the typical clinical manifestations of pSS and higher risk for early lymphoma development compared to HCV related CV. Though infrequent, pSS-CV constitutes a distinct severe clinical phenotype of pSS

SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.

SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUT cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUT cancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population

Intrusiveness management for focused, efficient, and enjoyable activities

When technologies for distributed activities develop, in particular the rapidly developing mobile technology, a larger part of our time will be spent connected to our various distributed contexts. When we meet physically we bring technology, both artifacts and services, which enable us to participate in these non-local contexts. Potentially this is a threat to focused and efficient activities due to the intrusiveness of the technology. Our aim is to contribute to the restoration of a number of the desirable properties of traditional local technology-free contexts. The intrusiveness itself is caused by at least four typical phenomena that have influenced current technology: • Focus-demanding and clearly distinguishable artifacts like phones or PCs explicitly mediate interaction with the distributed context • The functionality of services is traditionally based upon the assumption that communication is a deterministic flow of passive information, which for example, does not include information of the participants´ current context • Services in general perform individually and without coordinated communication schemes • The switches between contexts introduce a high cognitive load as each distributed context typically has its own system of characteristic objects and rules. In the FEEL project, we have developed a system called “Focused, Efficient and Enjoyable Local Activities with Intrusiveness Management” (FEELIM) that constitutes an intermediate alternative between the technology-dense and technology-free environments, which addresses the problems cited above. This research is based on a collaborative and cooperative setting where problems of intrusiveness management are confounded by several users meeting and cooperating together as opposed to isolated users dealing with similar problems of interruption management (Chen 2004; Ho 2005)