Background and purpose
Although Parkinson's disease (PD) is characterized by typical motor manifestations, non‐motor symptoms (NMS) are an outstanding part of the disease. At present, several ...specific instruments for assessment of NMS are available. The objective of our study was to determine the performance of the Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS): Part I – Non‐Motor Aspects of Experiences of Daily Living (nM‐EDL) compared with the Non‐Motor Symptoms Scale (NMSS).
Methods
To this purpose, 434 consecutive patients with PD were included in an international, observational, cross‐sectional study. The association between scores of both scales was determined by the Spearman rank correlation coefficient. Equations for transformation of total score of a scale to the other were constructed from weighted regression models and both, transformed and observed score, contrasted by means of the Lin's Concordance Correlation Coefficient (LCCC) and Bland–Altman plot.
Results
As a whole, the prevalence of the NMS according to each scale was quite similar, and most of the correlations between their corresponding components were high (rS > 0.60). The total score correlation of the MDS‐UPDRS Part I with the NMSS was high (rS = 0.81). Concerning the transformed scores, estimated scores only partially approach the observed ones (sharing about 60–64% of the variance) because residual variance increased with increasing magnitudes of the scores, i.e. the most severe patients (Bland–Altman plot; LCCC < 0.60 for severe patients).
Conclusions
(i) MDS‐UPDRS Part I (nM‐EDL) and NMSS showed a strong convergent validity; (ii) however, transformed scores using the equations from weighted regression models showed that for patients with the most severe NMS they are not concordant.
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The reliable assessment of water quality through water quality monitoring programs (WQMPs) is crucial in order for decision-makers to understand, interpret and use this information in support of ...their management activities aiming at protecting the resource. The challenge of water quality monitoring has been widely addressed in the literature since the 1940s. However, there is still no generally accepted, holistic and practical strategy to support all phases of WQMPs. The purpose of this paper is to report on the use cases a watershed manager has to address to plan or optimize a WQMP from the challenge of identifying monitoring objectives; selecting sampling sites and water quality parameters; identifying sampling frequencies; considering logistics and resources to the implementation of actions based on information acquired through the WQMP. An inventory and critique of the information, approaches and tools placed at the disposal of watershed managers was proposed to evaluate how the existing information could be integrated in a holistic, user-friendly and evolvable solution. Given the differences in regulatory requirements, water quality standards, geographical and geological differences, land-use variations, and other site specificities, a one-in-all solution is not possible. However, we advance that an intelligent decision support system (IDSS) based on expert knowledge that integrates existing approaches and past research can guide a watershed manager through the process according to his/her site-specific requirements. It is also necessary to tap into local knowledge and to identify the knowledge needs of all the stakeholders through participative approaches based on geographical information systems and adaptive survey-based questionnaires. We believe that future research should focus on developing such participative approaches and further investigate the benefits of IDSS's that can be updated quickly and make it possible for a watershed manager to obtain a timely, holistic view and support for every aspect of planning and optimizing a WQMP.
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•No holistic solution exists to cover all steps of water quality monitoring programs.•Existing approaches to plan or optimize water quality monitoring programs were reviewed.•Intelligent decision support systems are needed in support of watershed managers.•Participative geographical information systems are useful to tap into local knowledge.•Stakeholder involvement is necessary for successful integrated watershed management.
The Surface Water and Ocean Topography (SWOT) satellite mission planned for launch in 2020 will map river elevations and inundated area globally for rivers >100 m wide. In advance of this launch, we ...here evaluated the possibility of estimating discharge in ungauged rivers using synthetic, daily “remote sensing” measurements derived from hydraulic models corrupted with minimal observational errors. Five discharge algorithms were evaluated, as well as the median of the five, for 19 rivers spanning a range of hydraulic and geomorphic conditions. Reliance upon a priori information, and thus applicability to truly ungauged reaches, varied among algorithms: one algorithm employed only global limits on velocity and depth, while the other algorithms relied on globally available prior estimates of discharge. We found at least one algorithm able to estimate instantaneous discharge to within 35% relative root‐mean‐squared error (RRMSE) on 14/16 nonbraided rivers despite out‐of‐bank flows, multichannel planforms, and backwater effects. Moreover, we found RRMSE was often dominated by bias; the median standard deviation of relative residuals across the 16 nonbraided rivers was only 12.5%. SWOT discharge algorithm progress is therefore encouraging, yet future efforts should consider incorporating ancillary data or multialgorithm synergy to improve results.
Key Points:
SWOT discharge algorithms were tested on synthetic observations for 19 rivers
Algorithms accurately characterized temporal dynamics of river discharge
At least one algorithm estimated discharge to <35% relative RMSE on 14/16 of nonbraided rivers
Summary
Background
The molecular basis and effects of proton pump inhibitor (PPI) therapy on PPI‐responsive oesophageal eosinophilia (PPI‐REE) and eosinophilic oesophagitis (EoE) remain unknown.
Aim
...To compare symptom‐histological and cytokine gene expression in PPI‐REE and EoE patients, at baseline and after specific treatment.
Methods
In consecutive adult patients with an EoE phenotype (dysphagia/food impaction, typical endoscopic findings and > 15 eos/HPF), gene expression of eotaxin‐3, IL‐13, and IL‐5 were determined in distal and proximal oesophagus, at baseline and after omeprazole 40 mg b.d. for 8 weeks. PPI‐REE was defined by clinicohistological response. PPI nonresponders (EoE) were offered treatment with topical steroids.
Results
Fifty three patients were re‐evaluated on PPI therapy. 23 patients (43%) had PPI‐REE and 30 patients (57%) had EoE. At baseline, eotaxin‐3/IL‐13/IL‐5 gene expression was indistinguishable between EoE and PPI‐REE, excepting increased IL‐5 expression in proximal oesophagus (12.54 vs. 57, P = 0.029). PPI therapy significantly decreased eotaxin‐3/IL‐13 in PPI‐REE, at both oesophageal sites (P ≤ 0.008), and IL‐5 in distal (P = 0.016), but not in proximal oesophagus. Patients with steroid‐responsive EoE also showed a significant decrease in eotaxin‐3/IL‐5 expression at both oesophageal sites. In EoE patients, initial PPI trial significantly decreased distal oesophageal eosinophilia (63.78 to 41.79 eos/HPF, P = 0.025) and led to symptom remission in 16%, but did not influence Th2 markers.
Conclusions
Baseline cytokine gene expression in PPI‐REE was nearly indistinguishable from EoE. PPI therapy significantly downregulated oesophageal eotaxin‐3/Th2‐cytokine gene expression in PPI‐REE, similarly to that seen in steroid‐responsive EoE. A subset of EoE patients showed clinicohistological improvement on PPI therapy.
Type I autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-related SC) are now recognized as components of a multisystem IgG4-related disease (IgG4-RD). We aimed to define the ...clinical course and long-term outcomes in patients with AIP/IgG4-SC recruited from two large UK tertiary referral centers.
Data were collected from 115 patients identified between 2004 and 2013, and all were followed up prospectively from diagnosis for a median of 33 months (range 1-107), and evaluated for response to therapy, the development of multiorgan involvement, and malignancy. Comparisons were made with national UK statistics.
Although there was an initial response to steroids in 97%, relapse occurred in 50% of patients. IgG4-SC was an important predictor of relapse (P<0.01). Malignancy occurred in 11% shortly before or after the diagnosis of IgG4-RD, including three hepatopancreaticobiliary cancers. The risk of any cancer at diagnosis or during follow-up when compared with matched national statistics was increased (odds ratio=2.25, CI=1.12-3.94, P=0.02). Organ dysfunction occurred within the pancreas, liver, kidney, lung, and brain. Mortality occurred in 10% of patients during follow-up. The risk of death was increased compared with matched national statistics (odds ratio=2.07, CI=1.07-3.55, P=0.02).
Our findings suggest that AIP and IgG4-SC are associated with significant morbidity and mortality owing to extrapancreatic organ failure and malignancy. Detailed clinical evaluation for evidence of organ dysfunction and associated malignancy is required both at first presentation and during long-term follow-up.
Abstract X-linked juvenile retinoschisis (XLRS) is a retinal degenerative disorder caused by mutations in the RS1 gene encoding a protein termed retinoschisin. The disease is an excellent candidate ...for gene replacement therapy as the majority of mutations have been shown to lead to a complete deficiency of the secreted protein in the retinal structures. In this work, we have studied the ability of non-viral vectors based on solid lipid nanoparticles (SLN) to induce the expression of retinoschisin in photoreceptors (PR) after intravitreal administration to Rs1h-deficient mice. We designed two vectors prepared with SLN, protamine, and dextran (DX) or hyaluronic acid (HA), bearing a plasmid containing the human RS1 gene under the control of the murin opsin promoter (mOPS). In vitro, the nanocarriers were able to induce the expression of retinoschisin in a PR cell line. After injection into the murine vitreous, the formulation prepared with HA induced a higher transfection level in PR than the formulation prepared with DX. Moreover, the level of retinoschisin in the inner nuclear layer (INL), where bipolar cells are located, was also higher. Two weeks after vitreal administration into Rs1h-deficient mice, both formulations showed significant improvement of the retinal structure by inducing a decrease of cavities and PR loss, and an increase of retinal and outer nuclear layer (ONL) thickness. HA-SLN resulted in a significant higher increase in the thickness of both retina and ONL, which can be explained by the higher transfection level of PR. In conclusion, we have shown the structural improvement of the retina of Rs1h-deficient mice with PR specific expression of the RS1 gene driven by the specific promoter mOPS, after successful delivery via SLN-based non-viral vectors.
Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, ...which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.
•Active ageing is multidimensional: health-participation-lifelong learning-security.•There is no consensus on how to measure the construct and its different components.•Little care is paid to the ...role of active ageing in reducing mortality as people age.•We identified the factor structure of each active ageing domain using principal component analysis.•Promoting the physical health component of active ageing is key to enhance survival.
The World Health Organization’s active ageing model is based on the optimisation of four key “pillars”: health, lifelong learning, participation and security. It provides older people with a policy framework to develop their potential for well-being, which in turn, may facilitate longevity. We sought to assess the effect of active ageing on longer life expectancy by: i) operationalising the WHO active ageing framework, ii) testing the validity of the factors obtained by analysing the relationships between the pillars, and iii) exploring the impact of active ageing on survival through the health pillar.
Based on data from a sample of 801 community-dwelling older adults, we operationalised the active ageing model by taking each pillar as an individual construct using principal component analysis. The interrelationship between components and their association with survival was analysed using multiple regression models.
A three-factor structure was obtained for each pillar, except for lifelong learning with a single component. After adjustment for age, gender and marital status, survival was only significantly associated with the physical component of health (HR = 0.66; 95% CI = 0.47−0.93; p = 0.018). In turn, this component was loaded with representative variables of comorbidity and functionality, cognitive status and lifestyles, and correlated with components of lifelong learning, social activities and institutional support.
According to how the variables clustered into the components and how the components intertwined, results suggest that the variables loading on the biomedical component of the health pillar (e.g. cognitive function, health conditions or pain), may play a part on survival chances.
Adjuvant trastuzumab in HER2+ breast cancer reduces recurrence and mortality, and has been the standard treatment since 2006. The objective was to analyze health outcomes in the real world. ...Observational, retrospective study of patients with HER2+ breast cancer, stages I-III, treated with adjuvant trastuzumab in the past 15 years in only one center and for the first time in Spain. Survival was analyzed according to the number of cycles and cardiotoxicity. Two hundred and seventy-five HER2positive patients (18.60%) out of 1479 received adjuvant (73%) or neoadjuvant/adjuvant (26%) trastuzumab, concomitantly (90%) or sequentially (10%) with chemotherapy. The probability of overall and disease-free survival (OS and DFS) at 5 years was 0.93 (95% CI 0.89-0.96), and 0.88 (95% CI 0.83-0.92). The number of cases with a significant and asymptomatic decrease in ventricular ejection fraction and heart failure were 54 (19.64%) and 12 (4.36%), respectively. Sixty-eight patients (24.70%) received 16 or fewer cycles, especially those older than 65 (OR 0.371, 95% CI 0.152-0.903; p = 0.029) and with cardiotoxicity (OR 15.02, 95% CI 7.437-30.335; p < 0.001). The risk of cardiotoxicity was associated with having received radiotherapy (OR 0.0362, 95% CI 0.139-0.938; p = 0.037). Arterial hypertension (HR 0.361, 95% CI 0.151-0.863, p = 0.022), neoadjuvant treatment (HR 0.314, 95% CI 0.132-0.750, p = 0.009) and cardiotoxicity (HR 2.755, 95% CI 1.235-6.143, p = 0.013) maintained significant association with OS. Only neoadjuvant treatment maintained a significant association with DFS (HR 0.437, 95% CI 0.213-0.899, p = 0.024). The effectiveness of neoadjuvant and adjuvant trastuzumab can be considered comparable to those of clinical trials. In the real world, factors such as age, hypertension, radiotherapy, neoadjuvant treatment, and cardiotoxicity should be taken into consideration to optimize outcomes.
Seventeen Middle Pleistocene crania from the Sima de los Huesos site (Atapuerca, Spain) are analyzed, including seven new specimens. This sample makes it possible to thoroughly characterize a Middle ...Pleistocene hominin paleodeme and to address hypotheses about the origin and evolution of the Neandertals. Using a variety of techniques, the hominin-bearing layer could be reassigned to a period around 430,000 years ago. The sample shows a consistent morphological pattern with derived Neandertal features present in the face and anterior vault, many of which are related to the masticatory apparatus. This suggests that facial modification was the first step in the evolution of the Neandertal lineage, pointing to a mosaic pattern of evolution, with different anatomical and functional modules evolving at different rates.
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