Five-year trajectories of multimorbidity patterns in an elderly Mediterranean population using Hidden Markov Models

This is the final version. Available on open access from Nature Research via the DOI in this recordThis study aimed to analyse the trajectories and mortality of multimorbidity patterns in patients aged 65 to 99 years in Catalonia (Spain). Five year (2012–2016) data of 916,619 participants from a primary care, population-based electronic health record database (Information System for Research in Primary Care, SIDIAP) were included in this retrospective cohort study. Individual longitudinal trajectories were modelled with a Hidden Markov Model across multimorbidity patterns. We computed the mortality hazard using Cox regression models to estimate survival in multimorbidity patterns. Ten multimorbidity patterns were originally identified and two more states (death and drop-outs) were subsequently added. At baseline, the most frequent cluster was the Non-Specific Pattern (42%), and the least frequent the Multisystem Pattern (1.6%). Most participants stayed in the same cluster over the 5 year follow-up period, from 92.1% in the Nervous, Musculoskeletal pattern to 59.2% in the Cardio-Circulatory and Renal pattern. The highest mortality rates were observed for patterns that included cardio-circulatory diseases: Cardio-Circulatory and Renal (37.1%); Nervous, Digestive and Circulatory (31.8%); and Cardio-Circulatory, Mental, Respiratory and Genitourinary (28.8%). This study demonstrates the feasibility of characterizing multimorbidity patterns along time. Multimorbidity trajectories were generally stable, although changes in specific multimorbidity patterns were observed. The Hidden Markov Model is useful for modelling transitions across multimorbidity patterns and mortality risk. Our findings suggest that health interventions targeting specific multimorbidity patterns may reduce mortality in patients with multimorbidity.Carlos III Institute of Health, Ministry of Economy and Competitiveness (Spain)European Regional Development FundDepartment of Health of the Catalan GovernmentCatalan Governmen

6-thioguanine treatment in inflammatory bowel disease: A critical appraisal by a European 6-TG working party

Recently, the suggestion to use 6-thioguanine (6-TG) as an alternative thiopurine in patients with inflammatory bowel disease (IBD) has been discarded due to reports about possible (hepato) toxicity. During meetings arranged in Vienna and Prague in 2004, European experts applying 6-TG further on in IBD patients presented data on safety and efficacy of 6-TG. After thorough evaluation of its risk-benefit ratio, the group consented that 6-TG may still be considered as a rescue drug in stringently defined indications in IBD, albeit restricted to a clinical research setting. As a potential indication for administering 6-TG, we delineated the requirement for maintenance therapy as well as intolerance and/or resistance to aminosalicylates, azathioprine, 6-mercaptopurine, methotrexate and infliximab. Furthermore, indications are preferred in which surgery is thought to be inappropriate. The standard 6-TG dosage should not exceed 25 mg daily. Routine laboratory controls are mandatory in short intervals. Liver biopsies should be performed after 6-12 months, three years and then three-yearly accompanied by gastroduodenoscopy, to monitor for potential hepatotoxicity, including nodular regenerative hyperplasia (NRH) and veno-occlusive disease (VOD). Treatment with 6-TG must be discontinued in case of overt or histologically proven hepatotoxicity. Copyright (c) 2006 S. Karger AG, Basel

Activation kinetics of single P2X receptors

After the primary structure of P2X receptors had been identified, their function had to be characterized on the molecular level. Since these ligand-gated ion channels become activated very quickly after binding of ATP, methods with adequate time resolution have to be applied to investigate the early events induced by the agonist. Single-channel recordings were performed to describe conformational changes on P2X2, P2X4, and P2X7 receptors induced by ATP and also by allosteric receptor modifiers. The main results of these studies and the models of P2X receptor kinetics derived from these observations are reviewed here. The investigation of purinoceptors by means of the patch clamp technique following site-directed mutagenesis will probably reveal more details of P2X receptor function at the molecular level

Neuroinflammation and structural injury of the fetal ovine brain following intra-amniotic Candida albicans exposure.

BackgroundIntra-amniotic Candida albicans (C. Albicans) infection is associated with preterm birth and high morbidity and mortality rates. Survivors are prone to adverse neurodevelopmental outcomes. The mechanisms leading to these adverse neonatal brain outcomes remain largely unknown. To better understand the mechanisms underlying C. albicans-induced fetal brain injury, we studied immunological responses and structural changes of the fetal brain in a well-established translational ovine model of intra-amniotic C. albicans infection. In addition, we tested whether these potential adverse outcomes of the fetal brain were improved in utero by antifungal treatment with fluconazole.MethodsPregnant ewes received an intra-amniotic injection of 10(7) colony-forming units C. albicans or saline (controls) at 3 or 5 days before preterm delivery at 0.8 of gestation (term ~ 150 days). Fetal intra-amniotic/intra-peritoneal injections of fluconazole or saline (controls) were administered 2 days after C. albicans exposure. Post mortem analyses for fungal burden, peripheral immune activation, neuroinflammation, and white matter/neuronal injury were performed to determine the effects of intra-amniotic C. albicans and fluconazole treatment.ResultsIntra-amniotic exposure to C. albicans caused a severe systemic inflammatory response, illustrated by a robust increase of plasma interleukin-6 concentrations. Cerebrospinal fluid cultures were positive for C. albicans in the majority of the 3-day C. albicans-exposed animals whereas no positive cultures were present in the 5-day C. albicans-exposed and fluconazole-treated animals. Although C. albicans was not detected in the brain parenchyma, a neuroinflammatory response in the hippocampus and white matter was seen which was characterized by increased microglial and astrocyte activation. These neuroinflammatory changes were accompanied by structural white matter injury. Intra-amniotic fluconazole reduced fetal mortality but did not attenuate neuroinflammation and white matter injury.ConclusionsIntra-amniotic C. albicans exposure provoked acute systemic and neuroinflammatory responses with concomitant white matter injury. Fluconazole treatment prevented systemic inflammation without attenuating cerebral inflammation and injury

Protecting Endangered Species: Do the Main Legislative Tools Work?

It is critical to assess the effectiveness of the tools used to protect endangered species. The main tools enabled under the U.S. Endangered Species Act (ESA) to promote species recovery are funding, recovery plan development and critical habitat designation. Earlier studies sometimes found that statistically significant effects of these tools could be detected, but they have not answered the question of whether the effects were large enough to be biologically meaningful. Here, we ask: how much does the recovery status of ESA-listed species improve with the application of these tools? We used species' staus reports to Congress from 1988 to 2006 to quantify two measures of recovery for 1179 species. We related these to the amount of federal funding, years with a recovery plan, years with critical habitat designation, the amount of peer-reviewed scientific information, and time listed. We found that change in recovery status of listed species was, at best, only very weakly related to any of these tools. Recovery was positively related to the number of years listed, years with a recovery plan, and funding, however, these tools combined explain <13% of the variation in recovery status among species. Earlier studies that reported significant effects of these tools did not focus on effect sizes; however, they are in fact similarly small. One must conclude either that these tools are not very effective in promoting species' recovery, or (as we suspect) that species recovery data are so poor that it is impossible to tell whether the tools are effective or not. It is critically important to assess the effectiveness of tools used to promote species recovery; it is therefore also critically important to obtain population status data that are adequate to that task

Translation position determination in ptychographic coherent diffraction imaging

Accurate knowledge of translation positions is essential in ptychography to achieve a good image quality and the diffraction limited resolution. We propose a method to retrieve and correct position errors during the image reconstruction iterations. Sub-pixel position accuracy after refinement is shown to be achievable within several tens of iterations. Simulation and experimental results for both optical and X-ray wavelengths are given. The method improves both the quality of the retrieved object image and relaxes the position accuracy requirement while acquiring the diffraction patterns

Cosmology of a Scalar Field Coupled to Matter and an Isotropy-Violating Maxwell Field

Motivated by the couplings of the dilaton in four-dimensional effective actions, we investigate the cosmological consequences of a scalar field coupled both to matter and a Maxwell-type vector field. The vector field has a background isotropy-violating component. New anisotropic scaling solutions which can be responsible for the matter and dark energy dominated epochs are identified and explored. For a large parameter region the universe expands almost isotropically. Using that the CMB quadrupole is extremely sensitive to shear, we constrain the ratio of the matter coupling to the vector coupling to be less than 10^(-5). Moreover, we identify a large parameter region, corresponding to a strong vector coupling regime, yielding exciting and viable cosmologies close to the LCDM limit.Comment: Refs. added, some clarifications. Published in JHEP10(2012)06

Study of Zγ events and limits on anomalous ZZγ and Zγγ couplings in pp̄ collisions at s=1.96TeV

We present a measurement of the Zγ production cross section and limits on anomalous ZZγ and Zγγ couplings for form-factor scales of Λ=750 and 1000 GeV. The measurement is based on 138 (152) candidates in the eeγ (μμγ) final state using 320(290)pb-1 of pp̄ collisions at s=1.96TeV. The 95% C.L. limits on real and imaginary parts of individual anomalous couplings are |h10,30Z|<0.23, |h20,40Z|<0.020, |h10,30γ|<0.23, and |h20,40γ|<0.019 for Λ=1000GeV. © 2005 The American Physical Society

Ageing, Muscle Power and Physical Function: A Systematic Review and Implications for Pragmatic Training Interventions.

BACKGROUND: The physiological impairments most strongly associated with functional performance in older people are logically the most efficient therapeutic targets for exercise training interventions aimed at improving function and maintaining independence in later life. OBJECTIVES: The objectives of this review were to (1) systematically review the relationship between muscle power and functional performance in older people; (2) systematically review the effect of power training (PT) interventions on functional performance in older people; and (3) identify components of successful PT interventions relevant to pragmatic trials by scoping the literature. METHODS: Our approach involved three stages. First, we systematically reviewed evidence on the relationship between muscle power, muscle strength and functional performance and, second, we systematically reviewed PT intervention studies that included both muscle power and at least one index of functional performance as outcome measures. Finally, taking a strong pragmatic perspective, we conducted a scoping review of the PT evidence to identify the successful components of training interventions needed to provide a minimally effective training dose to improve physical function. RESULTS: Evidence from 44 studies revealed a positive association between muscle power and indices of physical function, and that muscle power is a marginally superior predictor of functional performance than muscle strength. Nine studies revealed maximal angular velocity of movement, an important component of muscle power, to be positively associated with functional performance and a better predictor of functional performance than muscle strength. We identified 31 PT studies, characterised by small sample sizes and incomplete reporting of interventions, resulting in less than one-in-five studies judged as having a low risk of bias. Thirteen studies compared traditional resistance training with PT, with ten studies reporting the superiority of PT for either muscle power or functional performance. Further studies demonstrated the efficacy of various methods of resistance and functional task PT on muscle power and functional performance, including low-load PT and low-volume interventions. CONCLUSIONS: Maximal intended movement velocity, low training load, simple training methods, low-volume training and low-frequency training were revealed as components offering potential for the development of a pragmatic intervention. Additionally, the research area is dominated by short-term interventions producing short-term gains with little consideration of the long-term maintenance of functional performance. We believe the area would benefit from larger and higher-quality studies and consideration of optimal long-term strategies to develop and maintain muscle power and physical function over years rather than weeks