Aims/hypothesis
The aim of this study was to assess the prevalence of (unknown) heart failure and left ventricular dysfunction in older patients with type 2 diabetes.
Methods
In total, 605 patients ...aged 60 years or over with type 2 diabetes in the south west of the Netherlands participated in this cross-sectional study (response rate 48.7%), including 24 with a cardiologist-confirmed diagnosis of heart failure. Between February 2009 and March 2010, the patients without known heart failure underwent a standardised diagnostic work-up, including medical history, physical examination, ECG and echocardiography. An expert panel used the criteria of the European Society of Cardiology to diagnose heart failure.
Results
Of the 581 patients studied, 161 (27.7%; 95% CI 24.1%, 31.4%) were found to have previously unknown heart failure: 28 (4.8%; 95% CI 3.1%, 6.6%) with reduced ejection fraction, and 133 (22.9%; 95% CI 19.5%, 26.3%) with preserved ejection fraction. The prevalence of heart failure increased steeply with age. Heart failure with preserved ejection fraction was more common in women. Left ventricular dysfunction was diagnosed in 150 patients (25.8%; 95% CI 22.3%, 29.4%); 146 (25.1%; 95% CI 21.6%, 28.7%) had diastolic dysfunction.
Conclusions/interpretation
This is the first epidemiological study that provides exact prevalence estimates of (previously unknown) heart failure and left ventricular dysfunction in a representative sample of patients with type 2 diabetes. Previously unknown heart failure and left ventricular dysfunction are highly prevalent. Physicians should pay special attention to ‘unmasking’ these patients.
Summary Background Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of ...adjuvant bisphosphonate treatment in breast cancer. Methods We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal combining natural and artificial or not), and bisphosphonate class (aminobisphosphonate eg, zoledronic acid, ibandronate, pamidronate or other ie, clodronate). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs). Findings We received data on 18 766 women (18 206 97% in trials of 2–5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87–1·01; 2p=0·08), distant recurrence (0·92, 0·85–0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83–0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73–0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78–0·94; 2p=0·002), distant recurrence (0·82, 0·74–0·92; 2p=0·0003), bone recurrence (0·72, 0·60–0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73–0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75–0·97; 2p=0·02). Interpretation Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began. Funding Cancer Research UK, Medical Research Council.
Subsurface habitats harbor novel diversity that has received little attention until recently. Accessible subsurface habitats include lava caves around the world that often support extensive microbial ...mats on ceilings and walls in a range of colors. Little is known about lava cave microbial diversity and how these subsurface mats differ from microbial communities in overlying surface soils. To investigate these differences, we analyzed bacterial 16S rDNA from 454 pyrosequencing from three colors of microbial mats (tan, white, and yellow) from seven lava caves in Lava Beds National Monument, CA, USA, and compared them with surface soil overlying each cave. The same phyla were represented in both surface soils and cave microbial mats, but the overlap in shared OTUs (operational taxonomic unit) was only 11.2%. Number of entrances per cave and temperature contributed to observed differences in diversity. In terms of species richness, diversity by mat color differed, but not significantly. Actinobacteria dominated in all cave samples, with 39% from caves and 21% from surface soils. Proteobacteria made up 30% of phyla from caves and 36% from surface soil. Other major phyla in caves were Nitrospirae (7%) followed by minor phyla (7%), compared to surface soils with Bacteroidetes (8%) and minor phyla (8%). Many of the most abundant sequences could not be identified to genus, indicating a high degree of novelty. Surface soil samples had more OTUs and greater diversity indices than cave samples. Although surface soil microbes immigrate into underlying caves, the environment selects for microbes able to live in the cave habitats, resulting in very different cave microbial communities. This study is the first comprehensive comparison of bacterial communities in lava caves with the overlying soil community.
Targeted protein degradation is a new therapeutic modality based on drugs that destabilize proteins by inducing their proximity to E3 ubiquitin ligases. Of particular interest are molecular glues ...that can degrade otherwise unligandable proteins by orchestrating direct interactions between target and ligase. However, their discovery has so far been serendipitous, thus hampering broad translational efforts. Here, we describe a scalable strategy toward glue degrader discovery that is based on chemical screening in hyponeddylated cells coupled to a multi-omics target deconvolution campaign. This approach led us to identify compounds that induce ubiquitination and degradation of cyclin K by prompting an interaction of CDK12-cyclin K with a CRL4B ligase complex. Notably, this interaction is independent of a dedicated substrate receptor, thus functionally segregating this mechanism from all described degraders. Collectively, our data outline a versatile and broadly applicable strategy to identify degraders with nonobvious mechanisms and thus empower future drug discovery efforts.
The Post-Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-4a trial is a randomized trial for women with high-intermediate risk endometrial cancer (EC), comparing individualized adjuvant ...treatment based on a molecular-integrated risk profile to standard adjuvant treatment; vaginal brachytherapy. To evaluate patient acceptability and pathology logistics of determining the risk profile, a pilot phase was included in the study.
PORTEC-4a is ongoing and the first 50 patients enrolled were included in the pilot phase. Primary endpoints of the pilot phase were patient acceptance, evaluated by analyzing the screening logs of the participating centers, and logistical feasibility of determination of the risk profile within 2 weeks, evaluated by analyzing the pathology database.
In the first year, 145 eligible women were informed about the trial at 13 centers, of whom 50 (35%) provided informed consent. Patient accrual ranged from 0 to 57% per center. Most common reasons for not participating were: not willing to participate in any trial (43.2%) and not willing to risk receiving no adjuvant treatment (32.6%). Analysis of the pathology database showed an average time between randomization and determination of the molecular-integrated risk profile of 10.2 days (1–23 days). In 5 of the 32 patients (15.6%), pathology review took >2 weeks.
The PORTEC-4a trial design was proven feasible with a satisfactory patient acceptance rate and an optimized workflow of the determination of the molecular-integrated risk profile. PORTEC-4a is the first randomized trial to investigate use of a molecular-integrated risk profile to determine adjuvant treatment in EC.
•Molecular-integrated risk profiling holds promise to improve individualization of treatment in endometrial cancer (EC).•PORTEC-4a is the first randomized clinical trial investigating molecular profile-based adjuvant treatment in EC.•The trial design was proven feasible with a good patient acceptance rate and logistical feasibility; accrual is ongoing.
Numerous investigations support decreased glutamatergic signaling as a pathogenic mechanism of schizophrenia, yet the molecular underpinnings for such dysregulation are largely unknown. In the ...post-mortem dorsolateral prefrontal cortex (DLPFC), we found striking decreases in tyrosine phosphorylation of N-methyl-D aspartate (NMDA) receptor subunit 2 (GluN2) that is critical for neuroplasticity. The decreased GluN2 activity in schizophrenia may not be because of downregulation of NMDA receptors as MK-801 binding and NMDA receptor complexes in postsynaptic density (PSD) were in fact increased in schizophrenia cases. At the postreceptor level, however, we found striking reductions in the protein kinase C, Pyk 2 and Src kinase activity that in tandem can decrease GluN2 activation. Given that Src serves as a hub of various signaling mechanisms affecting GluN2 phosphorylation, we postulated that Src hypoactivity may result from convergent alterations of various schizophrenia susceptibility pathways and thus mediate their effects on NMDA receptor signaling. Indeed, the DLPFC of schizophrenia cases exhibit increased PSD-95 and erbB4 and decreased receptor-type tyrosine-protein phosphatase-α (RPTPα) and dysbindin-1, each of which reduces Src activity via protein interaction with Src. To test genomic underpinnings for Src hypoactivity, we examined genome-wide association study results, incorporating 13 394 cases and 34 676 controls. We found no significant association of individual variants of Src and its direct regulators with schizophrenia. However, a protein-protein interaction-based network centered on Src showed significant enrichment of gene-level associations with schizophrenia compared with other psychiatric illnesses. Our results together demonstrate striking decreases in NMDA receptor signaling at the postreceptor level and propose Src as a nodal point of convergent dysregulations affecting NMDA receptor pathway via protein-protein associations.
Human activities are fundamentally altering biodiversity. Projections of declines at the global scale are contrasted by highly variable trends at local scales, suggesting that biodiversity change may ...be spatially structured. Here, we examined spatial variation in species richness and composition change using more than 50,000 biodiversity time series from 239 studies and found clear geographic variation in biodiversity change. Rapid compositional change is prevalent, with marine biomes exceeding and terrestrial biomes trailing the overall trend. Assemblage richness is not changing on average, although locations exhibiting increasing and decreasing trends of up to about 20% per year were found in some marine studies. At local scales, widespread compositional reorganization is most often decoupled from richness change, and biodiversity change is strongest and most variable in the oceans.
A human factors perspective on automated driving Kyriakidis, M.; de Winter, J. C. F.; Stanton, N. ...
Theoretical issues in ergonomics science,
05/2019, Letnik:
20, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Automated driving can fundamentally change road transportation and improve quality of life. However, at present, the role of humans in automated vehicles (AVs) is not clearly established. Interviews ...were conducted in April and May 2015 with 12 expert researchers in the field of human factors (HFs) of automated driving to identify commonalities and distinctive perspectives regarding HF challenges in the development of AVs. The experts indicated that an AV up to SAE Level 4 should inform its driver about the AV's capabilities and operational status, and ensure safety while changing between automated and manual modes. HF research should particularly address interactions between AVs, human drivers and vulnerable road users. Additionally, driver-training programmes may have to be modified to ensure that humans are capable of using AVs. Finally, a reflection on the interviews is provided, showing discordance between the interviewees' statements - which appear to be in line with a long history of HFs research - and the rapid development of automation technology. We expect our perspective to be instrumental for stakeholders involved in AV development and instructive to other parties.
Over the past 25 years, IRIS has become an integral resource in materials laboratories around the world, bringing together stimulating communities of rheology experimentalists and theoreticians, ...rheological experts, and experts from other fields, and even making rheology accessible to non-rheologists. The calculational tools of IRIS interface data from different experimental findings with predictions from rheology theories. Since its beginning, many theory groups used IRIS to share their original codes for rheology predictions. We demonstrate this in two examples, (1) the detailed analysis of small amplitude oscillatory shear data (SAOS) and predictions thereof and (2) a theory, newly implemented in IRIS, that elegantly unites dynamical quantities from small amplitude oscillatory shear (SAOS) with data from filament stretching rheometry and predictions of transient shear. IRIS supports this convergence with a standardizing data (Dealy et al., J Rheol 39:253-265,
1995
), which makes data sharing easy and independent of instrument brand-specific and laboratory-specific coding.
PDF
