Out-of-order commit processors

Modern out-of-order processors tolerate long latency memory operations by supporting a large number of in-flight instructions. This is particularly useful in numerical applications where branch speculation is normally not a problem and where the cache hierarchy is not capable of delivering the data soon enough. In order to support more in-flight instructions, several resources have to be up-sized, such as the reorder buffer (ROB), the general purpose instructions queues, the load/store queue and the number of physical registers in the processor. However, scaling-up the number of entries in these resources is impractical because of area, cycle time, and power consumption constraints. We propose to increase the capacity of future processors by augmenting the number of in-flight instructions. Instead of simply up-sizing resources, we push for new and novel microarchitectural structures that achieve the same performance benefits but with a much lower need for resources. Our main contribution is a new checkpointing mechanism that is capable of keeping thousands of in-flight instructions at a practically constant cost. We also propose a queuing mechanism that takes advantage of the differences in waiting time of the instructions in the flow. Using these two mechanisms our processor has a performance degradation of only 10% for SPEC2000fp over a conventional processor requiring more than an order of magnitude additional entries in the ROB and instruction queues, and about a 200% improvement over a current processor with a similar number of entries.Peer ReviewedPostprint (published version

Family caregiver emotional distress in advanced cancer : the DME- C scale psychometric properties

Publisher Copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Family caregivers of patients with advanced illness at end of life often report high levels of emotional distress. To address this emotional distress is necessary to have adequate and reliable screening tools. Aim: This study analyses the psychometric properties and clinical utility of the Family Caregiver Emotional Detection Scale for caregivers of patients with end-stage cancer (DME-C, Spanish acronym) who are receiving palliative care (PC). Design: Multicentre, cross-sectional study. Settings/participants: Family caregivers of patients with advanced cancer at end of life receiving palliative treatment were interviewed to explore their emotional distress through the DME-C scale and other instruments measuring anxiety and depression (Hospital Anxiety and Depression Scale (HADS)), distress thermometer (DT) and overload (B), as well as a clinical psychological assessment (CPA). Results: 138 family caregivers, 85 (61.6%) female and 53 (38.4%) male, with an average age of 59.69±13.3 participated in the study. The reliability of the scale, as measured by Cronbach's alpha, was 0.76, and its stability over time was 0.734. Positive, significant correlations were found between the DME-C and the scores for anxiety and depression registered on the HADS scale, as well as with the total result of this latter scale and the results for B, the DT and the CPA. A statistical analysis of the receiver-operating characteristic curves showed that the scale has a sensitivity and specificity of 75%, and that the cut-off point for the detection of emotional distress was a score ≥11. Fifty-four per cent of the caregivers displayed emotional distress according to this scale. Conclusions: The DME-C displays good psychometric properties. It is simple, short, reliable and easy to administer. We believe that the instrument is useful for the detection of emotional distress in the family caregivers of hospitalised patients suffering from end-stage illnesses and receiving PC

Vitamin D, cellular senescence and chronic kidney diseases: what is missing in the equation?

As life expectancy increases in many countries, the prevalence of age-related diseases also rises. Among these conditions, chronic kidney disease is predicted to become the second cause of death in some countries before the end of the century. An important problem with kidney diseases is the lack of biomarkers to detect early damage or to predict the progression to renal failure. In addition, current treatments only retard kidney disease progression, and better tools are needed. Preclinical research has shown the involvement of the activation of cellular senescence-related mechanisms in natural aging and kidney injury. Intensive research is searching for novel treatments for kidney diseases as well as for anti-aging therapies. In this sense, many experimental shreds of evidence support that treatment with vitamin D or its analogs can exert pleiotropic protective effects in kidney injury. Moreover, vitamin D deficiency has been described in patients with kidney diseases. Here, we review recent evidence about the relationship between vitamin D and kidney diseases, explaining the underlying mechanisms of the effect of vitamin D actions, with particular attention to the modulation of cellular senescence mechanismsThis research was funded by grants from the Instituto de Salud Carlos III (ISCIII) and Fondos FEDER European Union (PI20/00140, PI19/00240, PI19/00815, and DTS20/00083). Red de Investigación Renal REDINREN: RD16/0009/0003 to M.R.-O. and RICORS2040; RD21/0005/0002 funded by European Union—NextGenerationEU, INNOREN cm (P2022/BMD-7221) of the Comunidad de Madrid, Sociedad Española de Nefrología. Innovation programme under the Marie Skłodowska-Curie grant of the European Union’s Horizon 2020 (IMProve-PD ID: 812699) to M.R.-

Evidence for chiral superconductivity on a silicon surface

Tin adatoms on a Si(111) substrate with a one-third monolayer coverage form a two-dimensional triangular lattice with one unpaired electron per site. These electrons order into an antiferromagnetic Mott-insulating state, but doping the Sn layer with holes creates a two-dimensional conductor that becomes superconducting at low temperatures. Although the pairing symmetry of the superconducting state is currently unknown, the combination of repulsive interactions and frustration inherent in the triangular adatom lattice opens up the possibility of a chiral order parameter. Here we study the superconducting state of Sn/Si(111) using scanning tunnelling microscopy, scanning tunnelling spectroscopy and quasiparticle interference imaging. We find evidence for a doping-dependent superconducting critical temperature with a fully gapped order parameter, the presence of time-reversal symmetry breaking and a strong enhancement in zero-bias conductance near the edges of the superconducting domains. Although each individual piece of evidence could have a more mundane interpretation, our combined results suggest the possibility that Sn/Si(111) is an unconventional chiral d-wave superconducto

Biological Evaluation and Docking Studies of Synthetic Oleananetype Triterpenoids

Saponins are potential wide-spectrum antitumor drugs, and copper(I) catalyzed azide−alkyne 1,3-dipolar cycloaddition is a suitable approach to synthesizing saponinlike compounds by regioselective glycosylation of the C2/C3 hydroxyl and C28 carboxylic groups of triterpene aglycones maslinic acid (MA) and oleanolic acid (OA). Biological studies on the T-84 human colon carcinoma cell line support the role of the hydroxyl groups at C2/C3, the influence of the aglycone, and the bulky nature of the substituents in C28. OA bearing a α-D-mannose moiety at C28 (compound 18) focused our interest because the estimated inhibitory concentration 50 was similar to that reported for ginsenoside Rh2 against colon cancer cells and it inhibits the G1−S phase transition affecting the cell viability and apoptosis. Considering that triterpenoids from natural sources have been identified as inhibitors of nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling, docking studies were conducted to evaluate whether NF-κB may be a potential target. Results are consistent with the biological study and predict a similar binding mode of MA and compound 18 to the p52 subunit from NF- κB but not for OA. The fact that the binding site is shared by the NF-κB inhibitor 6,6-dimethyl-2-(phenylimino)-6,7- dihydrobenzo[d][1,3]oxathiol-4(5H)-one supports the result and points to NF-κB as a potential target of both MA and compound 18.This work was supported by a grant from Ramón Areces Foundation (Madrid, Spain) and by grant CTQ2014-55474- C2-1-R from the Spanish Ministerio de Economia y Competitividad (MINECO) co-financed by FEDER funds

Single chain variable fragment fused to maltose binding protein: a modular nanocarrier platform for the targeted delivery of antitumorals

This work was supported by grants CTQ2014-55474-C2-1-R, CTQ2014-55474-C2-2-R and CTQ2017-86125-P from the Ministerio Economia, Industria y Competitividad (co-financed by FEDER funds). SP is supported by a FPU fellowship (FPU17/ 04749). We acknowledge the University of Granada (Spain) cell culture, animal and microscopy central facilities (CIC-UGR).The use of the specific binding properties of monoclonal antibody fragments such as single-chain variable fragments (ScFv) for the selective delivery of antitumor therapeutics for cancer cells is attractive due to their smaller size, low immunogenicity, and low-cost production. Although covalent strategies for the preparation of such ScFv-based therapeutic conjugates are prevalent, this approach is not straightforward, as it requires prior chemical activation and/or modification of both the ScFv and the therapeutics for the application of robust chemistries. A non-covalent alternative based on ScFv fused to maltose-binding protein (MBP) acting as a binding adapter is proposed for active targeted delivery. MBP-ScFv proves to be a valuable modular platform to synergistically bind maltose-derivatized therapeutic cargos through the MBP, while preserving the targeting competences provided by the ScFv. The methodology has been tested by using a mutated maltose-binding protein (MBP I334W) with an enhanced affinity toward maltose and an ScFv coding sequence toward the human epidermal growth factor receptor 2 (HER2). Non-covalent binding complexes of the resulting MBP-ScFv fusion protein with diverse maltosylated therapeutic cargos (a near-infrared dye, a maltosylated supramolecular beta-cyclodextrin container for doxorubicin, and non-viral polyplex gene vector) were easily prepared and characterized. In vitro and in vivo assays using cell lines that express or not the HER2 epitope, and mice xenografts of HER2 expressing cells demonstrated the capability and versatility of MBP-ScFv for diagnosis, imaging, and drug and plasmid active targeted tumor delivery. Remarkably, the modularity of the MBP-ScFv platform allows the flexible interchange of both the cargos and the coding sequence for the ScFv, allowing ad hoc solutions in targeting delivery without any further optimization since the MBP acts as a pivotal element.Ministerio Economia, Industria y Competitividad - FEDER funds CTQ2014-55474-C2-1-R CTQ2014-55474-C2-2-R CTQ2017-86125-PSpanish Government FPU17/0474

Risk of suicide in households threatened with eviction: the role of banks and social support

Background: One of the greatest effects of the financial crisis in Spain has been the enormous increase in the number of evictions. Several studies have shown the association of evictions with different aspects of the physical and mental health. Furthermore, evictions have been associated with an increased risk of suicide. Our objective was to evaluate the risk of suicide among victims of eviction and investigate whether it is associated with specific characteristics of households and interviewees, the eviction process and social support, and health needs. Results: Almost half of the sample (46.7%) were at low (11.8%), moderate (16.9%), or high suicide risk (17.9%). Household and interviewee features had a limited association with suicide risk. On the contrary, the risk of suicide is greater with a longer exposure to the eviction process. In addition, threatening phone calls from banks increased significantly the risk of suicide, especially among men. Suicide risk was also associated with low social support, especially among women. Interviewees at risk of suicide received more help from nongovernmental organizations than those who were not at risk. In interviewees at risk, the main unmet needs were emotional and psychological help, especially in men. A high percentage of those at risk of suicide declare having large unmeet health needs. Finally, there was a tendency among the evicted at risk of suicide to visit emergency room and primary care more often than those not at risk, especially among women. Conclusions: To our knowledge, this is the first study showing that when banks adopt a threatening attitude, suicide risk increases among the evicted. As hypothesized, when the evicted felt socially supported, suicide risk decreased. Emotional help was the main mediator of suicide risk and the main unmet need, especially among me

Robust multi-view approaches for retinal layer segmentation in glaucoma patients via transfer learning

Background: Glaucoma is the leading global cause of irreversible blindness. Glaucoma patients experience a progressive deterioration of the retinal nervous tissues that begins with a loss of peripheral vision. An early diagnosis is essential in order to prevent blindness. Ophthalmologists measure the deterioration caused by this disease by assessing the retinal layers in different regions of the eye, using different optical coherence tomography (OCT) scanning patterns to extract images, generating different views from multiple parts of the retina. These images are used to measure the thickness of the retinal layers in different regions. Methods: We present two approaches for the multi-region segmentation of the retinal layers in OCT images of glaucoma patients. These approaches can extract the relevant anatomical structures for glaucoma assessment from three different OCT scan patterns: circumpapillary circle scans, macular cube scans and optic disc (OD) radial scans. By employing transfer learning to take advantage of the visual patterns present in a related domain, these approaches use state-of-the-art segmentation modules to achieve a robust, fully automatic segmentation of the retinal layers. The first approach exploits inter-view similarities by using a single module to segment all of the scan patterns, considering them as a single domain. The second approach uses view-specific modules for the segmentation of each scan pattern, automatically detecting the suitable module to analyse each image. Results: The proposed approaches produced satisfactory results with the first approach achieving a dice coefficient of 0.85±0.06 and the second one 0.87±0.08 for all segmented layers. The first approach produced the best results for the radial scans. Concurrently, the view-specific second approach achieved the best results for the better represented circle and cube scan patterns. Conclusions: To the extent of our knowledge, this is the first proposal in the literature for the multi-view segmentation of the retinal layers of glaucoma patients, demonstrating the applicability of machine learningbased systems for aiding in the diagnosis of this relevant pathology

Desarrollo de la escala EDSOL para la detección de la soledad existencial en enfermos al final de la vida

Objetivo: Presentar el desarrollo de la escala de detección de la soledad existencial (EDSOL) en personas con enfermedades avanzadas en tratamiento paliativo. Método: Se describe el proceso de elaboración de la escala Detección de la Soledad Existencial EDSOL. Para ello, 1) se ha revisado la bibliografía existente sobre el tema; 2) se ha establecido un marco teórico de referencia; 3) se han definido los criterios que debía cumplir el instrumento de cribado; y 4) se ha consultado con expertos y enfermos la adecuación de los ítems de la escala. Resultados: Se presenta a la escala EDSOL, que consta de dos partes: 1) tres preguntas dirigidas a los enfermos; y 2) diferentes observaciones realizadas por el personal sanitario acerca de la presencia de signos externos de soledad existencial. La escala final fue revisada por enfermos y profesionales. Conclusión: La escala EDSOL es una herramienta apropiada para identificar la presencia de Soledad Existencial en pacientes al final de la vida. En este caso, se propondrá su uso sistemático en la detección temprana de la Soledad Existencial y la implementación de intervenciones asistenciales específicasAim: This paper presents the development of Detection of Existential Loneliness Scale (EDSOL) of patients with advanced disease/terminal illness that receiving palliative care. Method: The process of preparing the scale is described. For this: 1) the literature on the subject has been revised, 2)theoretical framework has been established, 3) it has been defined the criteria to be met by the screening tool, and 4) the final scale was reviewed by patients and experts. Results: The EDSOL scale consists of two parts: 1) three questions addressed to patients and; 2) several questions addressed to health staff about the observation of external signs of Existential Loneliness. The final scale was reviewed by patients and experts (facie validity) showing good validity. Conclussion: The EDSOL scale will be an appropriate tool for identifying the Existential Loneliness of patients at the end of life or advanced illness. In this case, we will propose the systematic use of EDSOL for early detection and specific interventions on existential loneliness experience