Adverse effects of sodium-glucose cotransporter-2 inhibitors in patients with heart failure: a systematic review and meta-analysis.

Sodium-glucose cotransoporter-2 inhibitors (SGLT-2Is) improve prognosis in heart failure (HF) patients both with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). However, these drugs can have some side effects. To estimate the relative risk of side effects in HF patients treated with SGLT-2Is irrespective from left ventricular EF and setting (chronic and non-chronic HF). Five randomized controlled trials (RCTs) enrolling patients with HFrEF, 4 RCTs enrolling non-chronic HF, and 3 RCTs enrolling HFpEF were included. Among side effects, urinary infection, genital infection, acute kidney injury, diabetic ketoacidosis, hypoglycemia, hyperkalemia, hypokalemia, bone fractures, and amputations were considered in the analysis. Overall, 24,055 patients were included in the analysis: 9020 (38%) patients with HFrEF, 12,562 (52%) with HFpEF, and 2473 (10%) with non-chronic HF. There were no differences between SGLT-2Is and placebo in the risk to develop diabetic ketoacidosis, hypoglycemia, hyperkalemia, hypokalemia, bone fractures, and amputations. HFrEF patients treated with SGLT-2Is had a significant reduction of acute kidney injury (RR = 0.54 (95% CI 0.33-0.87), p = 0.011), whereas no differences have been reported in the HFpEF group (RR = 0.94 (95% CI 0.83-1.07), p = 0.348) and non-chronic HF setting (RR = 0.79 (95% CI 0.55-1.15), p = 0.214). A higher risk to develop genital infection (overall 2.57 (95% CI 1.82-3.63), p < 0.001) was found among patients treated with SGLT-2Is irrespective from EF (HFrEF: RR = 1.96 (95% CI 1.17-3.29), p = 0.011; HFpEF: RR = 3.04 (95% CI 1.88-4.90), p < 0.001). The risk to develop urinary infections was increased among SGLT-2I users in the overall population (RR = 1.13 (95% CI 1.00-1.28), p = 0.046) and in the HFpEF setting (RR = 1.19 (95% CI 1.02-1.38), p = 0.029), whereas no differences have been reported in HFrEF (RR = 1.05 (95% CI 0.81-1.36), p = 0.725) and in non-chronic HF setting (RR = 1.04 (95% CI 0.75-1.46), p = 0.806). SGLT-2Is increase the risk of urinary and genital infections in HF patients. In HFpEF patients, the treatment increases the risk of urinary infections compared to placebo, whereas SGLT-2Is reduce the risk of acute kidney disease in patients with HFrEF.

Towards X-ray transient grating spectroscopy.

The extension of transient grating spectroscopy to the x-ray regime will create numerous opportunities, ranging from the study of thermal transport in the ballistic regime to charge, spin, and energy transfer processes with atomic spatial and femtosecond temporal resolution. Studies involving complicated split-and-delay lines have not yet been successful in achieving this goal. Here we propose a novel, simple method based on the Talbot effect for converging beams, which can easily be implemented at current x-ray free electron lasers. We validate our proposal by analyzing printed interference patterns on polymethyl methacrylate and gold samples using ∼3 keV X-ray pulses.

Erratum: Resonance Effects in Photoemission Time Delays [Phys. Rev. Lett. 115, 133001 (2015)].

This corrects the article DOI: 10.1103/PhysRevLett.115.133001.

Comparison of attosecond streaking and RABBITT.

Recent progress in the generation of ultra-short laser pulses has enabled the measurement of photoionization time delays with attosecond precision. For single photoemission time delays the most common techniques are based on attosecond streaking and the reconstruction of attosecond beating by interference of two-photon transitions (RABBITT). These are pump-probe techniques employing an extreme-ultraviolet (XUV) single attosecond pump pulse for streaking or an attosecond pump pulse train for RABBITT, and a phase-locked infrared (IR) probe pulse. These techniques can only extract relative timing information between electrons originating from different initial states within the same atom or different atoms. Here we address the question whether the two techniques give identical timing information. We present a complete study, supported by both experiments and simulations, comparing these two techniques for the measurement of the photoemission time delay difference between valence electrons emitted from the Ne 2p and Ar 3p ground states. We highlight not only the differences and similarities between the two techniques, but also critically investigate the reliability of the methods used to extract the timing information.

Resonance Effects in Photoemission Time Delays.

We present measurements of single-photon ionization time delays between the outermost valence electrons of argon and neon using a coincidence detection technique that allows for the simultaneous measurement of both species under identical conditions. The analysis of the measured traces reveals energy-dependent time delays of a few tens of attoseconds with high energy resolution. In contrast to photoelectrons ejected through tunneling, single-photon ionization can be well described in the framework of Wigner time delays. Accordingly, the overall trend of our data is reproduced by recent Wigner time delay calculations. However, besides the general trend we observe resonance features occurring at specific photon energies. These features have been qualitatively reproduced and identified by a calculation using the multiconfigurational Hartree-Fock method, including the influence of doubly excited states and ionization thresholds.

Revealing the time-dependent polarization of ultrashort pulses with sub-cycle resolution.

We report on the first experiments characterizing the complete time-dependent 2D vector potential of a few-cycle laser pulse. The instantaneous amplitude and orientation of the electric field is determined with sub-cycle resolution, directly giving access to the polarization state of the pulse at any instant in time. This is achieved by performing an attosecond streaking experiment using a reaction microscope, where the full pulse characterization is performed directly in the target region.

Unified approach to probing Coulomb effects in tunnel ionization for any ellipticity of laser light.

We present experimental data that show significant deviations from theoretical predictions for the location of the center of the electron momenta distribution at low values of ellipticity ε of laser light. We show that these deviations are caused by significant Coulomb focusing along the minor axis of polarization, something that is normally neglected in the analysis of electron dynamics, even in cases where the Coulomb correction is otherwise taken into account. By investigating ellipticity-resolved electron momenta distributions in the plane of polarization, we show that Coulomb focusing predominates at lower values of ellipticity of laser light, while Coulomb asymmetry becomes important at higher values, showing that these two complementary phenomena can be used to probe long-range Coulomb interaction at all polarizations of laser light. Our results suggest that both the breakdown of Coulomb focusing and the onset of Coulomb asymmetry are linked to the disappearance of Rydberg states with increasing ellipticity.

Probing nonadiabatic effects in strong-field tunnel ionization.

We investigate experimentally the validity of proposed theories extending the tunneling approximation towards the multiphoton regime in strong-field ionization of helium. We employ elliptically polarized laser pulses and demonstrate how the influence of the ion potential on the released electron encoded in the measured observable provides the desired sensitivity to detect nonadiabatic effects in tunnel ionization. Our results show that for a large intensity range the proposed nonadiabatic theories contradict the experimental trends of the data, while adiabatic assumptions are confirmed.

Treatment of renal angiomyolipoma: surgery versus angioembolization.

Renal angiomyolipoma (AML) is a benign mesenchymal tumour. AML often leads to haemorrhagic complications such as retroperitoneal haematoma. Treatment varies from case to case, ranging from minimally invasive approaches such as selective embolization of the renal artery to invasive wedge resection, partial nephrectomy or, in more severe cases, radical nephrectomy. Here we report a case of retroperitoneal haematoma secondary to AML, treated with conservative approach by super-selective embolization of the lower-pole segmental renal artery.

Probing the longitudinal momentum spread of the electron wave packet at the tunnel exit.

We present an ellipticity-resolved study of momentum distributions arising from strong-field ionization of helium. The influence of the ion potential on the departing electron is considered within a semiclassical model consisting of an initial tunneling step and subsequent classical propagation. We find that the momentum distribution can be explained by including the longitudinal momentum spread of the electron at the exit from the tunnel. Our combined experimental and theoretical study provides an estimate of this momentum spread.

Neuronal gene expression in the waking state: a role for the locus coeruleus.

Several transcription factors are expressed at higher levels in the waking than in the sleeping brain. In experiments with rats, the locus coeruleus, a noradrenergic nucleus with diffuse projections, was found to regulate such expression. In brain regions depleted of noradrenergic innervation, amounts of c-Fos and nerve growth factor-induced A after waking were as low as after sleep. Phosphorylation of cyclic adenosine monophosphate response element-binding protein was also reduced. In contrast, electroencephalographic activity was unchanged. The reduced activity of locus coeruleus neurons may explain why the induction of certain transcription factors, with potential effects on plasticity and learning, does not occur during sleep.

Correlates of sleep and waking in Drosophila melanogaster.

Drosophila exhibits a circadian rest-activity cycle, but it is not known whether fly rest constitutes sleep or is mere inactivity. It is shown here that, like mammalian sleep, rest in Drosophila is characterized by an increased arousal threshold and is homeostatically regulated independently of the circadian clock. As in mammals, rest is abundant in young flies, is reduced in older flies, and is modulated by stimulants and hypnotics. Several molecular markers modulated by sleep and waking in mammals are modulated by rest and activity in Drosophila, including cytochrome oxidase C, the endoplasmic reticulum chaperone protein BiP, and enzymes implicated in the catabolism of monoamines. Flies lacking one such enzyme, arylalkylamine N-acetyltransferase, show increased rest after rest deprivation. These results implicate the catabolism of monoamines in the regulation of sleep and waking in the fly and suggest that Drosophila may serve as a model system for the genetic dissection of sleep.

Proteomic profiling of the rat cerebral cortex in sleep and waking.

Transcriptomic studies have shown that hundreds of genes change their expression levels across the sleep/waking cycle, and found that waking-related and sleep-related mRNAs belong to different functional categories. Proteins, however, rather than DNA or RNA, carry out most of the cellular functions, and direct measurements of protein levels and activity are required to assess the effects of behavioral states on the overall functional state of the cell. Here we used surface-enhanced laser desorption-ionization (SELDI), followed by time-of-flight mass spectrometry, to obtain a large-scale profiling of the proteins in the rat cerebral cortex whose expression is affected by sleep, spontaneous waking, short (6 hours) and long (7 days) sleep deprivation. Each of the 94 cortical samples was profiled in duplicate on 4 different ProteinChip Array surfaces using 2 different matrix molecules. Overall, 1055 protein peaks were consistently detected in cortical samples and 15 candidate biomarkers were selected for identification based on significant changes in multiple conditions (conjunction analysis): 8 "sleep" peaks, 4 "waking" peaks, and 4 "long sleep deprivation" peaks. Four candidate biomarkers were purified and positively identified. The 3353 Da candidate sleep marker was identified as the 30 amino acid C-terminal fragment of rat histone H4. This region encompasses the osteogenic growth peptide, but a possible link between sleep and this peptide remains highly speculative. Two peaks associated with short and long sleep deprivation were identified as hemoglobin alpha1/2 and beta, respectively, while another peak associated with long sleep deprivation was identified as cytochrome C. The upregulation of hemoglobins and cytochrome C may be part of a cellular stress response triggered by even short periods of sleep loss.

Cortical metabolic rates as measured by 2-deoxyglucose-uptake are increased after waking and decreased after sleep in mice.

A recent hypothesis suggests that a major function of sleep is to renormalize synaptic changes that occur during wakefulness as a result of learning processes [G. Tononi, C. Cirelli, Sleep and synaptic homeostasis: a hypothesis, Brain Res. Bull. 62 (2003) 143-150; G. Tononi, C. Cirelli, Sleep function and synaptic homeostasis, Sleep Med. Rev. 10 (2006) 49-62]. Specifically, according to this synaptic homeostasis hypothesis, wakefulness results in a net increase in synaptic strength, while sleep is associated with synaptic downscaling. Since synaptic activity accounts for a large fraction of brain energy metabolism, one of the predictions of the hypothesis is that if synaptic weight increases in the course of wakefulness, cerebral metabolic rates should also increase, while the opposite would happen after a period of sleep. In this study we therefore measured brain metabolic rate during wakefulness and determined whether it was affected by the previous sleep-wake history. Three groups of mice in which behavioral states were determined by visual observation were subjected to 6h of sleep deprivation (SD). Group 1 was injected with 2-deoxyglucose (2-DG) 45 min before the end of SD, while Group 2 and Group 3 were injected with 2-DG after an additional period (2-3h) of waking or sleep, respectively. During the 45-min interval between 2-DG injection and sacrifice all mice were kept awake. We found that in mice that slept approximately 2.5h the 2-DG-uptake was globally decreased, on average by 15-20%, compared to the first two groups that were kept awake. On average, Group 2, which stayed awake approximately 2h more than Group 1, showed only a small further increase in 2-DG-uptake relative to Group 1. Moreover, the brain regions in which 2-DG-uptake increased the least when waking was prolonged by approximately 2h showed the most pronounced decrease in DG-uptake after sleep. The data are consistent with the prediction that sleep may reset cerebral metabolic rates to a lower level.

Orientation-dependent stereo Wigner time delay and electron localization in a small molecule.

Attosecond metrology of atoms has accessed the time scale of the most fundamental processes in quantum mechanics. Transferring the time-resolved photoelectric effect from atoms to molecules considerably increases experimental and theoretical challenges. Here we show that orientation- and energy-resolved measurements characterize the molecular stereo Wigner time delay. This observable provides direct information on the localization of the excited electron wave packet within the molecular potential. Furthermore, we demonstrate that photoelectrons resulting from the dissociative ionization process of the CO molecule are preferentially emitted from the carbon end for dissociative 2Σ states and from the center and oxygen end for the 2Π states of the molecular ion. Supported by comprehensive theoretical calculations, this work constitutes a complete spatially and temporally resolved reconstruction of the molecular photoelectric effect.

Sleep and the fruit fly.

The function of sleep remains a long-standing mystery in neurobiology. The presence of a sleep-like state has recently been demonstrated in the fruit fly, Drosophila melanogaster, meeting the essential behavioral criteria for sleep and also showing pharmacological and molecular correlates of mammalian sleep. This development opens up the possibility of applying genetic analysis to the identification of key molecular components of sleep. A mutant of monoamine metabolism has already been found to affect the homeostatic regulation of sleep-like behavior in the fly. The record of Drosophila in laying the foundations for subsequent studies in mammals argues in favor of the force of this new approach.

Is climate change a threat for water uses in the Mediterranean region? Results from a survey at local scale.

Water scarcity and water security are linked, not only through the direct effects of water shortages on each water users' access to water, but also because of water conflicts generated. Climate change is predicted to raise temperatures in the Mediterranean region and reduce rainfall, leading to a reduction in water yield and possibly worsening the situation of water resource shortages that Mediterranean regions are already experiencing. In its dissemination strategy, the EU FP7 CLIMB project addressed water security threats through an analysis of water uses and water use rivalries within a few target catchments distributed over the Mediterranean region. The present work explores whether climate change is locally perceived by stakeholders (water users and managers) as a key issue for their water uses and water security. Individual interviews, meetings, and compilation of questionnaires were conducted at five sites located in the Mediterranean region. The methodology permitted an analysis of water use and its evolution in the water management context, an identification of the state of awareness of local stakeholders and of the pressures on water use and water use rivalries, and a prioritization of water uses. Currently, the main response to increasing water demand in the Mediterranean region, while not yet considering climate change as a driving force, is a progressive externalization of water resources, with limits represented by national borders and technological possibilities. Overall, 'climate change' was not mentioned by stakeholders during both interviews and in answers to the questionnaires. Even the prospect of decreasing precipitation was not considered a relevant or threatening issue in the coming 20years. This confirms the need to continue all efforts to disseminate the state of knowledge on climate change impacts in the Mediterranean region, such as water scarcity, especially to local water managers, as initiated by various research programs of the European Commission.

Differential expression of plasticity-related genes in waking and sleep and their regulation by the noradrenergic system.

Behavioral studies indicate that the ability to acquire long-term memories is severely impaired during sleep. It is unclear, however, why the highly synchronous discharge of neurons during sleep should not be followed by the induction of enduring plastic changes. Here we show that the expression of phosphorylated CRE-binding protein, Arc, and BDNF, three genes whose induction is often associated with synaptic plasticity, is high during waking and low during sleep. We also show that the induction of these genes during waking depends on the activity of the noradrenergic system, which is high in waking and low in sleep. These molecular results complement behavioral evidence and provide a mechanism for the impairment of long-term memory acquisition during sleep.