Interface Roughening in Nonequilibrium Phase-Separated Systems.

Interfaces of phase-separated systems roughen in time due to capillary waves. Because of fluxes in the bulk, their dynamics is nonlocal in real space and is not described by the Edwards-Wilkinson or Kardar-Parisi-Zhang (KPZ) equations, nor their conserved counterparts. We show that, in the absence of detailed balance, the phase-separated interface is described by a new universality class that we term |q|KPZ. We compute the associated scaling exponents via one-loop renormalization group and corroborate the results by numerical integration of the |q|KPZ equation. Deriving the effective interface dynamics from a minimal field theory of active phase separation, we finally argue that the |q|KPZ universality class generically describes liquid-vapor interfaces in two- and three-dimensional active systems.

Classical Nucleation Theory for Active Fluid Phase Separation.

Classical Nucleation Theory (CNT), linking rare nucleation events to the free-energy landscape of a growing nucleus, is central to understanding phase-change kinetics in passive fluids. Nucleation in nonequilibrium systems is much harder to describe because there is no free energy, but instead a dynamics-dependent quasipotential that typically must be found numerically. Here we extend CNT to a class of active phase-separating systems governed by a minimal field-theoretic model (Active Model B+). In the small noise and supersaturation limits that CNT assumes, we compute analytically the quasipotential, and hence, nucleation barrier, for liquid-vapor phase separation. Crucial to our results, detailed balance, although broken microscopically by activity, is restored along the instanton trajectory, which in CNT involves the nuclear radius as the sole reaction coordinate.

Living in endemic area for infectious diseases accelerates epigenetic age.

Inflammaging is a low-grade inflammatory state generated by the aging process that can contribute to frailty and age-related diseases in the elderly. However, it can have distinct effects in the elderly living in endemic areas for infectious diseases. An increased inflammatory response may confer protection against infectious agents in these areas, although this advantage can cause accelerating epigenetic aging. In this study, we evaluated the inflammatory profile and the epigenetic age of infected and noninfected individuals from an endemic area in Brazil. The profile of cytokines, chemokines and growth factors analyzed in the sera of the two groups of individuals showed similarities, although infected individuals had a higher concentration of these mediators. A significant increase in IL-1ra, CXCL8, CCL2, CCL3 and CCL4 production was associated with leprosy infection. Notably, elderly individuals displayed distinct immune responses associated with their infection status when compared to adults suggesting an adaptive remodelling of their immune responses. Epigenetic analysis also showed that there was no difference in epigenetic age between the two groups of individuals. However, individuals from the endemic area had a significant accelerated aging when compared to individuals from São Paulo, a non-endemic area in Brazil. Moreover, the latter cohort was also epigenetically aged in relation to an Italian cohort. Our data shows that living in endemic areas for chronic infectious diseases results in remodelling of inflammaging and acceleration of epigenetic aging in individuals regardless of their infectious status. It also highlights that geographical, genetic and environmental factors influence aging and immunosenescence in their pace and profile.

Erratum: Capillary Interfacial Tension in Active Phase Separation [Phys. Rev. Lett. 127, 068001 (2021)].

This corrects the article DOI: 10.1103/PhysRevLett.127.068001.

Capillary Interfacial Tension in Active Phase Separation.

In passive fluid-fluid phase separation, a single interfacial tension sets both the capillary fluctuations of the interface and the rate of Ostwald ripening. We show that these phenomena are governed by two different tensions in active systems, and compute the capillary tension σ_{cw} which sets the relaxation rate of interfacial fluctuations in accordance with capillary wave theory. We discover that strong enough activity can cause negative σ_{cw}. In this regime, depending on the global composition, the system self-organizes, either into a microphase-separated state in which coalescence is highly inhibited, or into an "active foam" state. Our results are obtained for Active Model B+, a minimal continuum model which, although generic, admits significant analytical progress.

Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials.

AIMS: Sodium glucose co-transport-2 (SGLT-2) inhibitors, a new class of glucose-lowering agents, reduce tubular glucose reabsorption, producing a reduction of blood glucose without stimulating insulin release. The aim of the present meta-analysis is the assessment of the overall efficacy and safety profile of these drugs. METHODS: A meta-analysis was performed including all trials with a duration of at least 12 weeks, comparing a SGLT-2 inhibitor with a non-SGLT-2 inhibitor agent in type 2 diabetes. The principal outcome of this analysis was the effect of SGLT-2 inhibitors on HbA1c at 12, 24 and 52 weeks. Hypoglycaemia, genital and urinary infections were retrieved and combined to calculate Mantel-Haenszel odds ratio (MH-OR). Furthermore, data on body mass index (BMI), endpoint fasting plasma glucose, systolic and diastolic blood pressure, creatinine, hematocrit and lipid profile were collected. RESULTS: Among placebo-controlled trials, HbA1c reduction at 12, 24 and 52 weeks was 0.5 [0.4; 0.6], 0.6 [0.6; 0.5] and 0.6 [0.7; 0.5]%. In placebo-controlled studies, 24-week reduction of HbA1c with SGLT-2 inhibitors was greater in trials enrolling patients with a lower mean age and duration of diabetes, and a higher baseline BMI, HbA1c and fasting glucose. In placebo-controlled trials, SGLT-2 inhibitors determined a weight loss during the first 24 weeks, which was maintained up to 52 weeks. CONCLUSIONS: SGLT-2 inhibitors are effective in the treatment of type 2 diabetes, providing additional benefits, such as weight loss, reduction of blood pressure and increase in high-density lipoprotein (HDL)-cholesterol. Apart from genital and urinary infections, rather frequent but usually mild, SGLT-2 inhibitors appear to be well tolerated.

Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials.

AIMS: New drugs for type 2 diabetes need to demonstrate their cardiovascular safety, due regulatory requirements from the Food and Drug Administration. For this reason, glucagon-like peptide-1 receptor agonists (GLP-1 RA) are currently undergoing large-scale, long-term randomized trials specifically designed for cardiovascular outcomes. Aim of the present meta-analysis of randomized clinical trials is the assessment of the effects of GLP-1 RA on major cardiovascular events (MACE), mortality and cardiovascular risk factors. METHODS: A meta-analysis was performed including all trials with a duration of at least 6 months, comparing a GLP-1 RA with a non-GLP-1 RA agent in type 2 diabetes. MACE and mortality were retrieved and combined to calculate Mantel-Haenzel odds ratio (MH-OR). Furthermore, data on endpoint systolic and diastolic blood pressure, total and high-density lipoprotein (HDL) cholesterol and triglyceride were collected. RESULTS: Of 37 selected trials, 33 reported information on MACE, and 25 reported at least one event. The difference in the incidence of MACE between GLP-1 RA and comparators did not reach statistical significance [MH-OR 0.78 (0.54-1.13), p = 0.18]. GLP-1 RA were associated with a significant reduction in the incidence of MACE in comparisons with placebo and pioglitazone, with a non-significant trend towards reduction in DPP4i-controlled studies. No significant effect of GLP-1 RA was observed on mortality, although a non-significant favourable trend was observed in comparisons with placebo. CONCLUSIONS: The present meta-analysis confirms the cardiovascular safety of GLP-1 RA, at least in the short term and in low-risk individuals. GLP-1 RA could have a beneficial effect on the incidence of MACE, at least in comparison with placebo.

Continuous EEG-SEP monitoring in severe brain injury.

AIMS: To monitor acute brain injury in the neurological intensive care unit (NICU), we used EEG and somatosensory evoked potentials (SEP) in combination to achieve more accuracy in detecting brain function deterioration. METHODS: Sixty-eight patients (head trauma and intracranial hemorrhage; GCS<9) were monitored with continuous EEG-SEP and intracranial pressure monitoring (ICP). RESULTS: Fifty-five patients were considered "stable" or improving, considering the GCS and CT scan: in this group, SEP didn't show significant changes. Thirteen patients showed neurological deteriorations and, in all patients, cortical SEP showed significant alterations (amplitude decrease>50% often till complete disappearance). SEP deterioration anticipated ICP increase in 30%, was contemporary in 38%, and followed ICP increase in 23%. Considering SEP and ICP in relation to clinical course, all patients but one with ICP less than 20 mmHg were stable, while the three patients with ICP greater than 40 mmHg all died. Among the 26 patients with ICP of 20-40 mmHg, 17 were stable, while nine showed clinical and neurophysiological deterioration. Thus, there is a range of ICP values (20-40 mmHg) were ICP is scarcely indicative of clinical deterioration, rather it is the SEP changes that identify brain function deterioration. Therefore, SEP have a twofold interest with respect to ICP: their changes can precede an ICP increase and they can constitute a complementary tool to interpret ICP trends. It has been very important to associate SEP and EEG: about 60% of our patients were deeply sedated and, because of their relative insensitivity to anesthetics, only SEP allowed us to monitor brain damage evolution when EEG was scarcely valuable. CONCLUSIONS: We observed 3% of nonconvulsive status epilepticus compared to 18% of neurological deterioration. If the aim of neurophysiological monitoring is to "detect and protect", it may not be limited to detecting seizures, rather it should be able to identify brain deterioration, so we propose the combined monitoring of EEG with SEP.

Progress in large-scale purification of factor VIII/von Willebrand factor concentrates using ion-exchange chromatography.

BACKGROUND AND OBJECTIVES: We investigated and optimized the parameters of a chromatographic process suitable for industrial scale to obtain a highly purified factor VIII (FVIII)/von Willebrand factor (VWF) concentrate. MATERIALS AND METHODS: Several chromatographic runs were performed on the same production intermediate using different anion-exchange supports. The best matrix was selected and the final product was characterized. Once the chromatographic medium was chosen, the other parameters were evaluated to obtain the highest purified product and to modulate the VWF content in the FVIII/VWF complex. RESULTS: Fractogel EMD TMAE was the best support among those tested. It was the only one maintaining good results either with standard or double loading and flow rate conditions with respect to a typical industrial process. The chromatographic recovery of FVIII co-purified with VWF was at least 86% with a specific activity not lower than 140 IU/mg. The FVIII/VWF complex obtained is highly pure and, with the exception of immunoglobulin M (IgM), all investigated contaminant proteins are under the detection limit. Different concentrates characterized by variable FVIII/VWF ratios were purified by varying the chromatographic conditions. CONCLUSIONS: Several highly purified products, suitable for haemophilia A and von Willebrand disease management, can be obtained, through the same chromatographic process, on an industrial scale.

The [(methyloxy)imino]methyl moiety as a bioisoster of aryl. A novel class of completely aliphatic beta-adrenergic receptor antagonists.

Previous studies in the field of beta-adrenergic drugs had supported the hypothesis of the existence of a bioisosterism between the [(methyleneamino)oxy]methyl moiety (C = NOCH2, MAOMM) of type B beta-blocking drugs and the aryl (Ar) of type A beta-blocking agents. In the MAOMM, however, the carbon of the CH2 linked to the oximic oxygen possesses a hybridization (sp3) and a geometry different from those of the corresponding carbon of Ar which possesses an sp2 hybridization. Furthermore, in the MAOMM, in its preferred conformation, the unsaturated portion (C = N) is situated in a spatial area which does not correspond exactly to the area occupied by Ar. The formal inversion of the atomic sequence C = NOCH2 of the MAOMM leads to a different type of group, the [(methyloxy)imino]methyl moiety (CH2ON = C, MOIMM), which, in the E configuration, appears to present greater steric and electronic analogies with an Ar, with respect to the MAOMM. On the basis of these observations, some completely aliphatic (E)-N-(3-amino-2- hydroxypropylidene)(alkyloxy)amino derivatives of type C (11a,b and 12a, b) were synthesized, the their beta-adrenergic properties were compared with those of the corresponding [(methyleneamino)oxy]-methyl isomers of type B (19a, b and 20a, b). The similar beta-adrenergic properties of 11, 12 and 19, 20 evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations, are discussed on the basis of considerations regarding the spatial correspondences and electronic analogies between the MOIMM and the MAOMM.

[Non-specific spondylodiscitis in children: report of a case in an infant. Review of the literature]. / La spondilodiscite aspecifica del bambino: un caso in un lattante. Revisione della letteratura.

A case of non-specific spondylitis in an infant has prompted us to an ample review of the literature. The disease is acknowledged as characteristically benign in children. However some publications seem to imply that in the very young child it would display a remarkable seriousness. From our case and half a score of others that we found in the literature, it appears that in the first year of life the nonspecific spondylitis has the same features as in the older children, namely a mild course and a good prognosis. The above publications probably refer to peculiar cases, which give rise to an as yet unsolved nosological problem. The characteristics of the disease, with special emphasis on its clinical and radiological presentation and evolution, are exposed.

[Campomelic dwarfism. Its placement in the heterogeneous group of congenital bowing of the limbs]. / Il nanismo campomelico. Sua collocazione nel gruppo eterogeneo degli incurvamenti congeniti degli arti.

The campomelic (camptomelic) dwarfism is a rare congenital syndrome which includes, in addition to typical angulations of femora and tibiae (campomelia or camptomelia = bowed or bent limbs), other skeletal abnormalities and visceral lesions, particularly of the brain and of the respiratory tract, which are almost always responsible of early death. Congenital bowing of limbs are seen in various conditions: as isolated deformity (or component of a strictly localised deformity); as integrating part of a more extensive syndrome (the campomelic dwarfism falls within this subgroup); as secondary element of complex syndromes, such as the severe congenital demineralizations of the skeleton. The differential diagnosis must take into account this various conditions, together with other congenital dwarfisms, particularly those incompatible with life (see table 1 e 2). A typical case of campomelic dwarfism is presented.