Design rules for controlling active topological defects.

Topological defects play a central role in the physics of many materials, including magnets, superconductors, and liquid crystals. In active fluids, defects become autonomous particles that spontaneously propel from internal active stresses and drive chaotic flows stirring the fluid. The intimate connection between defect textures and active flow suggests that properties of active materials can be engineered by controlling defects, but design principles for their spatiotemporal control remain elusive. Here, we propose a symmetry-based additive strategy for using elementary activity patterns, as active topological tweezers, to create, move, and braid such defects. By combining theory and simulations, we demonstrate how, at the collective level, spatial activity gradients act like electric fields which, when strong enough, induce an inverted topological polarization of defects, akin to a negative susceptibility dielectric. We harness this feature in a dynamic setting to collectively pattern and transport interacting active defects. Our work establishes an additive framework to sculpt flows and manipulate active defects in both space and time, paving the way to design programmable active and living materials for transport, memory, and logic.

Interactions between the gut microbiome, associated metabolites and the manifestation and progression of heart failure with preserved ejection fraction in ZSF1 rats.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is associated with systemic inflammation, obesity, metabolic syndrome, and gut microbiome changes. Increased trimethylamine-N-oxide (TMAO) levels are predictive for mortality in HFpEF. The TMAO precursor trimethylamine (TMA) is synthesized by the intestinal microbiome, crosses the intestinal barrier and is metabolized to TMAO by hepatic flavin-containing monooxygenases (FMO). The intricate interactions of microbiome alterations and TMAO in relation to HFpEF manifestation and progression are analyzed here. METHODS: Healthy lean (L-ZSF1, n = 12) and obese ZSF1 rats with HFpEF (O-ZSF1, n = 12) were studied. HFpEF was confirmed by transthoracic echocardiography, invasive hemodynamic measurements, and detection of N-terminal pro-brain natriuretic peptide (NT-proBNP). TMAO, carnitine, symmetric dimethylarginine (SDMA), and amino acids were measured using mass-spectrometry. The intestinal epithelial barrier was analyzed by immunohistochemistry, in-vitro impedance measurements and determination of plasma lipopolysaccharide via ELISA. Hepatic FMO3 quantity was determined by Western blot. The fecal microbiome at the age of 8, 13 and 20 weeks was assessed using 16s rRNA amplicon sequencing. RESULTS: Increased levels of TMAO (+ 54%), carnitine (+ 46%) and the cardiac stress marker NT-proBNP (+ 25%) as well as a pronounced amino acid imbalance were observed in obese rats with HFpEF. SDMA levels in O-ZSF1 were comparable to L-ZSF1, indicating stable kidney function. Anatomy and zonula occludens protein density in the intestinal epithelium remained unchanged, but both impedance measurements and increased levels of LPS indicated an impaired epithelial barrier function. FMO3 was decreased (- 20%) in the enlarged, but histologically normal livers of O-ZSF1. Alpha diversity, as indicated by the Shannon diversity index, was comparable at 8 weeks of age, but decreased by 13 weeks of age, when HFpEF manifests in O-ZSF1. Bray-Curtis dissimilarity (Beta-Diversity) was shown to be effective in differentiating L-ZSF1 from O-ZSF1 at 20 weeks of age. Members of the microbial families Lactobacillaceae, Ruminococcaceae, Erysipelotrichaceae and Lachnospiraceae were significantly differentially abundant in O-ZSF1 and L-ZSF1 rats. CONCLUSIONS: In the ZSF1 HFpEF rat model, increased dietary intake is associated with alterations in gut microbiome composition and bacterial metabolites, an impaired intestinal barrier, and changes in pro-inflammatory and health-predictive metabolic profiles. HFpEF as well as its most common comorbidities obesity and metabolic syndrome and the alterations described here evolve in parallel and are likely to be interrelated and mutually reinforcing. Dietary adaption may have a positive impact on all entities.

The first MASH drug therapy on the horizon: Current perspectives of resmetirom.

The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) poses a significant global health challenge, affecting over 30% of adults worldwide. MASLD is linked to increased mortality rates and substantial healthcare costs, primarily driven by its progression to metabolic dysfunction-associated steatohepatitis (MASH), which can lead to severe liver complications including cirrhosis and hepatocellular carcinoma. Despite its growing burden, effective pharmacotherapy for MASLD/MASH has been lacking until the recent conditional approval of resmetirom by the FDA. Resmetirom, a liver-targeted thyroid hormone receptor-ß selective drug, has shown promise in clinical trials for treating non-cirrhotic MASH with moderate to advanced fibrosis. It has demonstrated efficacy in reducing hepatic fat content, improving liver histology (both MASH resolution and fibrosis improvement), and ameliorating biomarkers of liver damage without significant effects on body weight or glucose metabolism. Notably, resmetirom also exhibits favourable effects on circulating lipids, potentially reducing cardiovascular risk in MASLD/MASH patients. The safety profile of resmetirom appears acceptable, with gastrointestinal adverse events being the most common, though generally mild or moderate. However, long-term surveillance is warranted to monitor for potential risks related to thyroid, gonadal, or bone diseases. Clinical implementation of resmetirom faces challenges in patient selection and monitoring treatment response, and will heavily rely on non-invasive tests for liver fibrosis assessment. Nonetheless, resmetirom represents a landmark breakthrough in MASLD/MASH treatment, paving the way for future therapeutic strategies aiming to mitigate the multifaceted risks associated with this complex metabolic liver disease.

Damping of Pseudo-Goldstone Fields.

Approximate symmetries abound in nature. If these symmetries are also spontaneously broken, the would-be Goldstone modes acquire a small mass, or inverse correlation length, and are referred to as pseudo-Goldstones. At nonzero temperature, the effects of dissipation can be captured by hydrodynamics at sufficiently long scales compared to the local equilibrium. Here, we show that, in the limit of weak explicit breaking, locality of hydrodynamics implies that the damping of pseudo-Goldstones is completely determined by their mass and diffusive transport coefficients. We present many applications: superfluids, QCD in the chiral limit, Wigner crystal and density wave phases in the presence of an external magnetic field or not, nematic phases, and (anti)ferromagnets. For electronic density wave phases, pseudo-Goldstone damping generates a contribution to the resistivity independent of the strength of disorder, which can have a linear temperature dependence provided the associated diffusivity saturates a bound. This is reminiscent of the phenomenology of strange metal high-T_{c} superconductors, where charge density waves are observed across the phase diagram.

NANOGrav Data Hints at Primordial Black Holes as Dark Matter.

The NANOGrav Collaboration has recently published strong evidence for a stochastic common-spectrum process that may be interpreted as a stochastic gravitational wave background. We show that such a signal can be explained by second-order gravitational waves produced during the formation of primordial black holes from the collapse of sizeable scalar perturbations generated during inflation. This possibility has two predictions: (i) the primordial black holes may comprise the totality of the dark matter with the dominant contribution to their mass function falling in the range (10^{-15}÷10^{-11})M_{⊙} and (ii) the gravitational wave stochastic background will be seen as well by the Laser Interferometer Space Antenna experiment.

GW190521 Mass Gap Event and the Primordial Black Hole Scenario.

The LIGO/Virgo Collaboration has recently observed GW190521, the first binary black hole merger with at least the primary component mass in the mass gap predicted by the pair-instability supernova theory. This observation disfavors the standard stellar-origin formation scenario for the heavier black hole, motivating alternative hypotheses. We show that GW190521 cannot be explained within the primordial black hole (PBH) scenario if PBHs do not accrete during their cosmological evolution, since this would require an abundance which is already in tension with current constraints. On the other hand, GW190521 may have a primordial origin if PBHs accrete efficiently before the reionization epoch.

Public health and clinical approach to proactive management of frailty in multidimensional arena.

Background: Demographic changes have forced communities and people themselves to reshape ageing concepts and approaches and try to develop actions towards active and healthy ageing. In this context, the European Commission launched different private-public partnerships to develop new solutions and answers on questions related to this topic. The European Innovation Partnership on Active and Healthy Ageing, including topic related action groups as well reference sites committed towards a common action to facilitate active and healthy ageing, has contributed key elements for interventions, scaled up best practices and evaluated impact of their action to drive innovation across many regions in Europe over the past years. Methods: This paper describes action taken by A3 action group in the European Innovation Partnership on Active and Healthy Ageing. This paper gives an overview of how the partnership combined the view on frailty coming from public health as well as the clinical management. Results: Within different European regions, to tackle frailty, EIPonAHA partners have conceptualized functional decline and frailty, making use of good practice models working well on community programs. The A3 Group of EIPonAHA has worked alongside a process of innovation, targeting all ageing citizens with the clear goal of involving communities in the preventive approach. Conclusion: Engagement needs of older people with a focus on functionally rather than disease management as primary objective is considered as an overarching concept, also embracing adherence, compliance, empowerment, health literacy, shared decision-making, and activation. Furthermore, training of staff working with ageing people across all sectors needs to be implemented and evaluated in future studies.

Minimal residual disease monitoring in early stage follicular lymphoma can predict prognosis and drive treatment with rituximab after radiotherapy.

Since 2000, we have investigated 67 consecutive patients with stage I/II follicular lymphoma (FL) for the presence of BCL2/IGH rearrangements by polymerase chain reaction (PCR), real time quantitative PCR (RQ-PCR) and digital droplet PCR (ddPCR). All patients were treated with involved-field radiotherapy (IF-RT) (24-30 Gy). From 2005, patients with minimal residual disease (MRD) after IF-RT received rituximab (R) (375 mg/m2 , 4 weekly administrations). The median follow-up is 82 months (17-196). At diagnosis, 72% of patients were BCL2/IGH+. Progression-free survival (PFS) was significantly better in patients with undetectable/low levels (<10-5 ) of circulating BCL2/IGH+ cells at diagnosis and in those who were persistently MRD- during follow-up (P = 0·0038). IF-RT induced an MRD- status in 50% of cases; 16/19 (84%) MRD+ patients after IF-RT became MRD- after R treatment. A significantly longer PFS was observed in MRD+ patients treated with R compared to untreated MRD+ patients (P = 0·049). In early stage FL, both circulating levels of BCL2/IGH+ cells at diagnosis and MRD status during follow-up bear prognostic implications. Standard IF-RT fails to induce an MRD-negative status in half of patients. Most patients become MRD- following treatment with R and this is associated with a significantly better PFS.

Redefining the prognostic likelihood of chronic lymphocytic leukaemia patients with borderline percentage of immunoglobulin variable heavy chain region mutations.

In chronic lymphocytic leukaemia (CLL), caution is warranted regarding the clinical implications of immunoglobulin variable heavy chain region (IGHV) rearrangements with a 'borderline' (BL) percentage of mutations (i.e. 97-97·9% IGHV identity). We analysed the IGHV mutational status in 759 untreated CLL patients (cohort 1). BL-CLL (n = 36, 5%) showed a time to first treatment (TFT) similar to that of M-CLL (n = 338) and significantly longer than that of UM-CLL (n = 385), despite the enrichment in subset #2 cases. In fact, CLLs belonging to subset #2 (n = 15/759, 2%) were significantly more frequent among BL-CLLs (n = 5/36, 14%), with a brief TFT. TFT of BL-CLL remained comparable to that of M-CLL also considering the 327 CLL patients evaluated at diagnosis. These findings were then validated in an independent cohort 2 of 759 newly diagnosed CLL patients (BL-CLL: n = 11, 1·4%) and in all newly diagnosed patients from cohorts 1 and 2 (n = 1 086, 84% stage A; BL-CLL: n = 47, 4·3%). BL-CLL at diagnosis showed a biological profile comparable to that of M-CLL with a low frequency of unfavourable prognostic markers, except for a significant enrichment in subset #2. Our data suggest that the prognosis of BL-CLL is good and similar to that of M-CLL, with the exception of subset #2 cases.

Breakdown of Diffusion on Chiral Edges.

We show that dirty quantum Hall systems exhibit large hydrodynamic fluctuations at their edge that lead to anomalously damped charge excitations in the Kardar-Parisi-Zhang universality class ω≃ck-iDk^{3/2}. The dissipative optical conductivity of the edge is singular at low frequencies σ(ω)∼1/ω^{1/3}. These results are direct consequences of the charge continuity relation, the chiral anomaly, and thermalization on the edge-in particular translation invariance is not assumed. Diffusion of heat similarly breaks down, with a universality class that depends on whether the bulk thermal Hall conductivity vanishes. We further establish the theory of fluctuating hydrodynamics for surface chiral metals, where charge fluctuations give logarithmic corrections to transport.

Deep learning in fracture detection: a narrative review.

Artificial intelligence (AI) is a general term that implies the use of a computer to model intelligent behavior with minimal human intervention. AI, particularly deep learning, has recently made substantial strides in perception tasks allowing machines to better represent and interpret complex data. Deep learning is a subset of AI represented by the combination of artificial neuron layers. In the last years, deep learning has gained great momentum. In the field of orthopaedics and traumatology, some studies have been done using deep learning to detect fractures in radiographs. Deep learning studies to detect and classify fractures on computed tomography (CT) scans are even more limited. In this narrative review, we provide a brief overview of deep learning technology: we (1) describe the ways in which deep learning until now has been applied to fracture detection on radiographs and CT examinations; (2) discuss what value deep learning offers to this field; and finally (3) comment on future directions of this technology.

Primordial Black Hole Dark Matter: LISA Serendipity.

There has recently been renewed interest in the possibility that the dark matter in the Universe consists of primordial black holes (PBHs). Current observational constraints leave only a few PBH mass ranges for this possibility. One of them is around 10^{-12} M_{⊙}. If PBHs with this mass are formed due to an enhanced scalar-perturbation amplitude, their formation is inevitably accompanied by the generation of gravitational waves (GWs) with frequency peaked in the mHz range, precisely around the maximum sensitivity of the LISA mission. We show that, if these primordial black holes are the dark matter, LISA will be able to detect the associated GW power spectrum. Although the GW source signal is intrinsically non-Gaussian, the signal measured by LISA is a sum of the signal from a large number of independent sources suppressing the non-Gaussianity at detection to an unobservable level. We also discuss the effect of the GW propagation in the perturbed Universe. PBH dark matter generically leads to a detectable, purely isotropic, Gaussian and unpolarized GW signal, a prediction that is testable with LISA.

Theory of Diffusive Fluctuations.

The recently developed effective field theory of fluctuations around thermal equilibrium is used to compute late-time correlation functions of conserved densities. Specializing to systems with a single conservation law, we find that the diffusive pole is shifted in the presence of nonlinear hydrodynamic self-interactions, and that the density-density Green's function acquires a branch point halfway to the diffusive pole, at frequency ω=-(i/2)Dk^{2}. We discuss the relevance of diffusive fluctuations for strongly correlated transport in condensed matter and cold atomic systems.

Publisher's Note: Transport Signatures of the Hall Viscosity [Phys. Rev. Lett. 119, 226602 (2017)].

This corrects the article DOI: 10.1103/PhysRevLett.119.226602.

Transport Signatures of the Hall Viscosity.

Hall viscosity is a nondissipative response function describing momentum transport in two-dimensional systems with broken parity. It is quantized in the quantum Hall regime, and contains information about the topological order of the quantum Hall state. Hall viscosity can distinguish different quantum Hall states with identical Hall conductances, but different topological order. To date, an experimentally accessible signature of Hall viscosity is lacking. We exploit the fact that Hall viscosity contributes to charge transport at finite wavelengths, and can therefore be extracted from nonlocal resistance measurements in inhomogeneous charge flows. We explain how to determine the Hall viscosity from such a transport experiment. In particular, we show that the profile of the electrochemical potential close to contacts where current is injected is sensitive to the value of the Hall viscosity.

Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways.

The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered association studies and ancestry-specific effects. In the present study, we performed a succinct review of case-control association studies published prior to April 2015. Meta-analyses were performed for candidate gene variants examined in at least three studies using the Cochrane Mantel-Haenszel fixed-effect model. Secondary analyses were also performed to assess the influences of sex, agoraphobia co-morbidity and ancestry-specific effects on panicogenesis. Meta-analyses were performed on 23 variants in 20 PD candidate genes. Significant associations after correction for multiple testing were observed for three variants, TMEM132D rs7370927 (T allele: odds ratio (OR)=1.27, 95% confidence interval (CI): 1.15-1.40, P=2.49 × 10(-6)), rs11060369 (CC genotype: OR=0.65, 95% CI: 0.53-0.79, P=1.81 × 10(-5)) and COMT rs4680 (Val (G) allele: OR=1.27, 95% CI: 1.14-1.42, P=2.49 × 10(-5)) in studies with samples of European ancestry. Nominal associations that did not survive correction for multiple testing were observed for NPSR1 rs324891 (T allele: OR=1.22, 95% CI: 1.07-1.38, P=0.002), TPH1 rs1800532 (AA genotype: OR=1.46, 95% CI: 1.14-1.89, P=0.003) and HTR2A rs6313 (T allele: OR=1.19, 95% CI: 1.07-1.33, P=0.002) in studies with samples of European ancestry and for MAOA-uVNTR in female PD (low-active alleles: OR=1.21, 95% CI: 1.07-1.38, P=0.004). No significant associations were observed in the secondary analyses considering sex, agoraphobia co-morbidity and studies with samples of Asian ancestry. Although these findings highlight a few associations, PD likely involves genetic variation in a multitude of biological pathways that is diverse among populations. Future studies must incorporate larger sample sizes and genome-wide approaches to further quantify the observed genetic variation among populations and subphenotypes of PD.

Bacillomycin D and its combination with amphotericin B: promising antifungal compounds with powerful antibiofilm activity and wound-healing potency.

AIMS: In this study, we evaluated the ability of the lipopeptide bacillomycin D and the antifungal drug amphotericin B as well as their combination, to inhibit Candida albicans biofilm formation and to accelerate keratinocyte cell migration. METHODS AND RESULTS: The antibiofilm activity of bacillomycin D and its combination with amphotericin B was carried out by crystal violet colorimetric method. Our results have shown that, when combined together at low concentrations nontoxic to mammalian cells, corresponding to 1/32 MIC (0·39 µg ml(-1) ) and 1/4 MIC (0·06 µg ml(-1) ) for bacillomycin D and amphotericin B, respectively, a clear antibiofilm activity is manifested (95% inhibition of biofilm formation) along with a clear inhibition of germ tube formation. Moreover, the effect of both drugs on preformed biofilm of C. albicans strain was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. The combination of the two antifungal compounds at 0·39 and 1 µg ml(-1) for bacillomycin D and amphotericin B, respectively, resulted in a clear enhancement of biofilm eradication compared to the results obtained with each drug alone. Furthermore, this combination was found to promote the closure of a gap produced in a monolayer of human keratinocytes. CONCLUSIONS: Bacillomycin D and its combination with amphotericin B display impressive anti-biofilm and wound-healing activities. SIGNIFICANCE AND IMPACT OF THE STUDY: Application of the lipopeptide bacillomycin D and the antifungal drug amphotericin B in medical devices may offer a promising alternative for topical treatment of Candida-associated infections in the setting of a wound.

Effects of concurrent aerobic and strength training on breast cancer survivors: a pilot study.

OBJECTIVES: The aim of the study was to evaluate the effects of a combined aerobic and strength program on physiological and psychological parameters in female breast cancer survivors. STUDY DESIGN: Randomised controlled trial. METHODS: 20 patients (age: 45.6 ± 2.7 yrs) surgically treated for breast cancer that had completed all cancer therapies at least 6 months before and with no contraindications to physical activity, were recruited and randomly assigned to an intervention group (n = 10) and a control group (n = 10). Intervention group patients attend to a 24-week combined aerobic and strength training program. Physiological (i.e. VO2max, bioelectrical impedance test, maximal strength of principal muscular groups) and psychological (i.e. functional assessment of chronic illness therapy-fatigue: FACIT-F) parameters were assessed at baseline and after 24 weeks. RESULTS: After 24 weeks the intervention group showed significant improvement in VO2max (38.8%), strength of upper and lower limbs (ranging from 13 to 60%) and decrease in fat mass percentage (-6.3%). The FACIT-F showed significant increase in all of the three scores that can be derived (FACIT-F Trial outcome: 13%; FACT-G total score: 18%; FACIT-F total score: 15%) showing patient's quality of life (QOL) improvement. No significant change in all the parameters was found for the control group. CONCLUSION: These results show the positive effects of a combined aerobic and strength training program on breast cancer survivors and underline the importance of the early inclusion of structured physical activity in the rehabilitation protocol.