Author Correction: Mapping the world's free-flowing rivers.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mapping the world's free-flowing rivers.

Free-flowing rivers (FFRs) support diverse, complex and dynamic ecosystems globally, providing important societal and economic services. Infrastructure development threatens the ecosystem processes, biodiversity and services that these rivers support. Here we assess the connectivity status of 12 million kilometres of rivers globally and identify those that remain free-flowing in their entire length. Only 37 per cent of rivers longer than 1,000 kilometres remain free-flowing over their entire length and 23 per cent flow uninterrupted to the ocean. Very long FFRs are largely restricted to remote regions of the Arctic and of the Amazon and Congo basins. In densely populated areas only few very long rivers remain free-flowing, such as the Irrawaddy and Salween. Dams and reservoirs and their up- and downstream propagation of fragmentation and flow regulation are the leading contributors to the loss of river connectivity. By applying a new method to quantify riverine connectivity and map FFRs, we provide a foundation for concerted global and national strategies to maintain or restore them.

Arcsine Laws of Light.

We demonstrate that the time-integrated light intensity transmitted by a coherently driven resonator obeys Lévy's arcsine laws-a cornerstone of extreme value statistics. We show that convergence to the arcsine distribution is algebraic, universal, and independent of nonequilibrium behavior due to nonconservative forces or nonadiabatic driving. We furthermore verify, numerically, that the arcsine laws hold in the presence of frequency noise and in Kerr-nonlinear resonators supporting non-Gaussian states. The arcsine laws imply a weak ergodicity breaking which can be leveraged to enhance the precision of resonant optical sensors with zero energy cost, as shown in our companion manuscript [V. G. Ramesh et al., companion paper, Phys. Rev. Res. (2024).PPRHAI2643-1564]. Finally, we discuss perspectives for probing the possible breakdown of the arcsine laws in systems with memory.

Barriers and facilitators to implementing a multilevel, multicomponent intervention promoting colorectal cancer screening in health centers: a qualitative study of key informant perspectives.

BACKGROUND: Colorectal cancer (CRC) continues to be a major cause of death in the U.S. despite the availability of effective screening tools. U.S. Latinos have lower rates of CRC screening and higher rates of death due to colorectal disease compared to non-Hispanic whites. Federally Qualified Health Centers (FQHCs) serve medically underserved populations, including many Latino patients. Given the low CRC screening rates, identifying culturally sensitive and cost-effective methods of promoting screening is a priority for many FQHCs. METHODS: We interviewed FQHC leaders and providers using the Consolidated Framework for Implementation Research (CFIR) to identify barriers and facilitators to implementation of a multilevel, multicomponent (ML-MC) CRC screening intervention (i.e., promotor navigation and group-based education) in FQHCs. A rapid qualitative analysis approach was used to identify themes organized according to the following CFIR constructs: intervention characteristics, outer and inner settings, and characteristics of the individual. RESULTS: We completed interviews with 13 healthcare professionals in leadership positions at six FQHCs. The participating FQHCs perceived the ML-MC screening CRC program as feasible and expressed interest in implementing the program at their sites. Facilitators included financial incentives for increasing screening rates, the need for patient education programming, and involving promotores to support the work of clinical teams. Barriers included concerns about available resources to implement new programs, lack of federal reimbursement for health education, competing priorities of other health concerns, and the need for more resources for confirmatory screening and treatment following a positive screen. CONCLUSIONS: FQHCs provide essential primary care to millions of underserved patients in the U.S. and have the ability and motivation to provide screenings for colorectal cancer. Partnering with an academic institution to deliver a group-based, promotor-led CRC screening intervention for patients not up to date with screening could help increase screening rates. By identifying the specific barriers and facilitators to implementing CRC intervention, findings suggest that group-based, promotor-led interventions are a promising approach.

Reliable and specific detection of Acanthamoeba spp. in dishcloths using quantitative real-time PCR assay.

Acanthamoeba spp., are ubiquitous protist which belongs to Free-Living Amoeba (FLA) group, is considered as causal agent of side-threatening keratitis or fatal encephalitis among other human infections. Besides, this parasite has been reported as host for other microorganisms important to human health such as Campylobacter spp. or Vibrio spp. among others. This role of Acanthamoeba as pathogen and environmental phagocyte has increased the reports confirming its presence in human related environments, acting as a water quality indicator. Considering the tide relationship between water and kitchen environments, and the high prevalence of Acanthamoeba in water sources, the present study aims to establish a quick and accurate protocol based on DNA extraction and a real time qPCR assay to detect Acanthamoeba spp. in dishcloths. The procedure has been validated by processing 17 used dishcloths. Our findings demonstrated the high sensitivity of the qPCR assay used which was capable of detecting up to one Acanthamoeba from an in vitro contaminated dishcloth. The protocol accurately detected 64.7% of positive samples for Acanthamoeba spp, (in 4 samples DNA concentrations corresponded to 1-102 amoebae). Our findings demonstrate the importance of FLA surveillance by efficient and sensitive methods since one amoeba is capable of colonizing human related food environments such as kitchens sinks and could be a potential source of infection.

Neuromuscular electrical stimulation in garments optimized for compliance.

PURPOSE: Physical inactivity is associated with muscle atrophy and venous thromboembolism, which may be prevented by neuromuscular electrical stimulation (NMES). This study aimed to investigate the effect on discomfort, current amplitude and energy consumption when varying the frequency and phase duration of low-intensity NMES (LI-NMES) via a sock with knitting-integrated transverse textile electrodes (TTE). METHODS: On eleven healthy participants (four females), calf-NMES via a TTE sock was applied with increasing intensity (mA) until ankle-plantar flexion at which point outcomes were compared when testing frequencies 1, 3, 10 and 36 Hz and phase durations 75, 150, 200, 300 and 400 µs. Discomfort was assessed with a numerical rating scale (NRS, 0-10) and energy consumption was calculated and expressed in milli-Joule (mJ). Significance set to p ≤ 0.05. RESULTS: 1 Hz yielded a median (inter-quartile range) NRS of 2.4 (1.0-3.4), significantly lower than both 3 Hz with NRS 2.8 (1.8-4.2), and 10 Hz with NRS 3.4 (1.4-5.4) (both p ≤ .014). Each increase in tested frequency resulted in significantly higher energy consumption, e.g. 0.6 mJ (0.5-0.8) for 1 Hz vs 14.9 mJ (12.3-21.2) for 36 Hz (p = .003). Longer phase durations had no significant effect on discomfort despite generally requiring significantly lower current amplitudes. Phase durations 150, 200 and 400 µs required significantly lower energy consumption compared to 75 µs (all p ≤ .037). CONCLUSION: LI-NMES applied via a TTE sock produces a relevant plantar flexion of the ankle with the best comfort and lowest energy consumption using 1 Hz and phase durations 150, 200 or 400 µs.

New perspectives on morphological and genetic variability of Corynosoma bullosum [Linstow, 1892] parasitizing southern elephant seals from the Antarctic Peninsula.

Previous descriptions of Corynosoma bullosum (Linstow, 1892) show that specimens vary greatly in the proportions of different body structures, measurements of females and males, number of rows of hooks, and egg measurements, among other features. We redescribe this species from specimens found in southern elephant seal faeces from King George Island. We also provide a molecular characterization, in addition to 5.8S and internal transcribed spacer (ITS) existing sequences. We examined 41 elephant seals, and 30 adult acanthocephalans were found in 15 of them. The specimens were identified as belonging to the genus Corynosoma due to each having a tubular body with an inflated anterior part forming a thorny disk and the posterior part bearing somatic spines on the ventral surface, and genital spines surrounding the genital pore. Individual morphology corresponded to C. bullosum: large size, marked sexual dimorphism, and proboscis with 16-18 rows of spines with 11-15 spines per row. The molecular profile of three specimens of C. bullosum was analysed using 18S rDNA. We inferred phylogenetic relationships of the family Polymorphidae using maximum likelihood and Bayesian inference. We provide an updated morphological redescription for C. bullosum including electron microscopy photographs and molecular data. The 18S gene sequences showed low genetic variation and supported that C. bullosum is a sister to Corynosoma australe.

Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).

Exceptional Precision of a Nonlinear Optical Sensor at a Square-Root Singularity.

Exceptional points (EPs)-spectral singularities of non-Hermitian linear systems-have recently attracted interest for sensing. While initial proposals and experiments focused on enhanced sensitivities neglecting noise, subsequent studies revealed issues with EP sensors in noisy environments. Here we propose a single-mode Kerr-nonlinear resonator for exceptional sensing in noisy environments. Based on the resonator's dynamic hysteresis, we define a signal that displays a square-root singularity reminiscent of an EP. However, our sensor has crucial fundamental and practical advantages over EP sensors: the signal-to-noise ratio increases with the measurement speed, the square-root singularity is easily detected through intensity measurements, and both sensing precision and information content of the signal are enhanced around the singularity. Our sensor also overcomes the fundamental trade-off between precision and averaging time characterizing all linear sensors. All these unconventional features open up new opportunities for fast and precise sensing using hysteretic resonators.

Spontaneous Symmetry Breaking in a Coherently Driven Nanophotonic Bose-Hubbard Dimer.

We report on the first experimental observation of spontaneous mirror symmetry breaking (SSB) in coherently driven-dissipative coupled optical cavities. SSB is observed as the breaking of the spatial or mirror Z_{2} symmetry between two symmetrically pumped and evanescently coupled photonic crystal nanocavities, and manifests itself as random intensity localization in one of the two cavities. We show that, in a system featuring repulsive boson interactions (U>0), the observation of a pure pitchfork bifurcation requires negative photon hopping energies (J<0), which we have realized in our photonic crystal molecule. SSB is observed over a wide range of the two-dimensional parameter space of driving intensity and detuning, where we also find a region that exhibits bistable symmetric behavior. Our results pave the way for the experimental study of limit cycles and deterministic chaos arising from SSB, as well as the study of nonclassical photon correlations close to SSB transitions.

Experience, prevalence, need for treatment and cost of care for caries: A multicenter study in a developing country.

OBJECTIVE: To assess the experience, prevalence, need for treatment and economic impact of caries among students 6-12 years old in four cities in Mexico. BASIC RESEARCH DESIGN: Cross-sectional clinical study. SETTING: Elementary public schools. PARTICIPANTS: 500 schoolchildren aged 6 to 12 years. METHOD: Oral clinical examinations using WHO criteria for caries in the primary (dmft) and permanent (DMFT) dentitions. MAIN OUTCOME MEASURES: Indicators of caries in the primary and permanent dentitions: experience, prevalence, severity and the Significant Caries Index. In addition, we calculated the treatment needs, dental care rate and cost of care. RESULTS: dmft in the primary dentition was 2.59±2.83, and DMFT was 0.82±1.44 in the permanent dentition. Caries prevalence reached 67.7% in the primary and 34.1% in permanent dentition. The treatment needs index was 85.9% and 91.3% in the primary and permanent dentitions, respectively; the dental care index was 13.9% and 8.5%, respectively. The cost of care for caries in the primary dentition was estimated at $22.087 millions of international dollars (PPP US$) when amalgam was the restorative material used, and PPP US$19.107 millions for glass ionomer. For the permanent dentition, the cost was PPP US$7.431 millions when amalgam was used and PPP US$7.985 millions when resin/composite was used as restorative material. CONCLUSIONS: The prevalence and experience of caries in the primary dentition were 50% greater than those of other studies carried out in Mexico. In the permanent dentition they were less. There is considerable need for the treatment of caries and minimal experience with restorative care. The cost of care for caries may be assumed to be high for a health system such as Mexico's.

Extremely Broadband Stochastic Resonance of Light and Enhanced Energy Harvesting Enabled by Memory Effects in the Nonlinear Response.

We report the first observation of non-Markovian stochastic resonance (SR), and we discover that memory effects in the nonlinearity extremely enlarge the SR bandwidth. Our experimental system is an oil-filled microcavity which, driven by a continuous wave laser, has memory in its nonlinear optical response. Modulating the cavity length while adding noise to the driving laser, we observe a peak in the transmitted signal-to-noise ratio as a function of the noise variance. Through simulations, we reproduce our observations and extrapolate that the SR bandwidth could be ∼3000 times larger in our cavity than in a Kerr-nonlinear cavity. Experiments evidencing this memory-enhanced bandwidth across two decades are presented. As an extension of our results, we numerically demonstrate an order-of-magnitude enhancement in energy harvesting thanks to a nonlinearity with memory.

The Surfaces of the Ceratonia siliqua L. (Carob) Leaflet: Insights from Physics and Chemistry.

The production of superhydrophobic coatings inspired by the surface of plant leaves is a challenging goal. Such coatings hold a bright technological future in niche markets of the aeronautical, space, naval, building, automobile, and biomedical sectors. This work is focused on the adaxial (top) and abaxial (bottom) surfaces of the leaflet of the Ceratonia silique L. (carob), a high-commercial-value Mediterranean tree cultivated in many regions of the world. The adaxial and abaxial surfaces feature hydrophobic and superhydrophobic behaviors, respectively. Their chemical composition is very simple: monopalmitin ester and palmitic acid are protuberant in the epicuticular and intracuticular wax layers of the adaxial surface, respectively, whereas 1-octacosanol dominates in the abaxial wax layers. In both surfaces, epicuticular wax is organized along a randomly oriented and intricate network of nanometer-thick and micrometer-long plates, whose density and degree of interconnection are significantly higher in the abaxial surface. The measured tilting angles for the abaxial surface (12-70°) reveal unusual variable density and water adhesion of the nanostructured plate-based texture. Optical measurements demonstrate that light reflectance/absorbance of the glaucous abaxial surface is significantly higher/lower than that of the nonglaucous adaxial surface. In both surfaces, diffuse reflectance is dominant, and the absorbance is weakly dependent on the light incidence angle. We show that the highly dense nanostructured platelike texture of the epicuticular abaxial layer of the C. siliqua leaflet works as a sophisticated light and water management system: it reflects solar radiation diffusely to lower the surface temperature, and it has superhydrophobic character to keep the surface dry. Such attributes enable efficient gas exchange (photosynthesis and respiration), transpiration, and evaporation. To mimic for the first time the abaxial surface, a templation approach was adopted using poly(dimethylsiloxane) (PDMS)/poly(methylphenylsiloxane) (PMPS) positive/negative replicas and a soft polymer/siloxane negative replica produced by the sol-gel process. Because high topographical variations of the biotemplate and wax adhesion to the biohybrid film affected the replication quality, the reproduction of the wax texture via the synthesis of 1-octacosanol-grafted siloxane-based hybrid materials is proposed as a suitable route to duplicate the abaxial surface with high fidelity. The natural chemical/physical strategy adopted by the C. siliqua leaflet to face the harsh Mediterranean climate is a powerful source of bioinspiration for the development of diffuse reflecting and superhydrophobic material systems with foreseen applications as dual-functional antiglare and water-repelling coatings.

[A reflection about the ethical implications of telemedicine]. / Una reflexión ética sobre la telemedicina.

Recognizing the role of technology in the development of medicine and the impact of telecommunication advances, we reflect on the meaning and ethics of the use of Telemedicine, both in its general dimension for the use and distribution of knowledge, as well as in the delivery of health actions, scientific research, and data management. Teleconsultation is discussed in greater detail, analyzing its process and application, reviewing its possible advantages and disadvantages, from the point of view of providers and patients. We highlight the need to carry out an appropriate evaluation of each instance, from the point of view of both the patient and the professional who uses it. The importance of maintaining a doctor-patient relationship in agreement with the nature and practice of Medicine, respecting people's dignity, is emphasized. We mention the ethical conditions that must be bore in mind for the proper use of telemedicine. We discuss the eventual influence that this practice will have on the concept and practice of medical care, while suggesting the need to legislate on the matter.

Periodontitis and Alzheimer´s disease.

BACKGROUND: Alzheimer's disease (AD), the main cause of dementia in the adult population, is characterized by a progressive loss of cognitive function. It is considered that neuroinflammation plays a fundamental role in its onset and progression. The bacteria present in the disbiotic microbiome generated during the course of periodontitis (PE) are capable of inducing a systemic inflammatory response, exacerbating the production of proinflammatory mediators that have the potential to spread to the systemic circulation. MATERIAL AND METHODS: A literature review was made using the databases Scielo, PubMed, EBSCO and key words "Alzheimer disease", "Periodontitis", "Neurodegeneration", "Inflammation mediators", "Elderly". RESULTS: Several hypotheses point to similar pathophysiological pathways in the establishment of AD and PE, sharing cellular and molecular proinflammatory characteristics. In periodontitis, locally produced cytokines and pro-inflammatory products spread from the ulcerated periodontal pocket into the systemic circulation, or around the trigeminal nerve terminals, which allows the passage of bacteria or their products to the brain. This fact leads to the formation of plaques of amyloid peptide and intraneuronal neurofibrillar tangles (NFTs) that activate the glial cells producing a significant increase in proinflammatory cytokines in the affected regions that lead to a loss of neuronal synapses and neurodegeneration, contributing to the progression of AD. CONCLUSIONS: This review of the literature contributes to the understanding of the pathological pathways shared by both diseases such as oxidative damage and inflammation. There is not enough evidence to determine an association between this two pathologies, so it is considered necessary to conduct studies for determine if periodontitis is capable of inducing or exacerbating the neuroinflammation that will trigger AD.

Universal Scaling in the Dynamic Hysteresis, and Non-Markovian Dynamics, of a Tunable Optical Cavity.

We investigate, experimentally and theoretically, the dynamics of a laser-driven cavity with noninstantaneous effective photon-photon interactions. Scanning the laser-cavity frequency detuning at different speeds across an optical bistability, we find a hysteresis area that is a nonmonotonic function of the speed. In the limit of fast scans comparable to the memory time of the interactions, we demonstrate that the hysteresis area decays following a universal power law with scaling exponent -1. We further demonstrate a regime of non-Markovian dynamics emerging from white noise. This regime is evidenced by peaked distributions of residence times in the metastable states of our system. Our results offer new perspectives for exploring the physics of scaling, universality, and metastability, in non-Markovian regimes using arrays of bistable optical cavities with low quality factors, driven by low laser powers, and at room temperature.

Evaluation of belimumab treatment in patients with systemic lupus erythematosus in a clinical practice setting: Results from a 24-month OBSErve study in Argentina.

OBJECTIVE: To describe clinical effectiveness of belimumab for systemic lupus erythematosus (SLE) in real-world practice in Argentina. METHODS: This retrospective, observational study analysed medical record data of patients with SLE treated with belimumab in 15 centres in Argentina. Primary endpoint: overall clinical response (assessed on a scale similar to the 6-point Physician Global Assessment) at months 6, 12, 18 and 24, all versus index (belimumab initiation). Secondary endpoints: improvement in disease activity (SELENA-SLEDAI), SLE manifestations, and corticosteroid dose change. RESULTS: Records for 81 patients (91% female) were analysed. Clinical improvements were reported for 95%, 95%, 98% and 100% patients at 6, 12, 18, and 24 months post index, respectively. Mean SELENA-SLEDAI score decreased from 11.21 at index to 4.76, 3.77, 3.86 and 2.17 at 6, 12, 18, and 24 months post index, respectively. Number of flares decreased from 1.05 at index to 0.21, 0.09, 0.22 and 0.30 at 6, 12, 18, and 24 months post index, respectively. Mean corticosteroid dose was 14.59 mg/day at index, and 6.45, 5.18, 5.17 and 4.78 mg/day at 6, 12, 18, and 24 months post index, respectively. CONCLUSIONS: Real-world patients with SLE treated with belimumab in Argentina demonstrated clinical improvements and reductions in corticosteroid dose.

Bacteriological and histopathological analysis of Penaeus vannamei experimentally infected with Vibrio parahaemolyticus-AHPND strains.

Vibrio parahaemolyticus strains have been identified as the causative agent of acute hepatopancreas necrosis disease (Vp AHPND+) in shrimp. In the present work, a highly virulent (M0904) and less virulent (M0607) strain of Vp AHPND+ were used in experimental infections of Penaeus vannamei. Throughout the experiment, histopathological analyses were conducted on shrimp tissues, and samples from the bottom (B) and water column (WC) of each aquarium were taken to estimate bacterial growth. The first deaths of shrimp challenged with Vp M0904 occurred 4 h post-infection (hpi), reached 50% mortality at 17 hpi, and showed more acute pathological progression associated with AHPND despite both strains having similar bacterial densities from 0-4 hpi. The first deaths of shrimp inoculated with Vp M0607 occurred at 13 hpi, a difference of 9 h. These shrimps displayed reduction of reserve vacuoles in R and B cells of the hepatopancreas, and reached 50% mortality at 27 hpi. As bacterial growth in the WC and B in the first hours was similar for both strains, bacterial density was not a significant factor in Vp virulence. Since pirAB toxin is the causative agent of AHPND, it is possible that there is a threshold level at which the toxin damages hepatopancreatic tissues, so production or secretion of the toxin can be dependent of the Vp strain. We propose new AHPND stage: remission with 3 main routes for the disease outcome after the remission stage (re-infection, chronic effect and recuperation). Hepatopancreatic embryonic cells can be used as a biological indicator of this stage.

Effect of the type of soil on dimethyl phthalate degradation by ozone.

In the present study, ozone was applied for the removal of dimethyl phthalate (DMP) from soil. The effect of several experimental parameters was investigated considering, the initial DMP concentration, ozone flow, the type of soil (sand and agricultural soil) and the presence of α-FeOOH as a potential catalyst in the reaction system with sand. The elimination of DMP using ozone is significantly affected by the type of soil. In the case of sand, conventional ozonation was capable to degrade 74% of the initial DMP concentration (0.5 mg g-1) after 8 h of the reaction, however, the mineralization degree was below 50%. Under the same experimental conditions, the complete elimination of DMP was achieved when calcined agricultural soil was present reaching a 70% of mineralization. The presence of metal oxides in calcined agricultural soil combined with ozone produced oxidants species which were responsible of incrementing the mineralization degree (around 20% in comparison with the sand). The toxicity tests on lettuce seed demonstrated lower toxicity of DMP byproducts after ozonation. The DMP high removal efficiencies and the lower toxicity of generated byproducts in soil prove the applicability of ozone treatment for soil remediation.

Medical Students' Exposure to Ethics Conflicts in Clinical Training: Implications for Timing UME Bioethics Education.

While there is significant consensus that undergraduate medical education (UME) should include bioethics training, there is widespread debate about how to teach bioethics to medical students. Educators disagree about course methods and approaches, the topics that should be covered, and the effectiveness and metrics for UME ethics training. One issue that has received scant attention is the timing of bioethics education during medical training. The existing literature suggests that most medical ethics education occurs in the pre-clinical years. Follow-up studies indicate that medical students in their clinical rotations have little recall or ability to apply ethics concepts that were learned in their pre-clinical training. Trainees also report a desire for medical ethics to be taught in the context of practical application, which would suggest that the timing of pre-clinical ethics education is flawed. However, moving bioethics training to the clinical years should not be assumed to be the solution to the problems of recall and theory application. We argue that the effectiveness of timing bioethics education will depend on when medical students witness or experience particular categories of ethical dilemmas during their training. Our overarching hypothesis is that ethics education will be most effective when the bioethics training on a particular topic correlates to experiential exposure to that ethical issue. The purpose of our current study was to describe medical students exposure to particular categories of ethical conflicts, dilemmas, or issues. Our results may help bioethics educators better strategize about the most effective timing of medical ethics training in UME.