Puerperal mastitis caused by limited community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) clones.

Objective: To outline the epidemiology of puerperal mastitis caused by methicillin-resistant Staphylococcus aureus (MRSA) and evaluate the effect of an infection control bundle on its incidence. Methods: A surge in MRSA puerperal mastitis was noted in a community hospital in September 2009. MRSA samples from mastitis cases and the environment underwent typing using multilocus sequence typing (MLST), staphylococcal cassette chromosome mec (SCCmec), gene encoding surface protein A (spa), accessory gene regulator (agr), and pulsed-field gel electrophoresis (PFGE). The phenotypic characteristics, including superantigen toxin profiles, gene encoding Panton-Valentine leucocidin (pvl), and minimal inhibitory concentration (MIC) against vancomycin, were ascertained. Subsequently, an infection control bundle emphasizing contact precautions was introduced, and mastitis incidence rates pre- and post-intervention were compared. Results: The majority of cases occurred within 6 weeks post-delivery in first-time mothers. Of the 42 S. aureus isolates (27 from mastitis and 15 from colonized staff and environmental sources), 25 (92.6%) clinical and 3 (20%) colonized MRSA were identified as ST59-SCCmecVT-spa t437-agr group I with a vancomycin MIC of 1 mg/L, pvl-positive, and predominantly with a consistent toxin profile (seb-selk-selr). PFGE revealed 13 patterns; pulsotype B exhibited clonal relatedness between two clinical and three colonized MRSA samples. Post-intervention, the incidence of both mastitis and MRSA mastitis notably decreased from 13.01 to 1.78 and from 3.70 to 0.99 episodes per 100 deliveries, respectively. Conclusion: Distinct community-associated MRSA (CA-MRSA) clones were detected among puerperal mastitis patients and colonized staff. The outbreak was effectively controlled following the implementation of a targeted infection control bundle.

Unraveling the Complexities of Toll-like Receptors: From Molecular Mechanisms to Clinical Applications.

Toll-like receptors (TLRs) are vital components of the innate immune system, serving as the first line of defense against pathogens by recognizing a wide array of molecular patterns. This review summarizes the critical roles of TLRs in immune surveillance and disease pathogenesis, focusing on their structure, signaling pathways, and implications in various disorders. We discuss the molecular intricacies of TLRs, including their ligand specificity, signaling cascades, and the functional consequences of their activation. The involvement of TLRs in infectious diseases, autoimmunity, chronic inflammation, and cancer is explored, highlighting their potential as therapeutic targets. We also examine recent advancements in TLR research, such as the development of specific agonists and antagonists, and their application in immunotherapy and vaccine development. Furthermore, we address the challenges and controversies surrounding TLR research and outline future directions, including the integration of computational modeling and personalized medicine approaches. In conclusion, TLRs represent a promising frontier in medical research, with the potential to significantly impact the development of novel therapeutic strategies for a wide range of diseases.

Electromagnetically induced transparency and quantum enhancement of transmission via dressed bloch photons in an array of three-level Λ-type atoms.

We investigate the interactions between an array of three-level atoms and two photon fields with distinct frequencies employing quantum electrodynamics (QED). The control beam, as expected, has a considerably higher intensity than the probe beam, and the probe photon's eigenstate notably then appears as a distinctive dressed Bloch wave. We calculate the dispersion relation and quantum amplitude of the probe photons for their transmission. At positions predicting electromagnetically induced transparency (EIT) phenomena, we unveil remarkable enhancements in the transmission of the probe beam. Crucially, these enhancements are intricately linked to the unique characteristics of the dressed Bloch wave eigenstate. Moreover, we demonstrate that modulating frequency and intensity of the control beam and the lattice constant would further tune these enhancements. Our study highlights the crucial role of the dressed Bloch wave eigenstate in substantially amplifying targeted light beams, thereby significantly enhancing the detection sensitivity for minute electromagnetic signals and emphasizing its pivotal role in unveiling intriguing phenomena.

Comparative Analysis of Two Commercial Automated Systems with Agar Dilution for Oxacillin Susceptibility and Their Association with Genotypes of Invasive Staphylococcus aureus Isolates (2011-2021).

Background: Determining oxacillin susceptibility using reference methods and automated systems is crucial for treating invasive infections caused by Staphylococcus aureus. This study compares the oxacillin susceptibility results from the two automated systems with agar dilution and correlates them with genotypes of invasive S. aureus. Methods: Non-duplicate S. aureus invasive isolates were collected over an 11-year period. The oxacillin susceptibility was determined with Phoenix 100 (Jan 2011 to Aug 2018) or Vitek 2 (Sep 2018 to Dec 2021), and susceptibility for oxacillin and cefoxitin was determined with agar dilution. Methicillin-resistant S. aureus (MRSA) was confirmed with mecA existence, and the genotype was determined using SCCmec. The association between genotype and antibiotic susceptibility using two automated systems and agar dilution was evaluated. Results: A total of 842 invasive S. aureus, including 443 mecA+ MRSA and 399 mecA- MSSA, were collected. The susceptibility rates of oxacillin determined by two automated systems and agar dilution were 68.8% (76.8% for Phoenix 100 and 57.6% for Vitek 2) and 54.0%, respectively. When compared with the oxacillin susceptibility using agar dilution, the categorical agreement for Phoenix 100 and Vitek 2 were 0.46% and 0.88%, respectively (p < 0.001). One hundred and forty-three isolates were misinterpreted as oxacillin-susceptible S. aureus (OSSA) using automated systems while comparing with agar dilution, among which molecularly community-associated MRSA (CA-MRSA) outnumbered healthcare-associated MRSA (HA-MRSA) (99 vs 34, p < 0.001). There were 70 mecA+ OSSA (OS-MRSA) using agar dilution, among which 42 harbored SCCmec types were predominantly categorized as CA-MRSA (38, p < 0.001). Conclusion: The categorical agreement of Vitek 2 in determining oxacillin susceptibility and predicting mecA existence is comparable with agar dilution, whereas Phoenix 100 is not. Most of those ORSA determined by agar dilution but misinterpreted as OSSA by automated systems and OS-MRSA are categorized as CA-MRSA.

Diabetes mellitus modifies the association between chronic kidney disease-mineral and bone disorder biomarkers and aortic stiffness in peritoneal dialysis patients.

This study aimed to investigate the relationship of four chronic kidney disease-mineral and bone disorder (CKD-MBD) biomarkers, including intact parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), soluble klotho, and fetuin-A, with aortic stiffness in peritoneal dialysis (PD) patients, comparing those with and without diabetes mellitus (DM). A total of 213 patients (mean age 58 ± 14 years; 81 (38.0%) patients with DM) were enrolled. Their aortic pulse wave velocity (PWV) was measured using pressure applanation tonometry, while serum intact PTH, FGF23, α-klotho, and fetuin-A levels were measured using enzyme-linked immunosorbent assay. Overall, patients with DM had higher aortic PWV than those without (9.9 ± 1.8 vs. 8.6 ± 1.4 m/s, p < 0.001). Among the four CKD-MBD biomarkers, FGF23 levels were significantly lower in DM group (462 [127-1790] vs. 1237 [251-3120] pg/mL, p = 0.028) and log-FGF23 independently predicted aortic PWV in DM group (ß: 0.61, 95% confidence interval: 0.06-1.16, p = 0.029 in DM group; ß: 0.10, 95% confidence interval: - 0.24-0.45, p = 0.546 in nonDM group; interaction p = 0.016). In conclusion, the association between FGF23 and aortic PWV was significantly modified by DM status in PD patients.

Associations of Glucometabolic Indices with Aortic Stiffness in Patients Undergoing Peritoneal Dialysis with and without Diabetes Mellitus.

Disruptions in glucose metabolism are frequently observed among patients undergoing peritoneal dialysis (PD) who utilize glucose-containing dialysis solutions. We aimed to investigate the relationship between glucometabolic indices, including fasting glucose, insulin resistance, advanced glycation end products (AGEs), PD-related glucose load, and icodextrin usage, and aortic stiffness in PD patients with and without diabetic mellitus (DM). This study involved 172 PD patients (mean age 58.3 ± 13.5 years), consisting of 110 patients without DM and 62 patients with DM. Aortic stiffness was assessed using the carotid-femoral pulse wave velocity (cfPWV). Impaired fasting glucose was defined as a fasting glucose level ≥ 100 mg/dL. Homeostatic model assessment for insulin resistance (HOMA-IR) scores, serum AGEs, dialysate glucose load, and icodextrin usage were assessed. Patients with DM exhibited the highest cfPWV (9.9 ± 1.9 m/s), followed by those with impaired fasting glucose (9.1 ± 1.4 m/s), whereas patients with normal fasting glucose had the lowest cfPWV (8.3 ± 1.3 m/s), which demonstrated a significant trend. In non-DM patients, impaired fasting glucose (ß = 0.52, 95% confidence interval [CI] = 0.01-1.03, p = 0.046), high HOMA-IR (ß = 0.60, 95% CI = 0.12-1.08, p = 0.015), and a high PD glucose load (ß = 0.58, 95% CI = 0.08-1.08, p = 0.023) were independently associated with increased cfPWV. In contrast, none of the glucometabolic factors contributed to differences in cfPWV in DM patients. In conclusion, among PD patients without DM, impaired fasting glucose, insulin resistance, and PD glucose load were closely associated with aortic stiffness.

Decoy peptides effectively inhibit the binding of SARS-CoV-2 to ACE2 on oral epithelial cells.

The entry of SARS-CoV-2 into host cells involves the interaction between the viral spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor. Given that the spike protein evolves rapidly to evade host immunity, therapeutics that block ACE2 accessibility, such as spike decoys, could serve as an alternative strategy for attenuating viral infection. Here, we constructed a drug screening platform based on oral epithelial cells to rapidly identify peptides or compounds capable of blocking the spike-ACE2 interaction. We engineered short decoy peptides, 8 to 14 amino acids in length, using the spike protein's receptor-binding motif (RBM) and demonstrated that these peptides can effectively inhibit virus attachment to host cells. Additionally, we discovered that diminazene aceturate (DIZE), an ACE2 activator, similarly inhibited virus binding. Our research thus validates the potential of decoy peptides as a new therapeutic strategy against SARS-CoV-2 infections, opening avenues for further development and study.

Effect of Danshen for improving clinical outcomes in patients with bladder cancer: a retrospective, population-based study.

Introduction: Traditional Chinese Medicine (TCM) has a broad application in healthcare, with Danshen being a notable herb used in Eastern medicine for cancer treatment. This study aims to explore the relationship between Danshen use and cardiovascular risks among bladder cancer patients. Methods: Patients were selected based on a confirmed diagnosis of bladder cancer with specific inclusion and exclusion criteria to control for certain comorbidities and treatments. Utilizing Taiwan's National Health Insurance data from 2003 to 2013, this retrospective, population-based study identified three groups: 525 patients treated with Danshen, 6,419 patients not treated with TCM, and 4,356 patients treated with TCM but not with Danshen. The Cox proportional hazard model was employed to estimate the risks of Major Adverse Cardiovascular Events (MACE) and mortality while accounting for various confounders. Results: The overall incidence of MACEs was significantly lower in the Danshen group (5%) compared to the TCM (8.1%) and non-TCM (9.9%) groups (p < 0.001). The Cox model revealed that bladder cancer patients treated with Danshen had the lowest risk of MACE (adjusted hazard ratio, 0.56; 95% confidence interval, 0.38-0.84) and all-cause mortality (adjusted hazard ratio, 0.60; 95% confidence interval, 0.44-0.82). Discussion: The findings suggest that Danshen reduces the risk of MACE and all-cause mortality in bladder cancer patients, highlighting its potential benefits. This underpins the necessity for further research to substantiate the cardiovascular benefits of Danshen in bladder cancer patients and potentially broaden its application in oncology healthcare.

Rydberg-Rydberg interaction strengths and dipole blockade radii in the presence of Förster resonances.

Achieving a substantial blockade radius is crucial for developing scalable and efficient quantum communication and computation. In this theoretical study, we present the enhancement of the Rydberg blockade radius by utilizing Förster resonance. This phenomenon occurs when the energy difference between two initial Rydberg states closely matches that between the corresponding final Rydberg states, giving rise to a resonant energy transfer process. We employ quantum defect theory to numerically calculate the 87Rb-87Rb Rydberg atomic pair, enabling us to accurately estimate the van der Waals interaction. Our investigation reveals that when the principal quantum numbers of two Rydberg states differ only slightly, the Förster transition is rarely able to achieve a large blockade radius. However, in cases where the principal quantum numbers differ significantly, we substantially improve the Rydberg blockade radius. Most notably, we identify transition channels exhibiting an extensive blockade radius, surpassing 50 µm. This significant increase in the blockade radius enables larger-scale quantum operations and advances quantum technologies, with broad implications for achieving long-range quantum entanglement and robust quantum processes.

Experimental Demonstration of Stationary Dark-State Polaritons Dressed by Dipole-Dipole Interaction.

Dark-state polaritons (DSPs) based on the effect of electromagnetically induced transparency are bosonic quasiparticles, representing the superpositions of photons and atomic ground-state coherences. It has been proposed that stationary DSPs are governed by the equation of motion closely similar to the Schrödinger equation and can be employed to achieve Bose-Einstein condensation (BEC) with transition temperature orders of magnitude higher than that of the atomic BEC. The stationary-DSP BEC is a three-dimensional system and has a far longer lifetime than the exciton-polariton BEC. In this Letter, we experimentally demonstrated the stationary DSP dressed by the Rydberg-state dipole-dipole interaction (DDI). The DDI-induced phase shift of the stationary DSP was systematically studied. Notably, the experimental data are consistent with the theoretical predictions. The phase shift can be viewed as a consequence of elastic collisions. In terms of thermalization to achieve BEC, the µm^{2}-size interaction cross section of the DDI can produce a sufficient elastic collision rate for the stationary DSPs. This Letter makes a substantial advancement toward the realization of the stationary-DSP BEC.

Positive Association of Serum Galectin-3 with the Development of Aortic Stiffness of Patients on Peritoneal Dialysis.

A novel cardiovascular stress biomarker known as galectin-3 might be useful for anticipating adverse cardiovascular outcomes. The objective of the current investigation was to assess the association between serum galectin-3 levels and aortic stiffness (AS) in 196 patients on peritoneal dialysis. An enzyme-linked immunosorbent examination and a cuff-based volumetric displacement were employed to determine the levels of serum galectin-3 and the carotid-femoral pulse wave velocity (cfPWV), respectively. The AS group had 48 patients in total (24.5%) with cfPWV greater than 10 m/s. The AS group, when compared with the group without AS, had a significantly higher prevalence of diabetes mellitus and hypertension in addition to greater fasting glucose levels, waist circumference, systolic blood pressure, and serum galectin-3 levels. Multivariate logistic and linear regression analysis demonstrated that serum glactin-3 levels, in addition to gender and age, were significantly and independently associated with cfPWV and AS. Serum galectin-3 levels were linked with AS, according to a receiver operating characteristic curve analysis, with an area under the curve of 0.648 (95% confidence interval, 0.576-0.714; p = 0.0018). In summary, there was a significant correlation between serum galectin-3 levels and cfPWV in patients undergoing peritoneal dialysis therapy for end-stage kidney disease.

The role of ultrasound synovitis scores for patients who are at risk of rheumatoid arthritis.

OBJECTIVES: The development of rheumatoid arthritis (RA) has been classified into 6 phases A-F according to the present risk factors in sequence of genes, environments, autoimmunity, arthralgia and joint swelling. To clarify the ultrasound synovitis scores in at-risk patients (phases C-E) and RA (phase F). METHODS: Patients who had been experiencing hand joint symptoms for at least 6 weeks and asymptomatic patients with positive rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies were enrolled. A 40-joint ultrasonography with semiquantitative synovitis scoring for gray scale (GS) and power Doppler (PD) images was performed. RESULTS: A total of 139 patients were enrolled and classified into non-RA, phase C, phase D, phase E and phase F. Total GS scores in phases C (17.4 ± 7.0), D (16.0 ± 5.4), E (18.5 ± 7.7) and F (21.8 ± 9.1) were higher than those in non-RA (9.8 ± 4.0, P < 0.001). The total PD score in phase F (3.1 ± 4.6) was higher than that in phases C (0.2 ± 0.5), D (0.1 ± 0.4), and E (0.1 ± 0.3), as well as in non-RA (0.0 ± 0.0, P < 0.01). A total GS score ≥14 differentiated patients at risk for RA from patients with non-RA (area under curve [AUC] 0.82), while a total PD score ≥2 differentiated patients with RA from patients at risk for RA (AUC 0.71). CONCLUSION: Total GS score may differentiate patients at risk for RA from non-RA patients, while total PD score may differentiate patients with RA from those who are at risk for RA.

Manipulating quantum interference of dressed photon fields.

Through quantum electrodynamics (QED) we investigate the interactions between a three-level atom and two photon fields under perturbation limit. The dispersion relation and (relative) transmission of the probe photons are obtained by calculating the corresponding Feynman diagrams. The quantum interference in this three-level system such as Fano resonance and electromagnetically induced transparency (EIT) can be tuned by varying the intensities of the control and probe beams. Moreover, by considering that the control beam with periodic modulation, that is, the so-called Landau-Zener-Stückelberg (LZS) type source, the accumulated phase after Landau-Zener transitions is found to show the alternating Fano (EIT) lineshapes in the transmission of the probe photons. We further find that the transmissions can become almost stationary in addition to a wide EIT window in time even though the control beam is a LZS-type oscillating source.

Energy Harvester Based on an Eccentric Pendulum and Wiegand Wires.

This study proposed an energy harvester that combines an eccentric pendulum with Wiegand wires to harvest the kinetic energy of a rotating plate. The energy harvester converts the kinetic energy into electrical energy to power sensors mounted on the rotating plate or wheel. The kinetic model is derived from the Euler-Lagrange equation. The eccentric pendulum generates a swing motion from the direction variation of the centrifugal force and the gravitational force. The magnetic circuit is designed such that, during the swing motion, an alternating magnetic field is formed to induce the output voltage of the Wiegand wire. COMSOL software was used to simulate magnetic flux density and optimize the geometric parameters of magnets. Response surface methodology was used to formulate the output voltage model. Magnetic flux density affects output voltage dramatically. However, the output voltage is not sensitive to the gradient of magnetic flux density. The experimental results indicate that when the Wiegand wire is 14.2 mm from the magnet, the generation power is 0.118-1.15 mW, in a speed range of 240-540 rpm. When the Wiegand wire is 7.0 mm from the magnet, the generation power is 0.741-1.06 mW, in a speed range of 480-660 rpm.

A Comparison of SARC-F, Calf Circumference, and Their Combination for Sarcopenia Screening among Patients Undergoing Peritoneal Dialysis.

Sarcopenia is frequently encountered in patients undergoing peritoneal dialysis (PD). We evaluated and compared the diagnostic performance of a strength, assistance walking, rise from a chair, climb stairs, and falls (SARC-F) questionnaire, SARC-F combined with calf circumference (SARC-CalF), and calf circumference (CC) for screening sarcopenia among patients undergoing PD. We measured the appendicular skeletal muscle mass, evaluated using a multifrequency bioimpedance spectroscopy device, handgrip strength, and 6-m gait speed. SARC-F, SARC-CalF, and CC were obtained in all participants. Sarcopenia was defined using four different diagnostic criteria, including the Asian Working Group for Sarcopenia (AWGS) 2019, revised European Working Group on Sarcopenia in Older People (EWGSOP2), Foundation for the National Institutes of Health (FNIH), and International Working Group on Sarcopenia (IWGS). Among 186 enrolled patients undergoing PD (mean age 57.5 ± 14.1 years), the sarcopenia prevalence was 25.8-38.2% using the four definitions. The discriminative powers of SARC-CalF (range 0.648-0.748) and CC (range 0.652-0.813) against the four definitions were better than those exhibited by SARC-F (range 0.587-0.625), which achieved significant difference, except when adopting the criteria of the FNIH. After stratification by gender, the superiority of SARC-CalF and CC over SARC-F was maintained when AWGS 2019, EWGSOP2, and IWGS were applied. In conclusion, CC and SARC-CalF outperformed SARC-F in the diagnostic accuracy of sarcopenia among patients undergoing PD.

Optimizing the Rydberg EIT spectrum in a thermal vapor.

We present Rydberg-state electromagnetically-induced-transparency (EIT) measurements examining the effects of laser polarization, magnetic fields, laser intensities, and the optical density of the thermal 87Rb medium. Two counter-propagating laser beams with wavelengths of 480 nm and 780 nm were employed to sweep the spectrum across the Rydberg states |33D3/2〉 and |33D5/2〉. An analytic transmission expression well fits the Rydberg-EIT spectra with multiple transitions under different magnetic fields and laser polarization after accounting for the relevant Clebsch-Gordan coefficients, Zeeman splittings, and Doppler shifts. In addition, the high-contrast Rydberg EIT can be optimized with the probe laser intensity and optical density. Rydberg EIT peak height was achieved at 13%, which is more than twice as high as the maximum peak height at room temperature. A quantitative theoretical model is employed to represent the spectra properties and to predict well the optimization conditions. A Rydberg EIT spectrum with high contrast in real time can be served as a quantum sensor to detect the electromagnetic field within an environment.

Hispolon Methyl Ether, a Hispolon Analog, Suppresses the SRC/STAT3/Survivin Signaling Axis to Induce Cytotoxicity in Human Urinary Bladder Transitional Carcinoma Cell Lines.

Bladder cancer is a leading human malignancy worldwide. Signal transducer and activator of transcription (STAT) 3 is an oncogenic transcription factor commonly hyperactivated in most human cancers, including bladder cancer. Notably, preclinical evidence has validated STAT3 blockade as a promising therapeutic strategy for bladder cancer. Hispolon Methyl Ether (HME) is a structural analog of hispolon, an anticancer component of the medicinal mushroom Phellinus linteus. Thus far, HME's anticancer activity and mechanisms remain largely unknown. We herein report HME was cytotoxic, more potent than cisplatin, and proapoptotic to various human bladder transitional carcinoma cell lines. Of note, HME blocked STAT3 activation, evidenced by HME-elicited reduction in tyrosine 705-phosphorylated STAT3 levels constitutively expressed or induced by interleukin-6. Significantly, HME-induced cytotoxicity was abrogated in cells expressing a dominant-active STAT3 mutant (STAT3-C), confirming STAT3 blockage as a pivotal mechanism of HME's cytotoxic action. We further revealed that survivin was downregulated by HME, while its levels were rescued in STAT3-C-expressing cells. Moreover, survivin overexpression abolished HME-induced cytotoxicity, illustrating survivin as a central downstream mediator of STAT3 targeted by HME. Lastly, HME was shown to lower tyrosine 416-phosphorylated SRC levels, suggesting that HME inhibits STAT3 by repressing the activation of SRC, a STAT3 upstream kinase. In conclusion, we present the first evidence of HME's anti-bladder cancer effect, likely proceeding by evoking apoptosis through suppression of the antiapoptotic SRC/STAT3/survivin signaling axis.

Self-assembled lanthanide-based helixes: synthetic control of the helical handedness by chirality of the ligand.

The control of the self-assembly of lanthanide helical chain and their helical handedness have been investigated for the first time. Δ- and Λ-form lanthanide chain complexes were obtained by introducing thiazolidine ligands that were synthesised from L- and D-cysteine, respectively, and shared the same formula: [Ln2(L)3(H2O)5]∞·3H2O (Ln: Sm and Eu) (L: 2-(2-hydroxy-3,5-dinitrophenyl)thiazolidine-4-carboxylic acid). The crystallographic, circular dichroism, and luminescence properties of these novel lanthanide chain complexes were studied.

Examining the Impact of and Sensitivity of Fit Indices to Omitting Covariates Interaction Effect in Multilevel Multiple-Indicator Multiple-Cause Models.

This study examined the impact of omitting covariates interaction effect on parameter estimates in multilevel multiple-indicator multiple-cause models as well as the sensitivity of fit indices to model misspecification when the between-level, within-level, or cross-level interaction effect was left out in the models. The parameter estimates produced in the correct and the misspecified models were compared under varying conditions of cluster number, cluster size, intraclass correlation, and the magnitude of the interaction effect in the population model. Results showed that the two main effects were overestimated by approximately half of the size of the interaction effect, and the between-level factor mean was underestimated. None of comparative fit index, Tucker-Lewis index, root mean square error of approximation, and standardized root mean square residual was sensitive to the omission of the interaction effect. The sensitivity of information criteria varied depending majorly on the magnitude of the omitted interaction, as well as the location of the interaction (i.e., at the between level, within level, or cross level). Implications and recommendations based on the findings were discussed.