Efficacy and safety of topically applied therapeutic ammonia oxidising bacteria in adults with mild-to-moderate atopic dermatitis and moderate-to-severe pruritus: a randomised, double-blind, placebo-controlled, dose-ranging, phase 2b trial.

Background: Topical anti-inflammatory therapy is a cornerstone of treatment for atopic dermatitis (AD). However, many unmet needs remain with existing therapies. B244 is a live topical biotherapeutic being tested for the reduction of pruritus and improvement of eczema signs in patients with AD. We aimed to assess the safety and efficacy of B244, compared to vehicle, for patients with mild-to-moderate AD and moderate-to-severe pruritus. Methods: In this randomised, placebo-controlled, double-blind phase 2b trial, adults aged 18-65 years with mild-to-moderate AD and moderate-to-severe pruritus were enrolled across 56 sites in the USA. Patients were randomised 1:1:1 into a low-dose (optical density at 600 nm [OD] 5.0), high-dose (OD 20.0), or vehicle group for the 4-week treatment period and a 4 week follow-up period. Patients were instructed to apply the topical spray twice daily throughout the treatment period. Randomisation was centrally based (random alternating blocks of 6 and 3) and stratified by site. All participants, investigators, and those assessing outcomes were blinded to the treatment group assignments. The primary endpoint was the mean change in pruritus as measured by the Worst Itch Numeric Rating Scale (WI-NRS) at 4 weeks. Safety was tracked throughout the study. Primary efficacy analyses included the modified intent-to-treat (mITT) population, encompassing those who received at least one dose of study drug and attended at least one post-baseline visit. The safety population included all participants who received at least one does of study drug. This study is registered with ClinicalTrials.gov, NCT04490109. Findings: Between June 4, 2020 and October 22, 2021, 547 eligible patients were enrolled. All study endpoints were meaningfully improved with B244 compared to vehicle. The WI-NRS score was reduced by 34% (-2.8 B244 vs -2.1 placebo, p = 0.014 and p = 0.015 for OD 20.0 and OD 5.0), from a baseline score of >8. B244 was well tolerated with no serious adverse events (SAEs); treatment-emergent adverse events (TEAEs) and treatment related TEAEs were low in incidence, mild in severity, and transient. 33 (18%) of 180 patients given B244 OD 5.0, 29 (16%) of 180 patients given B244 OD 20.0, and 17 (9%) of 186 patients given placebo reported treatment-emergent adverse events; headache was the most frequent (3%, 2%, and 1%, respectively). Interpretation: B244 was well tolerated and demonstrated improved efficacy compared to vehicle in all primary, secondary, and exploratory endpoints and should be further developed as a novel, natural, fast-acting topical spray treatment option for AD and associated pruritus. Funding: AOBiome Therapeutics.

Characterization of anisotropic myocardial backscatter using spectral slope, intercept and midband fit parameters.

The specific myocardial structural components that contribute to the observed level of backscatter from the heart and its dependence on the angle of insonification have not been completely identified: The objectives of this study were to measure the anisotropy of backscatter from myocardium using the approach first introduced by Lizzi et al. [J Acoust Soc Am 73, 1366-1373 (1983)] and to use the extracted spectral parameters (spectral slope, intercept and midband fit) to characterize changes in the apparent scatterer size, spatial concentration and acoustic impedance properties as functions of the angle of insonification. Backscatter measurements were performed in vitro on eight cylindrical formalin-fixed lamb myocardial specimens using a 5 MHz focused transducer. The backscattered spectral data as a function of angle of insonification relative to the myocardial fiber direction were analyzed over the frequency range of 4 to 6 MHz. The spectral parameters describing features of backscatter were determined by applying a linear fit to attenuation-compensated normalized spectra. Results show that values of the spectral slope do not exhibit a significant dependence on the angle of insonification within uncertainties; however, the zero-frequency intercept showed clear anisotropy and was found to be a maximum for insonification perpendicular to the predominant myofiber orientation and a minimum for parallel insonification. A comparison of midband fit values at 5 MHz with attenuation-compensated integrated backscatter values showed excellent agreement for all angles of insonification. These data suggest that measurements of spectral slope, intercept, and midband fit can provide insights regarding aspects of tissue microstructure underlying the observed anisotropy of myocardial scattering properties. Measurements of the slope parameter suggest a very modest change in effective scatterer size with angle of insonification. However, the observed anisotropy in intercept and midband fit and apparent absence of anisotropy in the spectral slope suggests an angle of insonification dependence of acoustic concentration, the combination of effective spatial scatterer concentration and acoustic impedance properties, without a significant contribution from changes in effective scatterer size.

Anisotropy of the backscatter coefficient of formalin-fixed ovine myocardium.

The objective of this study was to measure the backscatter coefficient of formalin-fixed myocardial tissue as a function of angle of insonification relative to the myocardial fiber direction. Backscatter measurements were performed on eight cylindrical formalin-fixed lamb myocardial specimens and compensated for attenuation and diffraction effects to determine the backscatter coefficient. The backscatter coefficient at 5 MHz was found to be maximum for insonification perpendicular to the predominant myofiber orientation and minimum for parallel insonification, with values of (17+/-14) and (1.2+/-0.7) x 10(-4) cm(-1) sr(-1) (mean+/-standard deviation), respectively.

Estimation of creatinine clearance in end-stage liver disease.

BACKGROUND: Estimation of renal function in patients with end-stage liver disease (ESLD) is complicated by several factors. OBJECTIVE: To develop a practical and relatively inexpensive method for estimating creatinine production and clearance in patients with ESLD. METHODS: Serum creatinine concentrations and urinary excretion of creatinine were measured in 27 patients with moderate-to-severe liver disease with the goal of developing equations to predict creatinine clearance from serum creatinine. Subjects were studied during an initial evaluation for a liver transplant program. Two 24 hour urine specimens were collected along with 3 serum samples over a 2 day evaluation period. Serum and urine creatinine concentrations were determined using both a modified Jaffé (autoanalyzer) method and an HPLC method. The data were analyzed using nonlinear mixed-effects modeling. RESULTS: Considering both statistical criteria and physiological conventions through allometric scaling theory, creatinine clearance (mL/min) in males can be estimated as (80/serum creatinine) x (actual body weight/70)0.75. For females, the same equation is valid, but the result is multiplied by 0.661. A simplified equation without the exponent is presented, along with equations that are appropriate when an HPLC assay is used for greater specificity. CONCLUSIONS: These equations offer potential for improved estimation of creatinine clearance in patients with liver impairment; however, they need further validation using an independent group of subjects.

Fusarium osteomyelitis of the foot in a patient with diabetes mellitus.

Diabetic foot osteomyelitis is among the most common and serious complications in patients with diabetes mellitus. It is often a polymicrobial infection. We report the first case of foot osteomyelitis in a diabetic patient caused by Fusarium solani.

Severe cellulitis/myositis caused by Stenotrophomonas maltophilia.

OBJECTIVE: To present a case of cellulitis/myositis due to Stenotrophomonas maltophilia in the absence of trauma and to discuss a potentially novel treatment option. CASE SUMMARY: A 57-year-old white man, having undergone an allogeneic bone marrow transplant, developed myositis with S. maltophilia of the left soleus muscle; there had been no trauma. Risk factors for infection included neutropenia, prolonged hospitalization and intensive care unit stay, and broad-spectrum antibiotic exposure. The affected area of muscle was resected and the patient successfully treated with trimethoprim/sulfamethoxazole (TMP/SMX), ticarcillin/clavulanate, and aztreonam. DISCUSSION: In severe myositis/cellulitis caused by S. maltophilia, TMP/SMX is considered the drug of choice. However, bacteriostatic agents such as TMP/SMX are less than ideal in neutropenic patients. The combination of ticarcillin/clavulanate plus aztreonam has been shown to improve activity in vitro against this organism compared with TMP/SMX. This is likely due to inhibition of the 2 beta-lactamases this organism produces by clavulanate and aztreonam. In our study of clinical isolates of S. maltophilia, this combination reduced the minimum inhibitory concentration at 90% by 128-fold and was synergistic against 10 of 12 isolates tested in time-kill analysis. CONCLUSIONS: S. maltophilia is emerging as an important pathogen in patients with compromised immunity, leading to severe infections that are difficult to treat. Based on in vitro synergy studied, we recommend considering ticarcillin/clavulanate plus aztreonam as a potential treatment option in immunocompromised patients with S. maltophilia infection.