Modeling of micro- and nano-scale domain recording by high-voltage atomic force microscopy in ferroelectrics-semiconductors

The equilibrium sizes of micro- and nano-domains caused by electric field of atomic force microscope tip in ferroelectric semiconductor crystals have been calculated. The domain was considered as a prolate semi-ellipsoid with rather thin domain walls. For the first time we modified the Landauer model allowing for semiconductor properties of the sample and the surface energy of the domain butt. The free carriers inside the crystal lead to the formation of the screening layer around the domain, which partially shields its interior from the depolarization field. We expressed the radius and length of the domain though the crystal material parameters (screening radius, spontaneous polarization value, dielectric permittivity tensor) and atomic force microscope tip characteristics (charge, radius of curvature). The obtained dependence of domain radius via applied voltage is in a good quantitative agreement with the ones of submicron ferroelectric domains recorded by high-voltage atomic force and scanning probe microscopy in LiNbO3 and LiTaO3 crystals.Comment: 21 pages, 5 figure

Performance of [(18)F]flutemetamol amyloid imaging against the neuritic plaque component of CERAD and the current (2012) NIA-AA recommendations for the neuropathologic diagnosis of Alzheimer's disease

INTRODUCTION: Performance of the amyloid tracer [(18)F]flutemetamol was evaluated against three pathology standard of truth (SoT) measures including neuritic plaques (CERAD "original" and "modified" and the amyloid component of the 2012 NIA-AA guidelines). METHODS: After [(18)F]flutemetamol imaging, 106 end-of-life patients who died underwent postmortem brain examination for amyloid plaque load. Blinded positron emission tomography scan interpretations by five independent electronically trained readers were compared with pathology measures. RESULTS: By SoT, sensitivity and specificity of majority image interpretations were, respectively, 91.9% and 87.5% with "original CERAD," 90.8% and 90.0% with "modified CERAD," and 85.7% and 100% with the 2012 NIA-AA criteria. DISCUSSION: The high accuracy of either CERAD criteria suggests that [(18)F]flutemetamol predominantly reflects neuritic amyloid plaque density. However, the use of CERAD criteria as the SoT can result in some false-positive results because of the presence of diffuse plaques, which are accounted for when the positron emission tomography read is compared with the 2012 NIA-AA criteria

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.

Dynamics of ferroelectric domain growth in the field of atomic force microscope

Application of very high voltage to atomic force microscope tip leads to the growth of narrow, string-like domains in some ferroelectrics, a phenomenon that was named “ferroelectric domain breakdown.” In this work the dynamics of domain breakdown have been studied experimentally and theoretically in stoichiometric lithium niobate (LN). The theory has been found to be in a good agreement with the measured domain radius temporal dependence. Dynamics of domain growth has also been studied in ultrathin LN crystals, where the domain breakdown phenomenon does not take place. It is also shown that domain formation processes occurring in bulk and ultrathin crystals are very different, and this is ascribed to the observed difference in depolarization energy dependence on the domain length

The Effects of Multiple Doses of Lomecel‐B, Longeveron’ s Cell‐based Therapy, on Alzheimer’s disease: Study Design and Rationale of this Phase 2a Multi‐ center Clinical trial

Background Lomecel‐B is an allogeneic medicinal signaling cell (MSC) formulation under clinical investigation for Alzheimer’s disease (AD). We have successfully completed a double‐blinded, placebo‐controlled Phase 1 safety trial, in which Lomecel‐B was found to be safe and tolerable in patients with mild AD, and yielded preliminary evidence supporting potential efficacy. Mechanistically, this included evidence of pro‐vascular and anti‐inflammatory activities. Extending upon these promising results, we present the rationale and design of the next‐phase 2a trial in this program. Method The primary objective of this double‐blinded, randomized, and placebo‐controlled Phase 2a trial is to evaluate the safety of multiple doses of Lomecel‐B versus a single dose or placebo. Forty‐eight participants will be equally randomized to four study arms, and will receive intravenous infusions at Weeks 0, 4, 8, and 12, and followed up through Week 39 post‐first infusion. Arm 1 will receive four intravenous infusions of placebo. Arm 2 will receive one infusion of low‐dose Lomecel‐B (2.5×107 cells) followed by three infusions of Placebo. Arm 3 will receive four infusions of low‐dose Lomecel‐B. Arm 4 will receive four infusions of high‐dose Lomecel‐B (108 cells). Enrolled subjects will undergo a multi‐tiered screening process (clinical evaluation, blood‐work, MRI, and PET). Major enrollment criteria are mild AD with confirmatory beta‐amyloid tracer PET, 60‐85 years of age, and a MMSE score of 18‐24. Safety will be monitored by examining vital signs, physical and neurological exams, laboratory tests (hematology, coagulation, blood chemistry, and urinalysis), and neuroimaging. The secondary objectives are to assess the effects of Lomecel‐B on the cognitive function, and pro‐vascular and anti‐inflammatory biomarkers. Exploratory objectives include neurocognitive, neuropsychiatric, quality‐of‐life, activities‐of‐daily‐living, frailty status, and biomarkers assessments. Result This multicenter phase 2a trial has been allowed to proceed by FDA, is IRB approved, and actively enrolling. Conclusion This trial is designed to obtain safety and preliminary efficacy data on the effects of a multiple doses of Lomecel‐B on mild AD, with an emphasis on biomarkers related to proposed mechanisms of action (MOAs). We anticipate this trial will have complete enrollment by early 2023, and preliminary safety findings available soon thereafter