A randomized, double-blind, placebo-controlled, single and multiple ascending dose Phase 1 study to determine the safety, pharmacokinetics and food and faecal microbiome effects of ibezapolstat administered orally to healthy subjects.

BACKGROUND: Clostridioides difficile infection is the most common cause of healthcare-associated infections in the USA, with limited treatment options. Ibezapolstat is a novel DNA polymerase IIIC inhibitor with in vitro activity against C. difficile. OBJECTIVES AND METHODS: Randomized, double-blind, placebo-controlled study to assess the safety, tolerability and pharmacokinetics of ibezapolstat in healthy volunteers. Microbiome changes associated with ibezapolstat were compared with vancomycin over a 10 day course using shotgun metagenomics. RESULTS: A total of 62 subjects aged 31 ± 7 years (45% female; average BMI: 25 ± 3 kg/m2) were randomized. Ibezapolstat was well tolerated with a safety signal similar to placebo. Ibezapolstat had minimal systemic absorption with the majority of plasma concentrations less than 1 µg/mL. In the multiday, ascending dose study, ibezapolstat concentrations of 2000 µg/g of stool were observed by Day 2 and for the remainder of the dosing time period. In the multiday, multiple-dose arm, baseline microbiota was comparable between subjects that received ibezapolstat compared with vancomycin. At Day 10 of dosing, differential abundance analysis and ß-diversity demonstrated a distinct difference between the microbiome in subjects given vancomycin compared with either dose of ibezapolstat (P = 0.006). α-Diversity changes were characterized as an increase in the Actinobacteria phylum in subjects that received ibezapolstat and an increase in Proteobacteria in subjects given vancomycin. CONCLUSIONS: Ibezapolstat was shown to be safe and well tolerated, with minimal systemic exposure, high stool concentrations and a distinct microbiome profile compared with oral vancomycin. These results support further clinical development of ibezapolstat for patients with C. difficile infection.

Applications of ultrasound elastography to hand and upper limb disorders.

Ultrasound elastography is a recently developed method for accurate measurement of soft tissue stiffness in addition to the clinician's subjective evaluation. The present review briefly describes the ultrasound elastography techniques and outlines clinical applications for tendon, muscle, nerve, skin and other soft tissues of the hand and upper limb. Strain elastography provides a qualitative evaluation of the stiffness, and shear-wave elastography generates quantitative elastograms superimposed on a B-mode image. The stiffness in degenerative tendinopathy and/or tendon injury was significantly lower than in a normal tendon in several studies. Elastography is also a reliable method to evaluate functional muscle activity, compared to conventional surface electromyography. The median nerve is consistently stiffer in patients with carpal tunnel syndrome than in healthy subjects, on whatever ultrasound elastography technique. Elastography distinguishes normal skin from scars and can be used to evaluate scar severity and treatment. Elastography has huge clinical applications in musculoskeletal tissues. Continued development of systems and increased training of clinicians will expand our knowledge of elastography and its clinical applications in the future.

Influence of group embryo culture strategies on the blastocyst development and pregnancy outcome.

PURPOSE: To compare two different embryo culture methods and to determine whether grouping embryos based on quality following Day 3 improved outcomes. METHODS: Two group embryo culture methods were compared in this study. All zygotes were individually cultured from Day 1 to Day 3. On Day 3, embryos were then cultured in group of 2-5 embryos per droplet until Day 5 or 6. The two group culture methods are: A, embryos were randomly grouped regardless of embryo quality; B, good and poor quality embryos were separately grouped. Blastocyst development rate, blastocyst utilization rate, implantation rate and pregnancy rate were detected. RESULTS: The group culture of Day 3 embryos, in which good or poor quality embryos were separately grouped, significantly promoted blastocyst development (61.2 %, 289/472) and blastocyst utilization rate (55.9 %, 264/472) in comparison with those embryos that were randomly grouped for culture regardless of embryo quality (44 %, 177/402 and 41.5 %, 167/402). There was no significant difference in the implantation rate and pregnancy rate between two group culture methods. CONCLUSIONS: Grouping of embryos after Day 3 based on embryo quality may benefit blastocyst formation. This may be due to secretion of beneficial factors by good embryos, or removal of detrimental factors from poor embryos. No impacts on pregnancy or implantation outcomes were observed.

Conservative and Surgical Treatment of Osteochondromas in Children, Particularly with or without Surgical Lengthening of the Ulna.

Prevention of rotatory impairment and radial head dislocation in the forearm is an important aspect when treating children with osteochondromas. Various studies tried to determine the best treatment, describing different surgical techniques. No consensus has been reached yet. This retrospective study compares the treatment outcome of patients with osteochondroma of the radius and ulna after surgical or conservative treatment. Seventeen forearms treated over a period of 20 years were analysed. Outcome parameters were the prospectively collected clinical data and the radiological findings: "relative shortening" of ulna/radius, the "radial articular angle" (RAA) and the "carpal slip" (CS). Our study shows an improvement of the range of motion and cosmetic appearance of the forearm after an operative procedure, with or without bone lengthening. We observed an increase in wrist and elbow mobility with a decrease in pain scores and a confirmed high cosmetic satisfaction in almost 70% of the patients after bone lengthening and up to 85% after simple excision. For patients suffering from functional impairment or pain, an operative approach is beneficial. Multiple and repetitive osteochondroma excisions are recommended during growth to prevent deformity and rotatory motion restriction. Lengthening procedures require a careful indication.

Single-isomer trisubstituted olefins from a novel reaction of (E)-beta-chloro-alpha-iodo-alpha,beta-unsaturated esters and amides.

(E)-beta-chloro-alpha-iodo-alpha,beta-unsaturated esters are converted to single isomer trisubstituted olefins bearing three different carbon substituents by cross-coupling under reflux. Mechanistic investigations suggest that this process transfers a hydrogen from the boronic acid to the alpha-position of the substrate and then introduces an aryl group to the beta-position of the intermediate template while replacing chloride. The reaction is highly stereoselective, showing preference for the E-isomer. The process proceeds through (E)-beta-chloro-alpha-aryl-alpha,beta-unsaturated esters that are transformed efficiently into the corresponding E-products through stereoselective Suzuki-type reactions giving single isomers. The observed stereochemistry is apparently enabled by the intermediacy of a palladium allenoate. The reaction involves a catalytic cycle in which Pd(II) is reduced to Pd(0) through the formation of biaryl-coupled products.

ERP measures of auditory word repetition and translation priming in bilinguals.

Motivated by the demonstration of similarly localized adaptation of the hemodynamic response in a first (L1) and second (L2) language, this study examined event-related brain potentials (ERPs) to spoken words in L1 and L2 in 15 English-French bilinguals. We examined whether the temporal pattern of N400 adaptation due to within-language repetitions (i.e., repetition priming) was similar in L1 and L2 and whether the release from adaptation elicited by a within-language word change was similar. Furthermore, using word changes across language, we examined the phonological mismatch negativity (PMN) and N400 components to determine the kind of information activated during translation priming. In contrast to within-language repetition, we expected between-language repetition (i.e., translations) to be characterized by conceptual rather than lexical/phonological word form priming. Overall, the pattern of adaptation and release from adaptation was similar in L1 and L2, with evidence of delayed semantic analysis in L2 in the form of a later N400 effect. A change in language (L1 to L2) elicited a similar pattern of PMN and N400 activity compared to a within-language change in meaning in L1, suggesting that neither word form nor conceptual information was available on-line for the forward translation. In contrast, the presence of strong PMN but minimal N400 effects for L2-to-L1 translations suggests that conceptual but not phonological information is available on-line for backwards translation. L2 proficiency influenced the extent to which conceptual representations were activated by translations. These data are discussed in light of current models of bilingual word processing and suggest modality differences in the pattern of activation of lexical and conceptual information.

Executive control modulates cross-language lexical activation during L2 reading: evidence from eye movements.

Models of bilingual reading such as Bilingual Interactive Activation Plus (Dijkstra & van Heuven, 2002) do not predict a central role for domain-general executive control during bilingual reading, in contrast with bilingual models from other domains, such as production (e.g., the Inhibitory Control Model; Green, 1998). We thus investigated whether individual differences among bilinguals in domain-general executive control modulate cross-language activation during L2 sentence reading, over and above other factors such as L2 proficiency. Fifty French-English bilinguals read L2-English sentences while their eye movements were recorded, and they subsequently completed a battery of executive control and L2 proficiency tasks. High- and low-constraint sentences contained interlingual homographs (chat = "casual conversation" in English, "a cat" in French), cognates (piano in English and French), or L2-specific control words. The results showed that greater executive control among bilinguals but not L2 proficiency reduced cross-language activation in terms of interlingual homograph interference. In contrast, increased L2 proficiency but not executive control reduced cross-language activation in terms of cognate facilitation. These results suggest that models of bilingual reading must incorporate mechanisms by which domain-general executive control can alter the earliest stages of bilingual lexical activation.

Bilingual lexical access during L1 sentence reading: The effects of L2 knowledge, semantic constraint, and L1-L2 intermixing.

Libben and Titone (2009) recently observed that cognate facilitation and interlingual homograph interference were attenuated by increased semantic constraint during bilingual second language (L2) reading, using eye movement measures. We now investigate whether cross-language activation also occurs during first language (L1) reading as a function of age of L2 acquisition and task demands (i.e., inclusion of L2 sentences). In Experiment 1, participants read high and low constraint English (L1) sentences containing interlingual homographs, cognates, or control words. In Experiment 2, we included French (L2) filler sentences to increase salience of the L2 during L1 reading. The results suggest that bilinguals reading in their L1 show nonselective activation to the extent that they acquired their L2 early in life. Similar to our previous work on L2 reading, high contextual constraint attenuated cross-language activation for cognates. The inclusion of French filler items promoted greater cross-language activation, especially for late stage reading measures. Thus, L1 bilingual reading is modulated by L2 knowledge, semantic constraint, and task demands.