Artificial intelligence scoring of liver biopsies in a phase II trial of semaglutide in nonalcoholic steatohepatitis.

BACKGROUND AND AIMS: Artificial intelligence-powered digital pathology offers the potential to quantify histological findings in a reproducible way. This analysis compares the evaluation of histological features of NASH between pathologists and a machine-learning (ML) pathology model. APPROACH AND RESULTS: This post hoc analysis included data from a subset of patients (n=251) with biopsy-confirmed NASH and fibrosis stage F1-F3 from a 72-week randomized placebo-controlled trial of once-daily subcutaneous semaglutide 0.1, 0.2, or 0.4 mg (NCT02970942). Biopsies at baseline and week 72 were read by 2 pathologists. Digitized biopsy slides were evaluated by PathAI's NASH ML models to quantify changes in fibrosis, steatosis, inflammation, and hepatocyte ballooning using categorical assessments and continuous scores. Pathologist and ML-derived categorical assessments detected a significantly greater percentage of patients achieving the primary endpoint of NASH resolution without worsening of fibrosis with semaglutide 0.4 mg versus placebo (pathologist 58.5% vs. 22.0%, p < 0.0001; ML 36.9% vs. 11.9%; p =0.0015). Both methods detected a higher but nonsignificant percentage of patients on semaglutide 0.4 mg versus placebo achieving the secondary endpoint of liver fibrosis improvement without NASH worsening. ML continuous scores detected significant treatment-induced responses in histological features, including a quantitative reduction in fibrosis with semaglutide 0.4 mg versus placebo ( p =0.0099) that could not be detected using pathologist or ML categorical assessment. CONCLUSIONS: ML categorical assessments reproduced pathologists' results of histological improvement with semaglutide for steatosis and disease activity. ML-based continuous scores demonstrated an antifibrotic effect not measured by conventional histopathology.

Inhibiting Isoprenylation Suppresses FcεRI-Mediated Mast Cell Function and Allergic Inflammation.

IgE-mediated mast cell activation is a driving force in allergic disease in need of novel interventions. Statins, long used to lower serum cholesterol, have been shown in multiple large-cohort studies to reduce asthma severity. We previously found that statins inhibit IgE-induced mast cell function, but these effects varied widely among mouse strains and human donors, likely due to the upregulation of the statin target, 3-hydroxy-3-methylgutaryl-CoA reductase. Statin inhibition of mast cell function appeared to be mediated not by cholesterol reduction but by suppressing protein isoprenylation events that use cholesterol pathway intermediates. Therefore, we sought to circumvent statin resistance by targeting isoprenylation. Using genetic depletion of the isoprenylation enzymes farnesyltransferase and geranylgeranyl transferase 1 or their substrate K-Ras, we show a significant reduction in FcεRI-mediated degranulation and cytokine production. Furthermore, similar effects were observed with pharmacological inhibition with the dual farnesyltransferase and geranylgeranyl transferase 1 inhibitor FGTI-2734. Our data indicate that both transferases must be inhibited to reduce mast cell function and that K-Ras is a critical isoprenylation target. Importantly, FGTI-2734 was effective in vivo, suppressing mast cell-dependent anaphylaxis, allergic pulmonary inflammation, and airway hyperresponsiveness. Collectively, these findings suggest that K-Ras is among the isoprenylation substrates critical for FcεRI-induced mast cell function and reveal isoprenylation as a new means of targeting allergic disease.

A randomized double-blinded trial to assess recurrence of systemic allergic reactions following COVID-19 mRNA vaccination.

BACKGROUND: Systemic allergic reactions (sARs) following coronavirus disease 2019 (COVID-19) mRNA vaccines were initially reported at a higher rate than after traditional vaccines. OBJECTIVE: We aimed to evaluate the safety of revaccination in these individuals and to interrogate mechanisms underlying these reactions. METHODS: In this randomized, double-blinded, phase 2 trial, participants aged 16 to 69 years who previously reported a convincing sAR to their first dose of COVID-19 mRNA vaccine were randomly assigned to receive a second dose of BNT162b2 (Comirnaty) vaccine and placebo on consecutive days in a blinded, 1:1 crossover fashion at the National Institutes of Health. An open-label BNT162b2 booster was offered 5 months later if the second dose did not result in severe sAR. None of the participants received the mRNA-1273 (Spikevax) vaccine during the study. The primary end point was recurrence of sAR following second dose and booster vaccination; exploratory end points included biomarker measurements. RESULTS: Of 111 screened participants, 18 were randomly assigned to receive study interventions. Eight received BNT162b2 second dose followed by placebo; 8 received placebo followed by BNT162b2 second dose; 2 withdrew before receiving any study intervention. All 16 participants received the booster dose. Following second dose and booster vaccination, sARs recurred in 2 participants (12.5%; 95% CI, 1.6 to 38.3). No sAR occurred after placebo. An anaphylaxis mimic, immunization stress-related response (ISRR), occurred more commonly than sARs following both vaccine and placebo and was associated with higher predose anxiety scores, paresthesias, and distinct vital sign and biomarker changes. CONCLUSIONS: Our findings support revaccination of individuals who report sARs to COVID-19 mRNA vaccines. Distinct clinical and laboratory features may distinguish sARs from ISRRs.

Modified Radical Neck Dissection for Papillary Thyroid Carcinoma via a Combined Endoscopy Approach: The Transoral Approach and the Chest Approach.

BACKGROUND: Recently, modified radical neck dissection (MRND) for papillary thyroid carcinoma (PTC) has been performed by the transoral endoscopic approach.1 However, dissection of level II lymph nodes using only the transoral approach is highly difficult because of the inadequate axis of surgical view. Hence, we decided to combine the transoral and chest approaches to perform MRND. To the best of our knowledge, this is the first video case of MRND using the combined approach. PATIENT AND METHODS: A 35-year-old woman was diagnosed with cT1aN1bM0 right PTC (metastatic to right level III lymph nodes). The patient underwent total thyroidectomy, bilateral central neck dissection (CND), and right MRND via a combined endoscopic approach: the transoral and chest approaches. Total thyroidectomy and bilateral central neck dissection were performed via the transoral approach, similar to prior studies.2-6 The chest approach can help the surgeon to perform level II and the transoral approach was used to dissect the lymph node of levels III and IV. RESULTS: The total time for total thyroidectomy, bilateral CND, and right MRND was 190 min. The time for MRND was 90 min. The number of harvested lymph nodes were 14 in the right lateral compartments, and the number of metastatic lymph nodes were 2 in the lateral compartments. There were no major postoperative complications. The patient was completely satisfied with the cosmetic result. CONCLUSIONS: The combined approach of the transoral and chest approaches was sufficient to perform total thyroidectomy and MRND for levels II, III, and IV.

Use of dual-lumen microcatheter pullback injection in complex percutaneous coronary intervention.

Dual-lumen microcatheters (DLMC) are utilized in challenging wiring scenarios as well as for contrast and medication injections. Nonetheless, lesion characterization remains extremely challenging in many cases. We describe a DLMC-facilitated technique which can assist in locating the distal anastomosis while navigating an occluded bypass graft during retrograde chronic total occlusion recanalization, as well as in the differential diagnosis of abrupt vessel closure. This "DLMC Pullback Injection" technique is performed by injecting contrast through the over-the-wire port of the DLMC, while the latter is quickly pulled back across the region of interest in a dynamic fashion. We believe this technique has the potential to solve challenging scenarios and to enrich the complex percutaneous coronary intervention operator's armamentarium.

Epidemiology of perioperative anaphylaxis in France in 2017-2018: the 11th GERAP survey.

BACKGROUND: Perioperative anaphylaxis is rare but is associated with significant morbidity. This complication has been well described in France by the GERAP (Groupe d'Etude des Réactions Anaphylactiques Périopératoires), a network focused on its study. The epidemiology of perioperative anaphylaxis is evolving, influenced by environmental factors and clinical practice. The aim of this study was to update the epidemiology of perioperative anaphylaxis in France. METHODS: This multicentre retrospective study was performed in 26 allergy clinics of the GERAP network in 2017-8. RESULTS: There were 765 patients with perioperative anaphylaxis included. Most cases were severe, with 428 (56%) reactions graded as 3 or 4 according to the Ring and Messmer classification. Skin test results were available for 676 patients, with a culprit agent identified in 471 cases (70%). Neuromuscular blocking agents were the main cause of perioperative anaphylaxis (n=281; 60%), followed by antibiotics (n=118; 25%) and patent blue dye (n=11; 2%). Cefazolin was the main antibiotic responsible for perioperative anaphylaxis (52% of antibiotic-related reactions). Suxamethonium and rocuronium were the main neuromuscular blocking agents responsible for perioperative anaphylaxis with 7.1 (6.1-8.4) and 5.6 (4.2-7.4) reactions per 100,000 vials sold, respectively, whereas cefazolin-related cases were estimated at 0.7 (0.5-0.9) reactions per 100,000 vials sold. CONCLUSIONS: Our results confirm that most commonly identified triggering agents remain neuromuscular blocking agents. Reactions to antibiotics, particularly cefazolin, are becoming increasingly frequent. The origin of sensitisation to cefazolin is unknown, as no cross-sensitisation has been described, and it should be the subject of further study. Perioperative anaphylaxis should be followed over the years and understood given the changing triggers. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT04654923).

Endoscopic Kyoto and Kimura-Takemoto Classifications Are Comparable in Predicting High-Risk Gastric Precancerous Lesions.

INTRODUCTION: Severe and extensive gastric atrophy, extensive or incomplete gastric intestinal metaplasia, and gastric dysplasia are considered high-risk gastric precancerous lesions (HGPLs). Endoscopic findings based on the endoscopic Kyoto classification (EKC) and the Kimura-Takemoto classification (KTC) have been reported to be significantly associated with HGPLs. This study aimed to compare these two classifications in predicting active Helicobacter pylori (H. pylori) infection and HGPLs. METHODS: This is a cross-sectional study conducted on naïve dyspeptic patients who underwent upper gastrointestinal endoscopy at a tertiary hospital. Endoscopic findings were scored according to the EKC and KTC. Mapping biopsies were taken, and H. pylori infection was determined using a locally validated rapid urease test and histology. The performance of EKC was compared with that of KTC using the area under the receiver operating characteristic curve (AUC) in predicting active H. pylori infection and HGPLs. RESULTS: There were 292 patients with a median age of 46 and a male-to-female ratio of 1:1. The rates of active H. pylori infection and HGPLs were 61.3% and 14.0%, respectively. The EKC was better than the KTC in predicting active H. pylori infection (AUC: 0.771 vs. 0.658, respectively; p < 0.001). However, these two classifications had comparable performance in predicting HGPLs (AUC: 0.792 vs. 0.791, respectively; p = 0.956). CONCLUSION: Compared to EKC, KTC is inferior in predicting active H. pylori infection but has comparable performance in predicting HGPLs.

The prevalence of Pfk13 polymorphism in malaria patients treated with artemisinin-based therapy: a systematic review and meta-analysis.

Artemisinin (ART) combination therapy is the main treatment for malaria. Pfk13 mutations (or K13 mutations, Kelch 13) are associated with ART resistance. This study aims to conduct a systematic review and meta-analysis of the prevalence of K13 mutations with ART resistance in malaria-endemic countries. An electronic search of studies in 2018 and a manual search in 2020 were performed to identify relevant studies. The risk of bias was assessed using the National Institutes of Health (NIH) quality assessment tool for observational cohort and cross-sectional studies. Data analysis was performed using R 4.1.0. Heterogeneity was estimated using the statistic I2 and Cochran Q test. A total of 170 studies were included in our review. Of these, 55 studies investigated the prevalence of K13 mutations in Southeast Asia. The meta-analysis showed that Southeast Asia had the highest prevalence of K13 mutations, whereas Africa, South America, Oceania, and other Asian countries outside Southeast Asia had a low prevalence of K13 mutations. The C580Y mutation was the most common in Southeast Asia with 35.5% (95%CI: 25.4-46.4%), whereas the dominant mutation in Africa was K189T (22.8%, 95%CI: 7.6-43.2%). This study revealed the emergence of ART resistance associated with K13 mutations in Southeast Asia. The diversity of each type of K13 mutation in other regions was also reported.

Field-Free High-Frequency Exchange-Spring Spin-Torque Nano-Oscillators.

Spin-torque nano-oscillators (STNOs) are a type of nanoscale microwave auto-oscillators utilizing spin-torque to generate magnetodynamics with great promise for applications in microwaves, magnetic memory, and neuromorphic computing. Here, we report the first demonstration of exchange-spring STNOs, with an exchange-spring ([Co/Pd]-Co) reference layer and a perpendicular ([Co/Ni]) free layer. This magnetic configuration results in high-frequency (>10 GHz) microwave emission at a zero magnetic field and exchange-spring dynamics in the reference layer and the observation of magnetic droplet solitons in the free layer at different current polarities. Our demonstration of bipolar and field-free exchange-spring-based STNOs operating over a 20 GHz frequency range greatly extends the design freedom and functionality of the current STNO technology for energy-efficient high-frequency spintronic and neuromorphic applications.

Transoral endoscopic thyroidectomy vestibular approach versus conventional open thyroidectomy for the treatment of benign thyroid tumours: A prospective cohort study.

INTRODUCTION: Thyroid tumours are a common condition and open surgery is a conventional method for treating benign thyroid tumours when surgery is indicated. In this study, we evaluate the outcomes of benign thyroid tumour treatment using transoral endoscopic thyroidectomy via vestibular approach (TOETVA) and compare the results with those of conventional open thyroidectomy (COT). PATIENTS AND METHODS: We conducted a prospective cohort study between 100 patients who underwent TOETVA and 100 who underwent COT surgery for benign diseases from June 2018 to December 2021 in our hospital. Outcomes between the two groups, including post-operative complications, operative time and length of stay, were compared. RESULTS: The surgical time in the TOETVA group was significantly longer than in the COT group. The operative time of lobectomy in the TOETVA and COT groups was 77.5 ± 13.3 and 51.5 ± 4.2 min, respectively, with a P < 0.001. The operative time of total thyroidectomy in the TOETVA and COT groups was 108.1 ± 7.0 and 65.0 ± 4.1 min, respectively, with a P < 0.001. There was no difference in post-operative length of stay between the two groups. In TOETVA group, there were no patients who converted to open surgery. Amongst all 200 patients in the study, there were no cases of post-operative bleeding. The transient hypoparathyroidism rate after surgery in the TOETVA and COT groups was 3% and 2%, respectively, with no statistically significant difference (P = 0.651). Similarly, the transient recurrent laryngeal nerve injury rate showed no difference between the two groups, with rates of 5% and 4% in the TOETVA and COT groups, respectively (P = 0.733). There were no cases of post-operative infection in either group in our study. At 3 months postoperatively, the cosmetic satisfaction were significantly higher in the endoscopic groups than in the conventional group (P < 0.001). CONCLUSIONS: TOETVA is a safe and effective method, with a low complication rate and optimal aesthetic results compared to traditional surgery to treat benign thyroid tumours.

Three-Port Transoral Robotic Thyroidectomy in Papillary Thyroid Carcinoma.

BACKGROUND: Although transoral thyroidectomy has become popular in thyroid surgery, transoral robotic thyroidectomy (TORT) has only been successfully applied in a very small number of medical centers worldwide.[1,2,3,4,5] In this video, we show a three-port TORT without an axillary incision for papillary thyroid carcinoma. PATIENT AND METHODS: A 35-year-old female with cT1aN0M0 papillary thyroid carcinoma had a strong motivation to proceed with surgery but avoid external neck incisions. Thus, we decided to perform a hemithyroidectomy with isthmusectomy using a transoral robotic approach, employing the da Vinci Xi surgical system. RESULTS: The operation was completed successfully without conversion to open surgery. The working space creation time, docking time, and console time were 30 min, 40 min, and 130 min, respectively. The pathological results were papillary thyroid carcinoma with 6- and 5-mm tumors. The patient was discharged 4 days after surgery without any complications such as bleeding, infection, mental nerve damage, permanent hoarseness, or hypoparathyroidism. The patient was completely satisfied with the cosmetic result. CONCLUSION: Three-port TORT without an axillary incision is a promising approach with optimal cosmetic outcomes. For Vietnam, a developing country, success in the application of TORT using the new da Vinci Xi robotic platform for thyroid cancer is an important milestone in the development of thyroid surgery.

NTRK-rearranged spindle cell neoplasms are ubiquitous tumours of myofibroblastic lineage with a distinct methylation class.

AIMS: NTRK gene fusions have been described in a wide variety of central nervous system (CNS) and soft tissue tumours, including the provisional tumour type 'spindle cell neoplasm, NTRK-rearranged' (SCN-NTRK), added to the 2020 World Health Organisation Classification of Soft Tissue Tumours. Because of histopathological and molecular overlaps with other soft tissue entities, controversy remains concerning the lineage and terminology of SCN-NTRK. METHODS AND RESULTS: This study included 16 mesenchymal tumours displaying kinase gene fusions (NTRK fusions and one MET fusion) initially diagnosed as infantile fibrosarcomas (IFS), SCN-NTRK and adult-type fibrosarcomas from the soft tissue, viscera and CNS. We used immunohistochemistry, DNA methylation profiling, whole RNA-sequencing and ultrastructural analysis to characterise them. Unsupervised t-distributed stochastic neighbour embedding analysis showed that 11 cases (two CNS tumours and nine extra-CNS) formed a unique and new methylation cluster, while all tumours but one, initially diagnosed as IFS, clustered in a distinct methylation class. All the tumours except one formed a single cluster within the hierarchical clustering of whole RNA-sequencing data. Tumours from the novel methylation class co-expressed CD34 and S100, had variable histopathological grades and frequently displayed a CDKN2A deletion. Ultrastructural analyses evidenced a myofibroblastic differentiation. CONCLUSIONS: Our findings confirm that SCN-NTRK share similar features in adults and children and in all locations combine an infiltrative pattern, distinct epigenetic and transcriptomic profiles, and ultrastructural evidence of a myofibroblastic lineage. Further studies may support the use of new terminology to better describe their myofibroblastic nature.

Formyl peptide receptors in bone research.

PURPOSE/AIM OF THE STUDY: The formyl peptide receptor (FPR) participates in the immune response, with roles in infection and inflammation. In this review article, we summarize the current literature on these roles before discussing the function of FPRs in the pathogenesis of musculoskeletal disorders including osteoarthritis (OA), degenerative disc disease (DDD), and rheumatoid arthritis (RA). Additionally, we discuss the potential diagnostic and therapeutic roles of FPRs in these domains. METHODS: PubMed and Ovid MEDLINE searches were performed from 1965 through March 2022. Keywords included "FPR, tissue expression, inflammation, infection, musculoskeletal disorder, bone, rheumatoid arthritis, osteoarthritis, degenerative disc disease, mitochondria." RESULTS: Sixty-nine studies were included in this review article. FPRs appear to be ubiquitous in the pathogenesis, diagnosis, and treatment of common musculoskeletal disorders. They can potentially be utilized for the earlier diagnosis of OA and DDD. They may be employed with mesenchymal stem cells (MSCs) to reverse OA and DDD pathologies. With anti-inflammatory, anti-osteolytic, and pro-angiogenic functions, they may broaden treatment options in RA. CONCLUSIONS: FPRs appear to be heavily involved in the pathogenesis of common musculoskeletal conditions, including arthritis, degenerative disc disease, and rheumatoid arthritis. Furthermore, they demonstrate much promise in the diagnosis and treatment of these conditions. Their roles should continue to be explored.

Clinical features and outcome of retinoblastoma at the Vietnam National Cancer Hospital.

OBJECTIVES: To characterize the clinical features, treatment, and outcome of children diagnosed with retinoblastoma (RB) at Vietnam National Cancer Hospital. METHODS: The study enrolled all RB patients newly diagnosed at Vietnam National Cancer Hospital from January 2018 to December 2022. The primary endpoint was overall survival (OS) and the eye salvage rate. RESULTS: In total, 139 patients were enrolled, 51.8% patients were male. Median age was 18.9 months. Most patients presented with leukocoria (63.3%), followed by strabismus (14.4%), and 43.9% had bilateral disease. Of 200 eyes, 129 (64.5%) were classified as group E. Extraocular extension was noted in 10 of 139 patients (7.2%). About one-third of the patients lived more than 300 kilometers (km) away from these hospitals, and 17.3% of the patients belonged to minority groups, both of which were dominated by group E and extraocular or high-risk eyes at the time of consultation. Primary enucleation was done for 57 eyes (28.5%), and 51 of 61 patients (83.6%) received eye salvage therapy in bilateral RB group. At study closure, 127 children were alive at the last follow-up, 12 cases were confirmed dead. The 5-year OS and progression-free survival (PFS) rates were 90.3% and 85.9%, respectively. In particular, ethnic minority, distance to hospital more than 150 km, and extraocular disease were significantly associated with higher mortality among children with RB treated in Vietnam National Cancer Hospital. CONCLUSIONS: There is a need to support for screening RB with early symptoms in grassroots medical facilities and raise awareness among patients' families through health education programs. Besides, caring and supporting treatment for patients from the ethnic minority and who live far from hospitals are also extremely necessary.

Effect of annealing temperature and capping ligands on the electron mobility and electronic structure of indium oxide nanocrystal thin films: a comparative study with oleic acid, benzoic acid, and 4-aminobenzoic acid.

The effect of annealing temperature and capping ligands on the electron mobility and electronic structure of indium oxide (In2O3) nanocrystals (NCs) was investigated using oleic acid (OA), benzoic acid (BA), and 4-aminobenzoic acid (4ABA). The NCs were deposited on SiO2/Si wafers for electron mobility measurements using a field effect transistor device, and the annealing temperature (TAnn) was varied from 150 to 350 °C. At TAnn = 200 °C, the electron mobility of the BA-capped In2O3 NC thin film was greater than that of 4ABA-capped In2O3 NCs, while the opposite trend was observed at TAnn = 250 °C. This difference can be attributed, at the lower annealing temperature, to the π-π interaction in the BA-capped In2O3 NC thin film, which is hindered in the ABA-capped In2O3 NC thin film owing to its -NH2 group. At higher annealing temperature, NN bond formation in the ABA-capped In2O3 NC thin film confirmed by Raman spectroscopy plays a key role even after significant thermal decomposition of the ligands in the In2O3 NC thin films. At TAnn = 250 °C, the reorganization energy of BA- or 4ABA-capped In2O3 NCs estimated in the framework of Marcus theory was very similar to each other, indicating that the ligands decompose almost completely, as confirmed by Fourier transform infrared spectroscopy (FT-IR) and thermogravimetric analysis (TGA). The electronic structure was studied by energy-resolved electrochemical impedance spectroscopy (ER-EIS) after annealing the NCs on ITO electrodes at TAnn = 150 °C, 200 °C, or 250 °C. The valence band peak was observed near -6.8 eV for the BA- or 4ABA-capped In2O3 NC films at TAnn =150 °C or 200 °C, but not at TAnn =250 °C. However, for the OA-capped In2O3 NCs, the peak near -6.8 eV was observed for all annealing conditions. Considering the exclusive perseverance of the carboxylate group in the OA-capped In2O3 NCs even at TAnn = 250 °C, as confirmed by FT-IR and TGA, one attributes the peak at -6.8 eV to an electronic state formed by the electronic interaction between the In2O3 NC and the carboxylate groups.

Pholcodine exposure increases the risk of perioperative anaphylaxis to neuromuscular blocking agents: the ALPHO case-control study.

BACKGROUND: Neuromuscular blocking agents (NMBAs) are among the leading cause of perioperative anaphylaxis, and most of these reactions are IgE mediated. Allergic sensitisation induced by environmental exposure to other quaternary ammonium-containing compounds, such as pholcodine, has been suggested. The aim of this study was to assess the relationship between pholcodine exposure and NMBA-related anaphylaxis. METHODS: ALPHO was a multicentre case-control study, comparing pholcodine exposure within a year before anaesthesia between patients with NMBA-related perioperative anaphylaxis (cases) and control patients with uneventful anaesthesia in France. Each case was matched to two controls by age, sex, type of NMBA, geographic area, and season. Pholcodine exposure was assessed by a self-administered questionnaire and pharmaceutical history retrieved from pharmacy records. The diagnostic values of anti-pholcodine and anti-quaternary ammonium specific IgE (sIgE) were also evaluated. RESULTS: Overall, 167 cases were matched with 334 controls. NMBA-related anaphylaxis was significantly associated with pholcodine consumption (odds ratio 4.2; 95% confidence interval 2.3-7.0) and occupational exposure to quaternary ammonium compounds (odds ratio 6.1; 95% confidence interval 2.7-13.6), suggesting that apart from pholcodine, other environmental factors can also lead to sensitisation to NMBAs. Pholcodine and quaternary ammonium sIgEs had a high negative predictive value (99.9%) but a very low positive predictive value (<3%) for identifying NMBA-related reactions. CONCLUSIONS: Patients exposed to pholcodine 12 months before NMBA exposure have a significantly higher risk of an NMBA-related anaphylaxis. The low positive predictive values of pholcodine and quaternary ammonium sIgEs precludes their use to identify a population with a high risk of NMBA-related anaphylaxis. CLINICAL TRIAL REGISTRATION: NCT02250729.

Co-occurrence of phthalic acid esters (PAEs) and cyclic volatile methylsiloxanes (cVMSs) in fine particulate matter (PM0.5 and PM0.1) collected from an industrial area in Vietnam.

Distribution patterns of 10 phthalic acid diesters (PAEs) and four cyclic volatile methylsiloxanes (cVMSs) were investigated in fine particulate matter (PM0.1 and PM0.5) collected from Bac Ninh, an industrial province in Vietnam during September-October in 2021. Total concentrations of PAEs found in PM0.1 and PM0.5 were in the ranges of 1.76-372 (median: 34.0 ng/m3) and 2.23-895 ng/m3 (median: 15.4 ng/m3), respectively. Among PAEs, di-n-butyl phthalate (DBP) was the most abundant compound found in PM0.1, whereas, di-2-(ethyl)hexyl phthalate (DEHP) was measured at the highest concentration in PM0.5. Total concentrations of cVMSs measured in PM0.1 and PM0.5 were in the ranges of method quantification limit (MQL)-203 (median: 2.10 ng/m3) and MQL-537 ng/m3 (median: 0.389 ng/m3), respectively. Among cVMSs, decamethylcyclopentasiloxane (D5) was found at the highest concentration in both PM0.1 and PM0.5 fractions of particulate matter. The concentration ratios between PAEs and cVMSs in PM0.1/PM0.5 were greater than 1 (except di-n-octyl phthalate: DnOP), suggesting that these chemicals tend to sorb to PM0.1 more preferentially than PM0.5. Among sampling locations, high concentrations of PAEs and cVMSs were found at traffic intersections (Que Vo district) and a craft village (Tu Son city). Relatively stronger correlations existed between cVMSs pairs in PM0.1 and PM0.5 (correlation coefficient: 0.73-1) than those of PAEs (-0.83-0.90). The human exposure doses to PAEs and cVMSs through inhalation of particulate matter were estimated based on the measured concentrations in PM0.1 and PM0.5 fractions. The estimated exposure doses of PAEs and cVMSs for infants (7.1 ng/kg-bw/d and 2.5 ng/kg-bw/d) were higher than those for adults (2.6 ng/kg-bw/d and 0.9 ng/kg-bw/d).

Using dinoprostone slow release vaginal insert for cervical ripening in term-pregnancy with oligohydramnios.

AIMS: The study purposed to evaluate the success rate of cervical ripening using dinoprostone controlled-release vaginal insert and reveal some factors relating to successful cervical ripening. METHODS: This cross-sectional study was conducted at Tu Du Hospital in Vietnam from December 2021 to August 2022. The study enrolled 200 pregnant women with gestational age ≥37 weeks diagnosed with oligohydramnios. These candidates underwent dinoprostone cervical ripening (DCR) according to the local protocol. The Bishop score ≥7 after 24 h was determined for the successful cervical ripening (SCR). RESULTS: In total, the success rate of DCR achieved at 57.5% and the cesarean delivery rate was 46.5%. None of the severe side-effects and complications was present. Using multivariable logistic regression, the study found that the body mass index ≥25 kg/m2 and oxytocin infusion drip related to SCR with adjusted odds ratio (aOR): 3.67 (95% confidence intervals [CI]: 1.78-7.57) and aOR: 4.68 (95% CI: 1.84-11.93), p < 0.001. Using the Kaplan-Meier curve, the present study revealed a significant difference between Bishop <3 and ≥3 following the duration time of cervical ripening, with hazard ratio: 1.38 (95% CI: 1.19-1.59), p < 0.001. The time duration of cervical ripening was not significantly different following amniotic fluid index from 3 to 5 cm. CONCLUSIONS: Cervical ripening using a dinoprostone vaginal insert is a potentially acceptable method in term pregnancy accompanying with oligohydramnios. The probability of SCR can be predicted on a careful assessment of relative factors by obstetricians. Further studies are required to strengthen these findings.

Development of Activity Rules and Chemical Fragment Design for In Silico Discovery of AChE and BACE1 Dual Inhibitors against Alzheimer's Disease.

Multi-target drug development has become an attractive strategy in the discovery of drugs to treat of Alzheimer's disease (AzD). In this study, for the first time, a rule-based machine learning (ML) approach with classification trees (CT) was applied for the rational design of novel dual-target acetylcholinesterase (AChE) and ß-site amyloid-protein precursor cleaving enzyme 1 (BACE1) inhibitors. Updated data from 3524 compounds with AChE and BACE1 measurements were curated from the ChEMBL database. The best global accuracies of training/external validation for AChE and BACE1 were 0.85/0.80 and 0.83/0.81, respectively. The rules were then applied to screen dual inhibitors from the original databases. Based on the best rules obtained from each classification tree, a set of potential AChE and BACE1 inhibitors were identified, and active fragments were extracted using Murcko-type decomposition analysis. More than 250 novel inhibitors were designed in silico based on active fragments and predicted AChE and BACE1 inhibitory activity using consensus QSAR models and docking validations. The rule-based and ML approach applied in this study may be useful for the in silico design and screening of new AChE and BACE1 dual inhibitors against AzD.

Emergence of Inequality in Income and Wealth Dynamics.

Increasing wealth inequality is a significant global issue that demands attention. While the distribution of wealth varies across countries based on their economic stages, there is a universal trend observed in the distribution function. Typically, regions with lower wealth values exhibit an exponential distribution, while regions with higher wealth values demonstrate a power-law distribution. In this review, we introduce measures that effectively capture wealth inequality and examine wealth distribution functions within the wealth exchange model. Drawing inspiration from the field of econophysics, wealth exchange resulting from economic activities is likened to a kinetic model, where molecules collide and exchange energy. Within this framework, two agents exchange a specific amount of wealth. As we delve into the analysis, we investigate the impact of various factors such as tax collection, debt allowance, and savings on the wealth distribution function when wealth is exchanged. These factors play a crucial role in shaping the dynamics of wealth distribution.