Geometric Mean Research Articles

The impact of surgery resident training on the duration of tibial plateau leveling osteotomy surgery.

To investigate the impact of surgery resident training on surgery duration in tibial plateau leveling osteotomy (TPLO) and evaluate whether surgery duration differs with each year of residency training. Retrospective medical record review. A total of 256 client-owned dogs underwent TPLO. Records of dogs that underwent TPLO between August 2019 and August 2022 were reviewed. The effects of the surgeon (faculty/resident) and the procedure (arthrotomy/arthroscopy) on TPLO surgery duration were examined with an analysis of variance, and geometric least squares means (GLSM) were compared. A linear mixed effects model (LMM) was fitted to quantify fixed and random effects. Four faculty surgeons performed 74 (29%) TPLOs, while 10 residents performed 182 (71%) TPLOs under the direct supervision of a faculty surgeon. All TPLOs were conducted with arthrotomy (109; 43%) or arthroscopy (147; 57%). Overall, residents (GLSM, 153 min) required 54% more surgery duration than faculty surgeons (GLSM, 99 min). Surgery duration among first-year residents (GLSM, 170 min) was 15% longer than second- (GLSM, 148 min) and third-year (GLSM, 147 min) residents, whereas the duration did not differ statistically between second- and third-year residents. Arthroscopy, meniscal tear treatment, surgery on the right stifle, and increasing patient weight were also associated with longer surgery duration. The duration of TPLO surgery significantly decreased after the first year of residency, but did not decrease afterward. The results will aid with resource allocation, curricula planning, and cost management associated with resident training.

Tenofovir, emtricitabine, lamivudine and dolutegravir concentrations in plasma and urine following drug intake cessation in a randomized controlled directly observed pharmacokinetic trial to aid point-of-care testing.

Poor adherence to ART and pre-exposure prophylaxis (PrEP) can impact patient and public health. Point-of-care testing (POCT) may aid monitoring and adherence interventions. We report the pharmacokinetics of tenofovir [dosed as tenofovir disoproxil (TDF) and tenofovir alafenamide (TAF)], emtricitabine (FTC), lamivudine (3TC) and dolutegravir (DTG) in plasma and urine following drug cessation to evaluate adherence targets in urine for POCT. Subjects were randomized (1:1) to receive DTG/FTC/TAF or DTG/3TC/TDF for 15 days. Plasma and spot urine were collected on Day 15 (0-336 h post final dose). Drug concentrations were quantified using LC-MS, and non-linear mixed-effects models applied to determine drug disposition between matrices and relationship with relevant plasma [dolutegravir protein-adjusted 90% inhibitory concentration (PA-IC90 = 64 ng/mL) and minimum effective concentration (MEC = 324 ng/mL)] and urinary thresholds [tenofovir disoproxil fumarate 1500 ng/mL]. Of 30 individuals enrolled, 29 were included (72% female at birth, 90% Caucasian). Median (range) predicted time to plasma dolutegravir PA-IC90 and MEC were 83.5 (41.0-152) and 49.0 h (23.7-78.9), corresponding to geometric mean (90%) urine concentrations of 5.42 (4.37-6.46) and 27.4 ng/mL (22.1-32.7). Tenofovir in urine reached 1500 ng/mL by 101 h (58.6-205) with an equivalent plasma concentration of 6.20 ng/mL (4.21-8.18). These data support use of a urinary tenofovir threshold of <1500 ng/mL (tenofovir disoproxil fumarate-based regimens) as a marker of three or more missed doses for a POCT platform. However, due to low dolutegravir concentrations in urine, POCT would be limited to a readout of recent dolutegravir intake (one missed dose).

Comparative analysis of cholera serum vibriocidal antibodies from Convalescent and vaccinated adults in Zambia

Cholera is responsible for 1.3 to 4.0 million cholera cases globally and poses a significant threat, with Zambia reporting 17,169 cases as of 4th February 2024. Recognizing the crucial link between natural cholera infections and vaccine protection, this study aimed to assess immune responses post cholera infection and vaccination. This was a comparative study consisting of 50 participants enrolled during a cholera outbreak in Zambia’s Eastern Province and an additional 56 participants who received oral cholera vaccinations in Zambia’s Central Province. Vibriocidal antibodies were plotted as geometric mean titres in the naturally infected and vaccinated individuals. A significant difference (p < 0.047) emerged when comparing naturally infected to fully vaccinated individuals (2 doses) on day 28 against V. cholerae Ogawa. Those who received two doses of the oral cholera vaccine had higher antibody titres than those who were naturally infected. Notably, the lowest titres occurred between 0–9 days post onset, contrasting with peak responses at 10–19 days. This study addresses a critical knowledge gap in understanding cholera immunity dynamics, emphasizing the potential superiority of vaccination-induced immune responses. We recommend post infection vaccination after 40 days for sustained immunity and prolonged protection, especially in cholera hotspots.

Immunohistochemical and transcriptomic characterization of T and myeloid cell infiltrates in canine malignant melanoma.

Immune checkpoint inhibitor therapy can provide significant clinical benefit in patients with certain cancer types including melanoma; however, objective responses are only observed for a subset of patients. Mucosal melanoma is a rare melanoma subtype associated with a poor prognosis and, compared with cutaneous melanoma, is significantly less responsive to immune checkpoint inhibitors. Spontaneous canine tumours have emerged as valuable models to inform human cancer studies. In contrast to human melanoma, most canine melanomas are mucosal-an incidence that may be leveraged to better understand the subtype in humans. However, a more comprehensive understanding of the immune landscape of the canine disease is required. Here, we quantify tumour infiltrative T and myeloid cells in canine mucosal (n = 13) and cutaneous (n = 5) melanomas using immunohistochemical analysis of CD3 and MAC387 expression, respectively. Gene expression analysis using the Canine IO NanoString panel was also performed to identify genes and pathways associated with immune cell infiltration. T and myeloid cell densities were variable with geometric means of 158.7 cells/mm2 and 166.7 cells/mm2, respectively. Elevated T cell infiltration was associated with increased expression of cytolytic genes as well as genes encoding the coinhibitory checkpoint molecules PD-1, CTLA-4, TIM-3 and TIGIT; whereas increased myeloid cell infiltration was associated with elevated expression of protumourigenic cytokines. These data provide a basic characterization of the tumour microenvironment of canine malignant melanoma and suggest that, like human melanoma, inherent variability in anti-tumour T cell responses exists and that a subset of canine melanomas may respond better to immunomodulation.

Blood eosinophils levels in a Colombian cohort of biomass-and tobacco-related COPD patients

IntroductionChronic obstructive pulmonary disease (COPD) is a major cause of illness and death among adults. In 2019, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy incorporated blood eosinophils as a biomarker to identify patients at increased risk of exacerbations which, with the history of exacerbations during the previous year, allows identification of patients who would benefit from anti-inflammatory treatment to reduce the risk of future exacerbations. The aim of this study was to describe demographic and clinical characteristics, eosinophil counts, and exacerbations in a cohort of COPD patients stratified by clinical phenotypes (non-exacerbator, frequent exacerbator, asthma-COPD overlap) in a Colombian cohort at 2600 meters above sea level.MethodsA descriptive analysis of a historical cohort of patients with a confirmed diagnosis of moderate to severe COPD (FEV1/FVC &amp;lt; 0.7 and at least one risk factor for COPD) from two specialized centers with comprehensive disease management programs was performed from January 2015 to March 2019. Data were extracted from medical records 1 year before and after the index date.Results200 patients were included (GOLD B: 156, GOLD E: 44; 2023 GOLD classification); mean age was 77.9 (SD 7.9) years; 48% were women, and 52% had biomass exposure as a COPD risk factor. The mean FEV1/FVC was 53.4% (SD 9.8), with an FEV1 of 52.7% (20.7). No differences were observed between clinical phenotypes in terms of airflow limitation. The geometric mean of absolute blood eosinophils was 197.58 (SD 2.09) cells/μL (range 0 to 3,020). Mean blood eosinophil count was higher in patients with smoking history and frequent exacerbators. At least one moderate and one severe exacerbation occurred in the previous year in 44 and 8% of patients, respectively; during the follow-up year 152 exacerbations were registered, 122 (80%) moderate and 30 (20%) severe. The highest rate of exacerbations in the follow-up year occurred in the subgroup of patients with the frequent exacerbator phenotype and eosinophils ≥300 cells/μL.DiscussionIn this cohort, the frequency of biomass exposure as a risk factor is considerable. High blood eosinophil count was related to smoking, and to the frequent exacerbator phenotype.

Safety and Immunogenicity of an mRNA-Based hMPV/PIV3 Combination Vaccine in Seropositive Children.

Human metapneumovirus (hMPV) and parainfluenza virus type 3 (PIV3) are common respiratory illnesses in children. The safety and immunogenicity of an investigational mRNA-based vaccine, mRNA-1653, encoding membrane-anchored fusion proteins of hMPV and PIV3, was evaluated in hMPV/PIV3-seropositive children. In this phase 1b randomized, observer-blind, placebo-controlled, dose-ranging study, hMPV/PIV3-seropositive children were enrolled sequentially into 2 dose levels of mRNA-1653 administered 2 months apart; children aged 12 to 36 months were randomized (1:1) to receive 10-μg of mRNA-1653 or placebo and children aged 12 to 59 months were randomized (3:1) to receive 30-μg of mRNA-1653 or placebo. Overall, 27 participants aged 18 to 55 months were randomized; 15 participants received 10-μg of mRNA-1653 (n = 8) or placebo (n = 7), whereas 12 participants received 30-μg of mRNA-1653 (n = 9) or placebo (n = 3). mRNA-1653 was well-tolerated at both dose levels. The only reported solicited local adverse reaction was tenderness at injection site; solicited systemic adverse reactions included grade 1 or 2 chills, irritability, loss of appetite, and sleepiness. A single 10-μg or 30-μg mRNA-1653 injection increased hMPV and PIV3 neutralizing antibody titers (geometric mean fold-rise ratio over baseline: hMPV-A = 2.9-6.1; hMPV-B = 6.2-13.2; PIV3 = 2.8-3.0) and preF and postF binding antibody concentrations (geometric mean fold-rise ratio: hMPV preF = 5.3-6.1; postF = 4.6-6.5 and PIV3 preF = 13.9-14.2; postF = 11.0-12.1); a second injection did not further increase antibody levels in these seropositive children. Binding antibody responses were generally preF biased. mRNA-1653 was well-tolerated and boosted hMPV and PIV3 antibody levels in seropositive children aged 12 to 59 months, supporting the continued development of mRNA-1653 or its components for the prevention of hMPV and PIV3.

Pharmacokinetics and Safety of Intramuscular Injectable Benzathine Penicillin G in Japanese Healthy Participants.

An intramuscular (IM) suspension of benzathine penicillin G (BPG) has been used as first-line therapy for the treatment of syphilis worldwide since its approval in the 1950s. However, there are limited reports about the pharmacokinetics of BPG. A Phase 1 study was conducted on eight Japanese healthy participants to investigate the pharmacokinetics (samples collected predose to 648 h post-dose) and safety of 2.4 million units of BPG after a single IM injection. Following administration, penicillin G, the active moiety of BPG, was absorbed slowly from the injection site with a median time to Cmax (tmax) of 48 h post-dose. After the achievement of Cmax, concentrations of penicillin G declined slowly in a monophasic fashion with a mean apparent terminal half-life of 189 h. Geometric mean AUCinf and Cmax were 50770 ng•h/mL and 259 ng/mL, respectively. Median time (range) above the well-accepted therapeutic concentration (18 ng/mL) for syphilis treatment was 561 h (439-608 h [18-25 days]), which reached and exceeded the necessary duration of 7-10 days for syphilis treatment. Two participants were underdosed with residual drug left in the syringe due to the high viscosity of the drug product. Only one (12.5%) participant reported a mild adverse event of nasopharyngitis, which was considered not related to the study treatment. The study results supported BPG approval in Japan as an option for syphilis treatment.

Explainable machine learning approach for cancer prediction through binarilization of RNA sequencing data.

In recent years, researchers have proven the effectiveness and speediness of machine learning-based cancer diagnosis models. However, it is difficult to explain the results generated by machine learning models, especially ones that utilized complex high-dimensional data like RNA sequencing data. In this study, we propose the binarilization technique as a novel way to treat RNA sequencing data and used it to construct explainable cancer prediction models. We tested our proposed data processing technique on five different models, namely neural network, random forest, xgboost, support vector machine, and decision tree, using four cancer datasets collected from the National Cancer Institute Genomic Data Commons. Since our datasets are imbalanced, we evaluated the performance of all models using metrics designed for imbalance performance like geometric mean, Matthews correlation coefficient, F-Measure, and area under the receiver operating characteristic curve. Our approach showed comparative performance while relying on less features. Additionally, we demonstrated that data binarilization offers higher explainability by revealing how each feature affects the prediction. These results demonstrate the potential of data binarilization technique in improving the performance and explainability of RNA sequencing based cancer prediction models.

Harmonic mean and geometric mean of a non negative random variable

Harmonic mean and geometric mean of a non negative random variable

Hg Content Characteristics and Safe Planting Zoning of Paddy Soil and Rice in Guizhou Province

Guizhou Province ranks first in terms of Hg reserves and production in the country, and rice is its largest grain crop. In order to study the characteristics and pollution causes of soil-rice Hg content at the provincial level in Guizhou and to carry out safe planting zoning, 1 564 pairs of soil-rice samples, 470 natural soil samples, and 203 individual paddy soil samples were collected to test their Hg content and basic physical and chemical properties of the soil. The results showed that:① Paddy soil was mainly neutral and acidic, the paddy soil ω (Hg) range was 0.005-93.06 mg·kg-1, and the geometric mean was 0.864 mg·kg-1. The Hg content of paddy soil in Guizhou Province was significantly higher than that in natural soil (0.16 mg·kg-1,P &lt; 0.05). Compared with the filtered value and control value, the soil samples exceeded the standard by 63.25% and 14.71%, respectively. Among them, the soil Hg pollution in Danzhai County of Qiandongnan Prefecture, Wuchuan County of Zunyi City, Zhenfeng County of Qianxinan Prefecture, and Wanshan District of Tongren City was more prominent. ② Rice ω(Hg) ranged from 0.000 5 to 0.52 mg·kg-1, and the geometric mean was 0.010 mg·kg-1, the percentage of rice Hg content exceeding the standard was 25.87%, and the exceeding points were mainly distributed in Suiyang County of Zunyi City, Zhenfeng County of Qianxinan Prefecture, Xixiu District of Anshun City, Bijiang District of Tongren City, and other industrial and mining activity-intensive areas. ③ The majority of the study area was in the priority protection category (74.75%); the safe use category accounted for (24.62%); and the strictly controlled category (0.93%) was scattered in Danzhai County at the border between Qiannan Prefecture and Qiandongnan Prefecture, Zhenfeng County in Qianxinan Prefecture, and Wanshan District in Tongren. It is not recommended to plant rice, which can be used as feed for reproduction.

Determinants of urinary dialkyl phosphate metabolites in midlife women: the Study of Women's Health Across the Nation Multi-Pollutant Study (SWAN-MPS).

Biomonitoring data and determinants of urinary dialkylphosphate (DAP) metabolites, markers of organophosphate pesticides, in racially diverse, non-occupationally exposed populations are scarce. This study evaluated urinary concentrations and potential determinants of DAP metabolites of organophosphate pesticides in a multi-site, multi-racial/ethnic cohort of women aged 45-56 years, the Study of Women's Health Across the Nation Multi-Pollutant Study (SWAN-MPS). We analyzed 963 urine samples collected in 1999-2000, the baseline of SWAN-MPS for longitudinal studies, and quantified DAP metabolites, including dimethyl alkylphosphates (DMAPs): dimethylphosphate (DMP), dimethylthiophosphate (DMTP), dimethyldithiophosphate (DMDTP); and diethyl alkylphosphates (DEAPs): diethylphosphate (DEP), diethylthiophosphate (DETP), diethyldithiophosphate (DEDTP), using gas chromatography and triple quadrupole mass spectroscopy. Adjusted least squared geometric means (LSGMs) and 95% confidence intervals (CIs) were computed to compare DAP concentrations by socio-demographic, behavioral and dietary factors. The geometric means (geometric standard deviations) of total DAPs, DMAPs, and DEAPs were 141 (2.63) nmol/L, 102 (2.99) nmol/L, and 26.8 (2.46) nmol/L, respectively. Body mass index (BMI) was inversely associated with DMAPs and DEAPs: LSGM (95% CI) = 68.8 (55.7-84.9) and 21.0 (17.7-25.0) nmol/L for women with obesity vs. 102 (84.7-123) and 30.1 (25.7-35.1) nmol/L for women with normal/underweight, respectively. Fruit consumption was positively (74.9 (62.1-90.2) for less than 5-6 servings/week vs. 105 (84.8-130) nmol/L for 1 serving/day and more) whereas meat consumption was inversely associated with DMAPs (110 (95.0-128) for seldom vs. 82.3 (59.5-114) nmol/L for often consumption). Fresh apple consumption appears to be attributed to the DMAP differences. Alcohol consumption was positively associated with DEAPs (27.5 (23.1-32.7) for 2 drinks/week and more vs. 23.0 (20.0-26.6) nmol/L for less than 1 drink/month). Black women had higher concentrations of DEAPs compared with White women (27.3 (21.2-35.2) vs. 23.2 (20.2-26.7) nmol/L). Organophosphate pesticides (OPs) are synthetic chemicals and currently the most widely used type of insecticides. We examined multi-site, multi-ethnic cohort of midlife women in the U.S. that offers a unique opportunity to evaluate major determinants of OP exposure. We improved OP metabolite detection rates and obtained accurate concentrations using an improved analytical technique. Our findings suggest that consumptions of fruit, meat and alcohol are important determinants of OP exposure for midlife women. Higher concentrations of diethyl OP metabolites in Black women compared to White women, even after accounting for dietary intake, suggests additional, but unknown racial-ethnic differences that affect exposure.

Hydroponic Screening at Early Seedling Stage Identified Sources of Salinity Tolerance in Wheat (Triticum aestivum L.) Crop

Wheat is a vital crop globally, essential for agriculture, economics, and food security. However, in arid and semi-arid conditions, wheat production faces significant challenges due to low water availability, uneven rainfall distribution, and high soil salinity. The germination and early seedling stages are particularly vulnerable to these stresses. Therefore, this study assessed 15 wheat genotypes for their tolerance to salinity stress during early growth stages, using a hydroponic system with four salt stress levels (0, 50, 100, and 150 mM NaCl). Significant differences were observed for genotype and salinity main effects and their interaction on all investigated traits, indicating considerable variability in the response to salt stress among the investigated wheat cultivars. High NaCl concentrations led to substantial reductions in measured parameters across genotypes, with some showing resilience while others exhibited heightened sensitivity. Stress tolerance indices, such as mean productivity (MP), geometric mean productivity (GMP), harmonic mean (HM), stress tolerance index (STI) and yield index (YI), were identified as reliable indicators for selecting salt-tolerant wheat cultivars. Consequently, Sidi Okba (G11), Ziad (G12), Tamezghida (G13) and Zidane (G14) emerged as the most promising, displaying acceptable performance under both non-stress and salt-stress conditions. These genotypes could serve as valuable genetic resources for breeding programs aimed at enhancing wheat’s salinity tolerance, particularly in arid and semi-arid regions.

Safety, tolerability, and pharmacokinetics of a single orally inhaled dose of PUR3100, a dry powder formulation of dihydroergotamine versus intravenous dihydroergotamine: A Phase 1 randomized, double-blind study in healthy adults.

Intravenous dihydroergotamine (DHE) has well-established efficacy for the acute treatment of migraine, but its use is limited by the need for in-hospital administration and the nausea/vomiting associated with a high maximum plasma concentration (Cmax). Inhalation is an alternative to intravenous dosing. The surface area of the lung allows for rapid absorption of a self-administered dose. This study evaluated the safety, tolerability, and systemic pharmacokinetics (PK) of a dry powder formulation (PUR3100) DHE when delivered via inhalation compared to intravenous delivery. In this double-blind, double-dummy Phase 1 study, healthy volunteers (N = 26) were randomized (1:1:1:1) to one of four groups: orally inhaled placebo plus intravenous DHE 1.0 mg or orally inhaled PUR3100 (0.5, 1.0, or 1.5 mg) plus intravenous placebo. Blood samples were drawn pre-dose and at time points post-dose over 48 h. Standard PK and safety parameters were assessed and values for Cmax and area under plasma concentration time curve (AUC) were used to assess comparative exposures of PUR3100 versus intravenous DHE. All doses of PUR3100 were associated with a lower incidence of nausea (21% vs. 86%), vomiting (0% vs. 29%), and headache (16% vs. 57%) compared to intravenous DHE. The PK profile of PUR3100 versus intravenous DHE was characterized by a similar mean time to Cmax (5 vs. 5.5 min), with reduced AUC0-2h (1120-4320 vs. 6340), and a lower Cmax (3620-14,400 vs. 45,000). Compared to intravenous DHE 1.0 mg, the highest nominal PUR3100 dose (1.5 mg), which delivers a fine-particle dose of approximately 0.9 mg to the lungs, had a geometric mean ratio percentage (90% confidence interval [CI]) for Cmax of 32% [17.2, 59.6] and AUC0-inf of 93% (62.9, 138.5), the latter of which was not significantly different. Inhaled PUR3100 is associated with rapid systemic PK within the therapeutic window and an improved safety profile relative to intravenous DHE.

The expanding universe of the geometric mean

AbstractIn this paper the authors seek to trace in an accessible fashion the rapid recent development of the theory of the matrix geometric mean in the cone of positive definite matrices up through the closely related operator geometric mean in the positive cone of a unital $$C^*$$ C ∗ -algebra. The story begins with the two-variable matrix geometric mean, moves to the breakthrough developments in the multivariable matrix setting, the main focus of the paper, and then on to the extension to the positive cone of the $$C^*$$ C ∗ -algebra of operators on a Hilbert space, even to general unital $$C^*$$ C ∗ -algebras, and finally to the consideration of barycentric maps that grow out of the geometric mean on the space of integrable probability measures on the positive cone. Besides expected tools from linear algebra and operator theory, one observes a surprisingly substantial interplay with geometrical notions in metric spaces, particularly the notion of nonpositive curvature. Added features include a glance at the probabilistic theory of random variables with values in a metric space of nonpositive curvature, and the appearance of related means such as the inductive and power means. The authors also consider in a much briefer fashion the extension of the theory to the setting of Lie groups and briefer still to the positive symmetric cones of finite-dimensional Euclidean Jordan algebras.

Effect of Food, Crushing of Tablets, and Antacid Coadministration on Maribavir Pharmacokinetics in Healthy Adult Participants: Results From 2 Phase 1, Open-Label, Randomized, Crossover Studies.

The effect of food composition, tablet crushing, and antacid coadministration on maribavir pharmacokinetics was assessed in 2 Phase 1 studies in healthy adults. In the first, a single maribavir 400-mg dose was administered under fasting conditions, with a low-fat/low-calorie or a high-fat/high-calorie meal. In the second, a single maribavir 100-mg dose was administered under fasting conditions, as a crushed tablet, or as a whole tablet alone or with an antacid. The 90% confidence intervals of the geometric mean ratios were within 80%-125% for area under the concentration-time curve (AUC), but not for maximum plasma concentration (Cmax) for low-fat/low-calorie and high-fat/high-calorie meals versus fasting or for whole tablet with antacid versus whole tablet alone. The 90% confidence intervals of the geometric mean ratios for AUC and Cmax were within 80%-125% for crushed versus whole tablet. Maribavir median time to Cmax value in plasma under fed conditions was delayed versus fasting conditions, but there was no statistical difference for crushed versus whole tablet or with versus without antacid. As the antiviral efficacy of maribavir is driven by AUC but not Cmax, findings suggest that maribavir can be administered with food or antacids or as a crushed tablet.

Environmental phenol exposures in 6- to 12-week-old infants: The Infant Feeding and Early Development (IFED) study

BackgroundExposure to phenols, endocrine-disrupting chemicals used in personal care and consumer products, is widespread. Data on infant exposures are limited despite heightened sensitivity to endocrine disruption during this developmental period. We aimed to describe distributions and predictors of urinary phenol concentrations among U.S. infants ages 6–12 weeks. MethodsThe Infant Feeding and Early Development (IFED) study is a prospective cohort study of healthy term infants enrolled during 2010–2013 in the Philadelphia region. We measured concentrations of seven phenols in 352 urine samples collected during the 6- or 8- and/or 12-week study visits from 199 infants. We used linear mixed models to estimate associations of maternal, sociodemographic, infant, and sample characteristics with natural-log transformed, creatinine-standardized phenol concentrations and present results as mean percent change from the reference level. ResultsMedian concentrations (μg/L) were 311 for methylparaben, 10.3 for propylparaben, 3.6 for benzophenone-3, 2.1 for triclosan, 1.0 for 2,5-dichlorophenol, 0.7 for BPA, and 0.3 for 2,4-dichlorophenol. Geometric mean methylparaben concentrations were approximately 10 times higher than published estimates for U.S. children ages 3–5 and 6–11 years, while propylparaben concentrations were 3–4 times higher. Infants of Black mothers had higher concentrations of BPA (83%), methylparaben (121%), propylparaben (218%), and 2,5-dichorophenol (287%) and lower concentrations of benzophenone-3 (−77%) and triclosan (−53%) than infants of White mothers. Triclosan concentrations were higher in breastfed infants (176%) and lower in infants whose mothers had a high school education or less (−62%). Phenol concentrations were generally higher in summer samples. ConclusionsWidespread exposure to select environmental phenols among this cohort of healthy U.S. infants, including much higher paraben concentrations compared to those reported for U.S. children, supports the importance of expanding population-based biomonitoring programs to infants and toddlers. Future investigation of exposure sources is warranted to identify opportunities to minimize exposures during these sensitive periods of development.

Cariprazine Orodispersible Tablet: A New Formulation for Cariprazine.

Cariprazine is an atypical dopamine receptor partial agonist antipsychotic available in the form of capsules. Although capsules are one of the most desirable routes of administration, there are certain situations (e. g., in an acute psychiatric setting, or when swallowing difficulties, or liquid shortages are present) when they cannot be administered. Therefore, alternative solutions like orodispersible tablets are needed. This study aimed to investigate the bioequivalence of a newly developed orodispersible tablet to the commercially available hard gelatine capsule of cariprazine 1.5 mg. This was a phase I, open-label, randomized, single-dose bioequivalence study. It had a 2-period, 2-sequence, cross-over design, where each subject received one test and one reference product in a randomized sequence, separated by a wash-out period of 55 days. Blood sampling was performed over 72 h after dosing. Cariprazine concentrations were analyzed by a validated HPLC-MS/MS method. Standard bioequivalence statistics was applied to PK parameters calculated by non-compartmental analysis. Safety measures were analyzed descriptively. Pharmacokinetic data of 43 healthy volunteers and safety data of 54 subjects was analyzed. Cariprazine AUC0-72h and Cmax geometric mean ratios were 117.76% and 100.88%, respectively. The 90% confidence intervals were within the pre-defined bioequivalence acceptance limits of 80.00% - 125.00%. Safety data was in line with the Summary of Product Characteristics of Cariprazine. The result of this clinical trial proved the bioequivalence of the new orodispersible tablet formulation when compared to hard gelatine capsules, enabling an alternative option for treatment of those suffering from schizophrenia.

Ultrapotent Broadly Neutralizing Human-llama Bispecific Antibodies against HIV-1.

Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV-1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion-stabilized HIV-1 envelope (Env) trimer, BG505 DS-SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4-binding site (CD4bs) of vulnerability. Two of the vaccine-elicited CD4bs-targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a-hinge region and human IgG1-constant region (G36×3-IgG2a and R27×3-IgG2a), neutralized 96% of a multiclade 208-strain panel at geometric mean IC80s of 0.314 and 0.033µg mL-1, respectively. Cryo-EM structures of these nanobodies in complex with Env trimer revealed the two nanobodies to neutralize HIV-1 by mimicking the recognition of the CD4 receptor. To enhance their neutralizing potency and breadth, nanobodies are linked to the light chain of the V2-apex-targeting broadly neutralizing antibody, CAP256V2LS. The resultant human-llama bispecific antibody CAP256L-R27×3LS exhibited ultrapotent neutralization and breadth exceeding other published HIV-1 broadly neutralizing antibodies, with pharmacokinetics determined in FcRn-Fc mice similar to the parent CAP256V2LS. Vaccine-elicited llama nanobodies, when combined with V2-apex broadly neutralizing antibodies, may therefore be able to fulfill anti-HIV-1 therapeutic and prophylactic clinical goals.

Effects of water temperature on soil aggregate stability between soils developed from different parent materials in the subtropical hilly area of China

Water temperature has an important effect on soil aggregate stability. In this study, six soils derived from different parent materials in the hilly region of southern China were selected, and the mean weight diameter (MWD), geometric mean diameter (GMD), and soil erodibility (K value) were measured under different water temperature conditions. The aim of this study was to investigate the influence of water temperature on soil aggregate stability and erodibility. As the water temperature increased from 5 °C to 40 °C, the average content of >5 mm water-stable aggregates decreased by 57.13 %, while the average content of <0.25 mm water-stable aggregates increased by 214.41 %. The MWD and GMD of the six different parent soil types exhibited a decreasing trend with increasing water temperature. The trend of the K value was opposite to that of these values. The influence of water temperature on soil aggregate stability is mainly attributed to the thermal effect on the viscosity of soil water and the expansion of clay minerals. As the water temperature increases, the water viscosity coefficient, water density and water surface tension gradually decrease. Moreover, the response of soil aggregate stability and erosion resistance to water temperature varies with soil depth and parent material type. The topsoil exhibits greater sensitivity to water temperature than does the subsoil. Shale (SH) soils and quartz sandstone (QS) soils exhibited higher sensitivities, and Quaternary red clay (QRC) soils exhibited the lowest sensitivity to water temperature among the six soils. This difference is mainly attributed to differences in the contents of expansive clay minerals and organic matter. These results indicate that soil aggregate stability and erosion resistance decrease with increasing water temperature, which may be one reason for severe soil erosion under extremely high temperature and rainfall conditions in the southern red soil hilly region during summer.

Safety of marketed biosimilar monoclonal antibody cancer treatments in the US: a disproportionality analysis using the food and drug administration adverse event reporting system (FAERS) database

ABSTRACT Background By 31 December 2022, the United States Food and Drug Administration (FDA) has approved 12 biosimilar monoclonal antibody cancer treatments. This study detected disproportionate adverse event (AE) reporting signals and compared safety profile of individual biosimilars to their originator biologics and between each pair of biosimilars. Research design and methods The FDA Adverse Event Reporting System data (6/1/2018–12/31/2022) were used to identify AE reports for rituximab, bevacizumab, trastuzumab, and their marketed biosimilars. Reporting odds ratios and empirical Bayesian geometric mean were computed to detect reporting disproportionality in serious, death, and specific AEs between studied biologics/biosimilars and all other drugs. Results Significant AE reporting signals were identified: 1) death for biological rituximab, pruritus for biosimilar rituximab-pvvr, and infusion-related reactions for biological rituximab and biosimilar rituximab-pvvr (significantly higher ROR for rituximab-pvvr than biological rituximab, p < .0001); 2) death for biological bevacizumab and biosimilar bevacizumab-bvzr (significantly higher ROR for bevacizumab-bvzr than biological bevacizumab, p < .0001), hypertension, platelet count decreased (PCD), and proteinuria for biological bevacizumab and biosimilar bevacizumab-awwb (significantly higher ROR of PCD for bevacizumab-awwb than originator bevacizumab, p = .001); and 3) rash for biosimilar trastuzumab-anns. Conclusions Findings call for large, longitudinal studies to examine causality of certain AEs with rituximab-pvvr and bevacizumab biosimilars.