Mean Ratio Research Articles

HLA class I expression on human platelets is highly variable and correlates with distinct allele group frequencies.

Human leukocyte antigen (HLA) class I molecules are expressed on platelets and can represent a source of alloimmunization in recipients of platelet transfusions. HLA mismatch between donors and recipients may be associated with the induction of anti-HLA antibodies, which can culminate in refractoriness to platelet transfusions. In the present study we analyzed HLA allele group frequencies and HLA expression levels on human platelets from blood donors. Platelet-rich plasma was collected from 139 donors to monitor platelet HLA class I expression by flow cytometry. DNA from donors with high and low platelet HLA expression was used in the genotype studies. Frequencies of large and normal-sized platelet subpopulations were determined and HLA class I expression was studied. Mean platelet volume (MPV) and platelet large-cell ratio (P-LCR) were analyzed in both groups of donors. The analysis showed variable platelet HLA class I expression with significant differences among donors. HLA class I allele group frequencies in donors with high and low platelet HLA expression showed distinctive genotypic features strictly related to expression level. The main allele groups found in samples with high platelet HLA class I expression were HLA-A*02, -A*68, -B*15, -B*49, and -C*03. Platelet HLA class I expression did not change over time or during freezing-thawing cycles. The analysis of platelet subpopulations showed a statistically significant higher expression of HLA class I molecules on large platelets than on normal-sized platelets. Moreover, donors with high HLA class I expression showed a higher frequency of large platelets (p<0.0001). The analysis of P-LCR in both groups of donors showed a statistically significant difference (p<0.05) within high HLA-expressing donors. Our data suggest an allele-dependent expression of HLA class I molecules on human platelets with distinct HLA allele group frequencies and different platelet subpopulation frequencies among blood donors.

Safety and immunogenicity of a single-dose omicron-containing COVID-19 vaccination in adolescents: an open-label, single-arm, phase 2/3 trial

Most individuals show immunity to SARS-CoV-2 from vaccination or infection, or both. We aimed to determine the safety and immunogenicity of an omicron-containing COVID-19 vaccine (mRNA-1273.222) in vaccine-naive adolescents who were SARS-CoV-2 positive. Part 3 of the phase 2/3 TeenCOVE trial was a phase 3, open-label, single-arm part done in the USA and the Dominican Republic that enrolled healthy, vaccine-naive adolescents (aged 12-17 years) to receive two 50 μg doses of mRNA-1273.222 (ancestral strain Wuhan-Hu-1 and omicron subvariants BA.4 and BA.5), 6 months apart. Primary reactogenicity and safety outcomes included assessment of solicited local or systemic adverse reactions 7 days after vaccination, and unsolicited and prespecified adverse events throughout study participation. Inferred effectiveness (primary immunogenicity outcome) was established by comparing neutralising antibody responses 28 days after dose 1 of mRNA-1273.222 in SARS-CoV-2-positive adolescents with responses 28 days after dose 2 of mRNA-1273 100 μg primary series in SARS-CoV-2-negative young adults (aged 18-25 years) from the COVE trial. This study is registered with ClinicalTrials.gov (NCT04649151). Between Dec 21, 2022, and June 5, 2023, 379 adolescents (378 of whom were SARS-CoV-2 positive) received at least one mRNA-1273.222 dose and were included in the safety analysis set. The reactogenicity profile was favourable compared with the mRNA-1273 primary series, with no new safety concerns identified. Unsolicited adverse events were reported in 49 (13%) of 379 participants; no deaths or adverse events leading to study discontinuation were reported. The immunogenicity set included 245 adolescents from the per-protocol immunogenicity subset who were SARS-CoV-2 positive at baseline and 296 young adults who were SARS-CoV-2 negative. Compared with the mRNA-1273 primary series in SARS-CoV-2-negative young adults, a single dose of mRNA-1273.222 induced superior (geometric mean ratio [GMR] 95% CI lower bound >1) neutralising antibody responses against omicron BA.4 and BA.5 (GMR 48·95 [95% CI 44·21-54·21]) and non-inferior (GMR 95% CI lower bound >0·667) neutralising antibody responses against ancestral SARS-CoV-2 (GMR 4·25 [95% CI 3·69-4·88]) in SARS-CoV-2-positive adolescents. In vaccine-naive, SARS-CoV-2-positive adolescents, single-dose mRNA-1273.222 was effective against COVID-19 based on successful immunobridging to the two-dose mRNA-1273 primary series in young adults. The findings support a simplified single-dose vaccination schedule with variant-containing mRNA vaccines, regardless of previous vaccination status. Moderna.

Clinical Assessment of Breast Cancer Resistance Protein (BCRP)-Mediated Drug-Drug Interactions of Sepiapterin with Curcumin and Rosuvastatin in Healthy Volunteers.

Sepiapterin, also known as PTC923 and CNSA-001, is a synthetic form of endogenous sepiapterin being developed as a novel oral treatment for phenylketonuria. Sepiapterin is a natural precursor of tetrahydrobiopterin (BH4) and, when orally administered, is converted to BH4 via the pterin salvage pathway. In vitro studies have demonstrated that both sepiapterin and BH4 are both substrates and inhibitors of the breast cancer resistance protein (BCRP) transporter. This phase I study investigated BCRP-mediated drug-drug interactions of sepiapterin as a victim and as a perpetrator. An open-label, fixed-sequence, four-period, crossover, single-dose study was conducted in adult male and female healthy volunteers (18-55 years of age). In a given treatment period, subjects received a single oral dose of sepiapterin (20 mg/kg), sepiapterin (20 mg/kg) plus curcumin (2 g), rosuvastatin (10 mg), or rosuvastatin (10 mg) plus sepiapterin (60 mg/kg). The pharmacokinetics of sepiapterin, its metabolite BH4, and rosuvastatin were studied, and geometric mean ratios of exposures in the presence and absence of the BCRP inhibitor curcumin or sepiapterin were estimated. The presence of the BCRP c.421C>A polymorphism was evaluated in all subjects. A total of 29 subjects were enrolled and included in the safety analysis. Among them, 26 subjects were included in the pharmacokinetic and drug-drug interaction analyses. Following oral administration20 mg/kg sepiapterin, sepiapterin was rapidly and extensively converted to BH4, and BH4 maximum observed concentration (415.0 ng/mL) was observed 4.95 h (time to maximum observed concentration) post-dose. Sepiapterin maximum observed concentration and area under the concentration-time curve from time 0 to time of the last quantifiable measurement or the last sample collection time (AUClast) were <1% of BH4 values. Coadministration of the BCRP inhibitor curcumin (2 g) increased BH4 maximum observed concentration, AUClast, and area under the concentration-time curve from time 0 extrapolated to infinity by 24%, 21%, and 20%, respectively. When sepiapterin was coadministered with the BCRP substrate rosuvastatin, there was no effect on the pharmacokinetics of rosuvastatin. BCRP c.421C/A carriers (n = 4) had higher plasma exposures of BH4 (1.39 × for AUClast) and rosuvastatin (1.61 × for AUClast) than c.421C/C carriers (n = 22). Greater increases in BH4 exposures (1.33 vs 1.18 for AUClast) were observed in c.421C/A carriers compared with c.421C/C carriers when sepiapterin was coadministered with curcumin. All treatments were well tolerated during the study. Oral coadministration of the BCRP inhibitor curcumin slightly increased the plasma exposure of sepiapterin and its metabolite BH4 in healthy volunteers. This modest increase was deemed not clinically meaningful. Sepiapterin did not alter the pharmacokinetics of the BCRP substrate rosuvastatin.

EXPOSURE EFFECTS ON COUNT OUTCOMES WITH OBSERVATIONAL DATA, WITH APPLICATION TO INCARCERATED WOMEN.

Causal inference methods can be applied to estimate the effect of a point exposure or treatment on an outcome of interest using data from observational studies. For example, in the Women's Interagency HIV Study, it is of interest to understand the effects of incarceration on the number of sexual partners and the number of cigarettes smoked after incarceration. In settings like this where the outcome is a count, the estimand is often the causal mean ratio, i.e., the ratio of the counterfactual mean count under exposure to the counterfactual mean count under no exposure. This paper considers estimators of the causal mean ratio based on inverse probability of treatment weights, the parametric g-formula, and doubly robust estimation, each of which can account for overdispersion, zero-inflation, and heaping in the measured outcome. Methods are compared in simulations and are applied to data from the Women's Interagency HIV Study.

Subcutaneous versus intravenous nivolumab for renal cell carcinoma

The evolving oncology treatment paradigm has created an unmet need for administration options that improve patient experiences and health care efficiencies. CheckMate 67T (NCT04810078) was a phase III, open-label, multicenter, noninferiority trial in which patients with advanced/metastatic clear cell renal cell carcinoma were randomized to subcutaneous nivolumab (1200 mg every 4 weeks; coformulated with recombinant human hyaluronidase PH20 20 000 units) or intravenous nivolumab (3 mg/kg every 2 weeks). The primary objective was to assess the noninferiority of subcutaneous versus intravenous nivolumab by coprimary endpoints determined from a population pharmacokinetics analysis [time-averaged serum concentration over the first 28 days (Cavgd28), and minimum steady-state serum concentration (Cminss); noninferiority threshold: lower boundary of 90% confidence interval (CI) of the geometric mean ratios (GMR) ≥0.8]. Objective response rate (ORR) was a key secondary endpoint powered for noninferiority [noninferiority threshold: lower boundary of 95% CI of relative risk of ORR (subcutaneous versus intravenous nivolumab) ≥0.60]. Overall, 495 patients were randomized. Relative exposure in the subcutaneous versus intravenous arm reported by the GMR of Cavgd28 and Cminss was 2.098 (90% CI 2.001-2.200) and 1.774 (90% CI 1.633-1.927), respectively. After 8 months of minimum follow-up, ORR was 24.2% with subcutaneous nivolumab (95% CI 19.0%-30.0%) versus 18.2% with intravenous nivolumab [95% CI 13.6%-23.6%; relative risk: 1.33 (95% CI 0.94-1.87)]. Coprimary endpoints and ORR met noninferiority thresholds. Additional efficacy and safety measures were similar. Subcutaneous nivolumab was noninferior to intravenous nivolumab based on pharmacokinetics and ORR. No new safety signals were observed.

MB09, a denosumab biosimilar candidate: Biosimilarity demonstration in a phase I study in healthy subjects.

This was a Phase I, randomized, double-blinded, three-arm, single-dose, parallel study aimed to demonstrate pharmacokinetic (PK) similarity between MB09 (a denosumab biosimilar candidate) and reference denosumab (XGEVA® from European Union [EU-reference] and United States [US-reference]) in a healthy male population. The primary PK endpoints included: Area under the serum concentration versus time curve from time 0 to the last quantifiable concentration timepoint (AUC0-last); and maximum observed serum concentration (Cmax). Secondary endpoints included: AUC from time 0 extrapolated to infinity (AUC0-∞), time to reach maximum observed concentration, clearance, terminal phase half-life, pharmacodynamic, safety, and immunogenicity assessments. A total of 255 subjects were randomized (1:1:1) to receive a subcutaneous 35 mg dose of MB09 or reference denosumab. Cmax was reached after denosumab administration, followed by a decline in the concentration with similar terminal phase half-live across treatment arms. Systemic exposure of MB09 (AUC0-last and Cmax) was equivalent to the reference denosumab, as the 90% confidence intervals around the geometric least square mean ratios laid within the predefined acceptance limits (80.00%, 125.00%) across all comparisons. Pharmacodynamic parameters, based on the percent of change from baseline in serum C-terminal telopeptide of Type 1 collagen levels, were similar across the three arms. The treatments were considered safe and generally well tolerated, with 92 treatment-emergent adverse events reported (most Grade 2 and 3) and similarly distributed. Immunogenicity was low and similarly distributed. These results provide strong evidence that supports the biosimilarity between MB09 and denosumab reference products.

Effect of SARS-CoV-2 on semen parameters: A meta-analysis of 39 articles from 15 countries.

Declining birth rates during the pandemic have led to concerns about the potential impact of the of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on fertility among men. As previous studies have had inconsistent conclusions, we conducted a meta-analysis to evaluate the effects of SARS-CoV-2 on semen parameters. We searched several databases for articles published between 1 January 2020 and 25 July 2023. We performed a robust screening process based on predetermined inclusion and exclusion criteria and, following quality assessment, extracted data from high-quality studies for the meta-analysis. We determined the P-values and 95% confidence intervals (CIs) for both continuous and dichotomous variables, which we described using mean differences (MDs) and odds ratios (ORs), respectively. Lastly, we used the leave-one-out approach for our sensitivity analysis, and Begg's and Egger's tests to determine publication bias. We included 39 articles with 1887 cases and 2097 controls. In patients infected with SARS-CoV-2, the sperm volume (MD = -0.29; 95% CI = -0.50, -0.07; P = 0.008) and concentration (MD = -8.71; 95% CI = -16.94, -0.48; P = 0.04) were decreased, which increased oligospermia risk (OR = 2.49; 95% CI = 1.04, 5.99; P = 0.04). Furthermore, we observed reduced sperm motility (MD = -8.18; 95% CI = -12.19, -4.17; P < 0.001) and increased immotility (MD = 4.06; 95% CI = 1.57, 6.54; P = 0.001) in infected patients, which increased asthenospermia risk (OR = 3.86; 95%CI = 1.83, 8.14; P = 0.0004). We also saw a decreased proportion of semen with normal sperm morphology (MD = -1.67; 95% CI = -2.68, -0.66; P = 0.001) and an increased proportion of semen with abnormal sperm morphology (MD = -1.31; 95% CI = -2.14, -0.49; P = 0.002,), along with increases in teratospermia (OR = 1.98; 95% CI = 1.00, 3.92; P = 0.05) in infected compared non-infected patients. Although we found consistency within most subgroups, we observed differences in severity, follow-up time, and country of origin. The results of the main meta-analysis results remained stable in the sensitivity analysis, while Begg's and Egger's tests showed no publication bias. Based on sufficient evidence, we see that the effects of SARS-CoV-2 on semen parameters resulted in a decline in male fertility. The increased severity and shorter duration of the SARS-CoV-2 infection increased the likelihood of altering of semen parameters. INPLASY: INPLASY202420083.

Burst steroid therapy for acute heart failure: The CORTAHF randomized, open-label, pilot trial.

Burst steroid therapy, effective in acute respiratory diseases, may benefit patients with acute heart failure (AHF) in whom inflammatory activation is associated with adverse outcomes. CORTAHF assessed whether burst steroid therapy reduces inflammation and results in better quality of life and clinical outcomes in AHF. Patients with AHF, N-terminal pro-B-type natriuretic peptide >1500 pg/ml, and high-sensitivity C-reactive protein (hsCRP) >20 mg/L were randomized 1:1 to oral, once daily 40 mg prednisone for 7 days or usual care, without blinding. Patients were followed for 90 days. A total of 101 patients were randomized. At day 7 the primary endpoint, hsCRP decreased in both arms-adjusted geometric mean ratios (GMRs) were 0.30 and 0.40 in the prednisone and usual care arms (ratio of GMRs 0.75, 95% confidence interval [CI] 0.56-1.00, p = 0.0498). The 90-day risk of worsening heart failure (HF), HF readmission or death as reported by the unblinded investigators was significantly lower in the prednisone group (10.4%) than in usual care (30.8%) (hazard ratio 0.31, 95% CI 0.11-0.86, p = 0.016). The EQ-5D visual analogue scale score as reported by the unblinded patients increased more in the prednisone group on day 7 (least squares mean difference 2.57, 95% CI 0.12-5.01 points, p = 0.040). All effects were statistically significant in the pre-specified subgroup with centrally-measured interleukin-6 >13 pg/ml. Adverse events, particularly hyperglycaemia, occurred more in the prednisone group with no difference in infection rate. In this small open-label study of patients with AHF, burst steroid therapy was associated with reduced inflammation as measured by hsCRP levels at day 7 (primary endpoint). Secondary endpoints showed improved quality of life at day 7 and reduced 90-day risk of death or worsening HF. Large prospective studies are needed to evaluate these findings.

Machine learning-based prediction method for drying shrinkage of recycled aggregate concrete

The objective of this study is to develop a broadly applicable, high-precision, and robust prediction model for the drying shrinkage of recycled aggregate concrete, a material that exhibits significantly greater shrinkage compared to natural aggregate concrete due to its complex characteristics. To achieve this, the study began by selecting relevant characteristic parameters based on international concrete codes, followed by the application of various machine learning algorithms including Backpropagation Neural Network, Support Vector Machine, Random Forest, eXtreme Gradient Boosting, Gaussian Process Regression, k-Nearest Neighbor, Linear Regression, and Long Short-Term Memory to model and forecast the drying shrinkage of recycled aggregate concrete. Subsequently, the SHapley Additive exPlanations (SHAP) method was employed to identify the crucial factors influencing RAC drying shrinkage, such as drying age, elastic modulus, and water-binder ratio, thereby optimizing the input parameters of the ML model. To further enhance the XGBoost algorithm, the sparrow search algorithm (SSA) and the whale optimization algorithm (WOA) were utilized. The optimized WOA-XGBoost model exhibits superior predictive performance, with a determination coefficient of 0.980 and a mean ratio of predicted to experimental values of 1.025, significantly outperforming traditional specification models. The model's applicability may be limited since the dataset is mainly derived from laboratory conditions, which may differ from actual engineering environments. Future research could consider different types of recycled aggregates and curing conditions and test the model on larger data sets to improve its robustness and applicability.

Unusual morphology of an aberrant right subclavian artery: a case report and systematic review of cadaveric studies .

An aberrant right subclavian artery (ARSA) is a rare vascular anomaly defined by the origin of the right subclavian artery from the aorta, distal to the left subclavian artery (LSA). An ARSA was found in an 83-year-old female during cadaveric dissection for anatomy teaching, which had an unusually narrow lumen compared to previously reported cases. The specific morphology of this ARSA variant was characterised by further dissection and measurements. A systematic review of cadaveric case reports with quantitative evaluation of ARSA dimensions was conducted for comparison with this case. This ARSA variant exhibited an unusually narrow lumen (8.22 mm²) compared to the LSA (152.55²), with an ARSA: LSA ratio of 0.24. The systematic review included 17 studies with 23 cases of ARSAs. Of these cases, 20 contained details of ARSA diameter, 19 of which were wider than in this case. In all studies where both ARSA and LSA diameters were measured, ARSA was found to be significantly wider than LSA (mean ratio of ARSA to LSA: 1.49, range: 1.09-2.00). Several other variations were reported in these studies, such as concomitant aortic arch branch anomalies and differing origins of ARSA as defined by vertebral level and relation to the aortic arch. This case report presents an unusually narrow ARSA which has not been previously described in the literature. As there is limited evidence on how ARSA morphology affects clinical outcomes, further research is needed to better inform management of ARSAs.

Associations of hair cortisol levels with violence, poor mental health, and harmful alcohol and other substance use among female sex workers in Nairobi, Kenya

Violence, poor mental health, and harmful substance use are commonly experienced by female sex workers (FSWs) in sub-Saharan Africa, all of which are associated with increased HIV susceptibility. We aimed to investigate the associations between violence, poor mental health and harmful alcohol/substance use with hair cortisol concentration (HCC) levels as a potential biological pathway linking the experiences of these stressors and HIV vulnerability. We used the baseline data of the Maisha Fiti study of FSWs in Nairobi, Kenya. Participants reported recent violence, poor mental health, and harmful alcohol/substance use. Hair samples proximal to the scalp were collected to measure cortisol levels determined by ELISA. We analysed the data of 425 HIV-negative respondents who provided at least 2 cm of hair sample. The prevalence of recent violence was 89.3% (physical 54.6%; sexual 49.4%; emotional 77.0% and financial 66.5%), and 29.1% had been arrested due to sex work. 23.7% of participants reported moderate/severe depression, 11.6% moderate/severe anxiety, 13.5% PTSD and 10.8% recent suicidal thoughts and/or attempts. About half of the participants (48.8%) reported recent harmful alcohol and/or other substance use. In multivariable linear regression analyses, both physical and/or sexual violence (adjusted geometric mean ratio (aGMR) = 1.28; 95% CI 1.01–1.62) and harmful alcohol and/or other substance use (aGMR = 1.31; 95% CI 1.03–1.65) were positively and independently associated with increased HCC levels. Findings suggest a role of violence and substance use in elevated HCC levels, which could increase HIV risk due to cortisol-related T cell activation. However, longitudinal and mechanistic studies are needed to confirm this hypothesis.

Pharmacokinetic Evaluation of Amlodipine Tablet Compared with Norvask® Tablet in Healthy Indonesian Adults

This study objective to evaluate the pharmacokinetics of Amlodipine 10 mg Produced by PT. Tropica Mas Pharmaceuticals compared to Norvask® 10 mg Tablet Produced by PT. Pfizer Indonesia, in healthy Indonesian Adults through bioequivalence study. This study is utilized by randomized, single-dose, openlabel, two-way cross-over design with a washout period 14 days and fasting. This study involved 18 subjects, with only 17 subjects included in the statistical analysis, because 1 subject withdrew due to diarrhoea in the 2nd period. Plasma samples were collected 17 times for 72-hour per period. Amlodipine concentrations were measured using LCMS/MS. Bioequivalence was determined by value of 90% confidence interval (CI) with α = 5.00% within the range of 80.00–125.00% for AUC and Cmax. The geometric mean ratios (90% CI) of the test drug vs. the innovator drug were 101.67% (97.16 – 106.39) for AUC0-t and 100.46% (95.00 – 106.23) for Cmax. Based on the result, the test drug is bioequivalent to the comparator drug.

Comparative clinical efficacy and safety of biosimilar ABP 959 and eculizumab reference product in patients with paroxysmal nocturnal hemoglobinuria.

ABP 959 is a biosimilar to the eculizumab reference product (RP), which is approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH). This multicenter, randomized, double-blind, active-controlled, two-period crossover study randomized eculizumab RP-treated patients with PNH to one of two treatment sequences (ABP 959/eculizumab RP or eculizumab RP/ABP 959) to evaluate the clinical similarity of ABP 959 when compared with eculizumab RP. This study evaluated the efficacy of ABP 959 when compared with eculizumab RP based on control of intravascular hemolysis as measured by lactate dehydrogenase (LDH) and by the time-adjusted area under the effect curve of LDH. Secondary outcomes included safety, pharmacokinetics, and immunogenicity. Forty-two patients were randomized (20 in the ABP 959/eculizumab RP group and 22 in the eculizumab RP/ABP 959 group) across 25 centers. Similarity of efficacy was established by a ratio of geometric least squares means of LDH (ABP 959/eculizumab RP) of 1.0628, with a one-sided 97.5% upper CI of 1.1576 at week 27, and a geometric means ratio of time-adjusted area under the effect curve (ABP 959 vs. eculizumab RP) of LDH of 0.981, with a 90% CI of 0.9403-1.0239 from week 13 to 27, week 39 to 53, and week 65 to 79. All secondary efficacy endpoints were comparable between treatment groups. No new safety concerns were identified. The results of this study in patients with PNH, along with previously demonstrated similarity of analytical, nonclinical, and clinical pharmacokinetics and pharmacodynamics in healthy volunteers support a demonstration of no clinically meaningful differences between ABP 959 and eculizumab RP. Clinical Trial Registration: NCT03818607.

Effects of individualized positive end-expiratory pressure on intraoperative oxygenation and postoperative pulmonary complications in patients requiring pneumoperitoneum with Trendelenburg position: A systematic review and meta-analysis.

Whether individualized positive end-expiratory pressure (PEEP) improves intraoperative oxygenation and reduces postoperative pulmonary complications (PPCs) remains unclear. This systematic review and meta-analysis examined whether individualized PEEP is associated with improved intraoperative oxygenation and reduce PPCs for patients needing pneumoperitoneum with the Trendelenburg position during surgery. Medline, Embase, the Cochrane Library, and www.clinicaltrials.gov were searched for randomized controlled trials evaluating the effects of individualized PEEP on intraoperative oxygenation and PPCs in patients who required Trendelenburg positioning with pneumoperitoneum. The primary outcome was the oxygenation (PaO2/FiO2) during the procedure. Secondary outcomes included PPCs, intraoperative respiratory mechanics (driving pressure, compliance), and vasopressor consumption. DerSimonian-Laird random effects models were used to calculate mean differences (MDs) and log risk ratios (log RRs) with 95% confidence intervals (CIs). The Cochrane Risk-of-Bias tool 2.0 was applied to assess the risk of bias in included studies. The protocol of this meta-analysis has been registered in PROSPERO. We included 14 studies (1121 patients) that employed different individualized PEEP strategies. Compared with control groups, individualized PEEP groups exhibited a significantly improved intraoperative PaO2/FiO2 (MD=56.52mm Hg, 95% CI: [33.98, 79.06], P<0.001) and reduced incidence of PPCs (log RR=-0.50, 95% CI: [-0.84, -0.16], P=0.004). Individualized PEEP reduced driving pressure while improving respiratory compliance. Intraoperative vasopressor consumption was similar between both groups. The weighted mean PEEP in the individual PEEP groups was 13.2 [95% CI, 11.7, 14.6] cmH2O. No evidence indicated that one individualized PEEP strategy is superior to others. Individualized PEEP seems to work positively for lung protection in the Trendelenburg position and pneumoperitoneum in patients undergoing general anesthesia.

Equivalence of freeze-dried and liquid-frozen formulations of MVA-BN as smallpox and mpox vaccine

ABSTRACT Modified Vaccinia Ankara Bavarian Nordic (MVA-BN) as a smallpox and mpox vaccine has been approved in its liquid-frozen (LF) formulation in the US, Canada, and EU. A freeze-dried (FD) formulation may offer additional benefits, such as a longer shelf life and reduced dependence on cold chain storage and transport. In a phase 2 clinical trial, 651 vaccinia-naïve participants were vaccinated with two doses of MVA-BN LF or FD, 4 weeks apart. The objectives were to compare MVA-BN FD with LF in terms of vaccine-induced immune responses, safety, and reactogenicity. Non-inferiority of the immune response was assessed by the 95% CI of the geometric mean ratios. Both formulations induced robust vaccinia-specific humoral and cellular immune responses. At peak humoral responses (Week 6), geometric means of total antibody titers were 1096 (95% CI 1013, 1186) from the FD group and 877 (95% CI 804, 956) from the LF group, achieving the primary endpoint of non-inferiority of MVA-BN FD compared to MVA-BN LF. At peak cellular responses (Week 2), geometric means of T cell spot forming units were 449 (95% CI 341, 590) from the FD group and 316 (95% CI 234, 427) from the LF group. Both formulations of MVA-BN were well tolerated, with similar unsolicited AEs and solicited systemic reactions in both groups but slightly more local reactions in the FD group. No vaccine-related serious adverse events (SAEs) or vaccine-related AE of special interest were reported. The FD formulation of MVA-BN was shown to be equivalent to MVA-BN LF.

Correlation Between Serum and CSF Concentrations of Midazolam and 1-Hydroxy-Midazolam in Critically Ill Neurosurgical Patients.

Midazolam (MZ) is commonly used in critically ill neurosurgical patients. Neuro-penetration of MZ and its metabolite, 1-hydroxy-midazolam (1-OH-MZ), is not well characterized. This study evaluated correlations between serum and cerebrospinal fluid (CSF) concentrations of MZ and 1-OH-MZ and assessed implications on patient sedation. Adults in the neurosurgical intensive care unit (ICU) with external ventricular drains receiving MZ via continuous infusion were prospectively studied. Serum and CSF samples were obtained 12-24 h and 72-96 h after initiation, and concentrations were determined in duplicate by high-performance liquid chromatography with tandem mass spectrometry. Bivariate correlation analyses used Pearson coefficient. A total of 31 serum and CSF samples were obtained from 18 subjects. At sampling, mean MZ infusion rate was 3.9 ± 4.4 mg/h, and previous 12-h cumulative dose was 51.4 ± 78.2 mg. Mean concentrations of MZ and 1-OH-MZ in serum and CSF were similar between timepoints. Similarly, ratios of 1-OH-MZ to MZ in serum and CSF remained stable over time. Serum MZ (126.2 ± 89.3 ng/mL) showed moderate correlation (r2 = 0.68, P < 0.001) with serum 1-OH-MZ (17.7 ± 17.6 ng/mL) but not CSF MZ (3.9 ± 2.5 ng/mL; r2 = 0.24, P = 0.005) or CSF 1-OH-MZ (2.5 ± 0.6 ng/mL; r2 = 0.47, P = 0.30). CSF MZ did not correlate with CSF 1-OH-MZ (r2 = 0.003, P < 0.001). Mean serum ratio of 1-OH-MZ to MZ (0.14 ± 0.2 ng/mL) did not correlate with CSF ratio (1.06 ± 0.83 ng/mL; r2 = 0.06, P = 0.19). Concentrations and ratios were unrelated to MZ infusion rate or 12-h cumulative dose. Sedation was weakly correlated with CSF 1-OH-MZ, but not with serum MZ, serum 1-OH-MZ, or CSF MZ. Continuous infusions of MZ result in measurable concentrations of MZ and 1-OH-MZ in CSF; however, CSF concentrations of MZ and 1-OH-MZ poorly represent serum concentrations or dosages. Accumulation of MZ and 1-OH-MZ in serum or CSF over time was not evident. Concentrations of MZ and 1-OH-MZ do not predict sedation levels, reinforcing that pharmacodynamic assessments are warranted.

Determinants of tree population temporal stability in a temperate mixed forest over a gradient of nitrogen addition

Nitrogen (N) deposition is a significant threat to the functioning of forests and negatively impacts the delivery of forest goods and services. Contemporary management approaches seek to adapt forests to such N-deposition stressors, but to date how plant populations in natural forests respond to N deposition and what factors determine the contrasting responses among populations are still unclear. Here, we investigated the impact of N-addition (control: 0 kg ha−1 yr−1; low: 25 kg ha−1 yr−1; medium: 50 kg ha−1 yr−1; high: 75 kg ha−1 ha yr−1) on tree population temporal stability and how initial tree size, mycorrhizal type, and leaf N content (LNC; as a surrogate for functional trait composition) mediate tree population responses to N-addition in a Korean pine and mixed broadleaved dominated temperate forest in northern China. We quantified tree species population temporal stability as the ratio of mean to standard deviation of the year-by-year stem increments recorded in individual trees from 2015 to 2022 experimental period. The results showed different temporal stabilities of tree species among four N-addition levels, with the highest population stability observed within the high N-addition plots. Furthermore, initial tree size had significantly (p < 0.001) positive effects on population temporal stability. The effect of LNC and initial tree size were also contingent on the level of N applied. Specifically, increase in tree population LNC reduced population temporal stability in all plots where N was added. Our results imply that retention of large-sized trees and species with resource-conservative strategies (e.g., low LNC) could enhance forest stability under N deposition.

Pharmacokinetics and Safety of Linezolid Tablets of 2 Different Manufacturers in Healthy Chinese Subjects in Fasting and Fed States.

This study aimed to evaluate the pharmacokinetics (PKs) and safety of a generic drug, linezolid, compared to those of a reference drug in healthy Chinese subjects under both fasting and fed conditions. This was a randomized, open-label, 2-period, 2-sequence crossover study. The subjects received a single dose of the test or reference drug, linezolid (600mg), in each period. The PK parameters were calculated using a non-compartmental method and compared between the 2 drugs. Bioequivalence was analyzed using geometric mean ratios (GMRs) of the 2 formulations and their corresponding 90% confidence intervals (CIs). The safety of the 2 formulations was assessed under both fasting and fed conditions. Forty-eight subjects completed the study, 24 each in the fasting and feeding groups. The average plasma concentration-time patterns of linezolid were similar for both medications under both conditions. The GMR and 90% CIs of the maximum plasma concentration and the area under the plasma concentration-time curve of linezolid were ranged from 0.80 to 1.25. Both drugs were well tolerated with a similar incidence of adverse drug reactions. In conclusion, the PK and safety profiles of the 2 formulations were comparable. Food intake did not influence the PK profiles of linezolid. These results suggest that the test drug can be used as an alternative to reference drugs.

Dicloxacillin is an inducer of intestinal P-glycoprotein but neither dicloxacillin nor flucloxacillin increases the risk of stroke/systemic embolism in direct oral anticoagulant users.

We aimed to assess if dicloxacillin/flucloxacillin reduces the therapeutic efficacy of direct oral anticoagulants (DOACs) and the underlying molecular mechanism. In a randomized, crossover study, we assessed whether dicloxacillin reduces oral absorption of drugs through P-glycoprotein (P-gp) during 10 and 28 days of treatment. To study the impact of dicloxacillin/flucloxacillin on intestinal and hepatic expression of P-gp in vitro, we usd LS174T cells and 3D spheroids of primary human hepatocytes. Finally, we used nationwide Danish health registries and the UK's Clinical Practice Research Datalink to estimate hazard ratios (HRs) for the risk of stroke and systemic embolism following dicloxacillin/flucloxacillin exposure among DOAC users, using phenoxymethylpenicillin and amoxicillin as active comparators. Dicloxacillin reduced the area under the curve of dabigatran to a geometric mean ratio 10days of 0.67 (95% confidence interval [CI]: 0.42-1.1) and geometric mean ratio 28 days of 0.72 (95% CI: 0.39-1.4), suggesting reduced oral absorption via increased P-gp expression. In vitro, dicloxacillin raised P-gp expression in both intestinal and liver cells, while flucloxacillin only affected liver cells. In the pharmacoepidemiologic study, dicloxacillin and flucloxacillin were not associated with increased risk of stroke/systemic embolism (dicloxacillin vs. phenoxymethylpenicillin HR: 0.93, 95% CI: 0.72-1.2; flucloxacillin vs. amoxicillin HR: 0.89, 95% CI: 0.51-1.5). Dicloxacillin increases expression of intestinal P-gp, leading to reduced oral absorption of dabigatran. However, concomitant use of dicloxacillin/flucloxacillin was not associated with stroke and systemic embolism among DOAC users, suggesting no clinical impact from the drug-drug interaction between dicloxacillin/flucloxacillin and DOACs.

Bioequivalence study of two formulations of afatinib dimaleate tablets in healthy subjects under fasting conditions: A randomized, open-label, single-dose, crossover trial.

To evaluate the bioequivalence of two different afatinib dimaleate formulations in healthy Chinese subjects under fasting conditions and to assess their pharmacokinetic and safety profiles. This randomized, open-label, 2-period, crossover, bioequivalence study included 32 healthy Chinese subjects. The subjects were assigned to receive a single 40-mg dose of generic or brand-named afatinib dimaleate tablet. Blood samples were collected pre-dose and up to 120hours after dosing. Healthy subjects orally took the trial preparation (T) (afatinib maleate tablets developed by Jiangxi Shanxiang Pharmaceutical Co., Ltd., Gan Zhou, China) and the reference preparation (R) (afatinib maleate tablets developed by Boehringer Ingelheim Pharma GmbH & Co., Ingelheim, Germany) under fasting conditions in the appropriate period according to the randomization. We measured the blood concentrations, calculated the pharmacokinetic parameters of the two preparations in the human body, and evaluated whether formulations were bioequivalent. Safety of the preparations in healthy subjects was monitored during the whole trial. Safety assessment was conducted by vital signs, physical examination, laboratory examination, and 12-lead electrocardiogram during the study, i.e., from the time the subject received the test drug to the end of the last visit. Under fasting conditions, the 90% confidence intervals (CIs) of the geometric mean ratios of the test/reference for afatinib dimaleate were 93.34 - 103.92% for AUC0-t, 90.26 - 105.52% for Cmax, and 93.49 - 104.05% for AUC0-∞. The 90% CI for the geometric mean ratios (test/reference) of Cmax, AUC0-t, and AUC0-∞ were within the range of 80.00 - 125.00%, indicating that the test formulation was equivalent to the reference formulation in healthy Chinese subjects under fasting conditions. Both products were similar in terms of safety.