Lower Trough Research Articles

P0597 Clinical and biochemical correlates of infliximab pharmacokinetics in adult patients with Inflammatory Bowel Disease

Abstract Background Antibodies against tumor necrosis factor-alpha (TNF-α) such as infliximab (IFX) are important in the treatment of patients with inflammatory bowel disease (IBD), but many patients lose drug response over time or do not respond at all. Loss-of-response and non-response can at least be partially attributed to suboptimal dosing due to individual differences in pharmacokinetics (PK)1. In this real-world study, we aimed to identify clinical, biochemical and endoscopic variables influencing IFX PK in patients with IBD. Methods Patients diagnosed with IBD aged ≥18 years who were treated with IFX were included based on available IFX trough levels from a hospital-based pharmacy registry. Information on endoscopic, clinical, and biochemical parameters was collected. Univariable and multivariable linear mixed-effects models were used to model associations between individual IFX trough level trajectories and identified factors to examine their relative contributions to IFX PK. In addition, a systematic literature study on IFX PK in adults with IBD and other immune-mediated inflammatory diseases was performed to better contextualize the obtained findings. Results A total of 200 patients were included (Crohn’s disease [CD] (n=163) and ulcerative colitis [UC] (n=37)) with 452 IFX trough levels available for analysis (Figure 1). Patients with antibodies (ATI) to IFX (unstandardized β=4.35, p<0.001) and those treated with longer dosing intervals (β=-1.89, p=<0.001) exhibited lower trough levels (Figure 2). Higher levels of aspartate aminotransferase (AST) (β=0.04, p=0.027), hemoglobin (β=0.76, p=0.022) and albumin (β=0.15, p=0.029) were positively associated with IFX trough levels. Among clinical factors, Simple Clinical Colitis Activity Index (SCCAI) scores in patients with UC, both as continuous (β=3.31, p=0.03) and as categorical variable (β=13.25, p=0.033), were positively associated with higher IFX trough levels. The presence of endoscopic inflammation, regardless of its severity, was also positively correlated with IFX trough levels (β=2.60, p=0.045). Conclusion This data demonstrates a role of AST, albumin, hemoglobin, SCCAI, and endoscopic inflammation as covariates potentially relevant to IFX PK in IBD. Findings of albumin, endoscopic inflammation, dosage interval and ATI were supported by our systematic review confirming them as previously identified covariates. AST, hemoglobin, and SCCAI were newly identified covariates. These covariates could optimize treatment strategies and should therefore be considered for integration in population-PK/PD models and PK dashboards in order to make patient-specific prediction models for IFX treatment.

HIGH BODY MASS INDEX IS ASSOCIATED WITH LOWER ADALIMUMAB SERUM LEVELS AND HIGHER DISEASE ACTIVITY IN NON-INFECTIOUS UVEITIS.

Adalimumab, a TNF-alpha inhibitor, is the only FDA-approved biologic for non-infectious uveitis (NIU). However, treatment responses vary, potentially due to interindividual pharmacokinetic differences influenced by body mass index (BMI). This study aimed to evaluate the impact of BMI on adalimumab serum trough levels and therapeutic efficacy in patients with NIU. cross-sectional, clinical study METHOD: : - Setting: Single-center study. - Study Population: 80 patients with NIU treated with Adalimumab - Observation Procedure: Adalimumab serum trough levels and anti-Adalimumab antibody (AAA) levels were measured. BMI was calculated at treatment initiation, and patients were categorized into normal weight, overweight, obese, and morbidly obese groups. - Main Outcome Measures: The correlation between BMI, adalimumab levels, and clinical response was analyzed using Pearson correlation, chi-square tests, and logistic regression. Higher BMI was associated with lower adalimumab serum levels and a reduced likelihood of clinical response. A significant negative correlation was found between BMI and adalimumab levels (r = -0.408, p = 0.007). Logistic regression identified BMI as a significant predictor of treatment response (p = 0.017). A BMI threshold of 26.4 was identified, above which the probability of a positive response significantly decreased. Additionally, 51.2% of patients were non-responders, all of whom demonstrated detectable AAA. Higher BMI is associated with lower adalimumab trough levels and reduced treatment efficacy in NIU patients. A BMI threshold of 26.4 may serve as a clinical marker for tailoring adalimumab therapy, highlighting the need for personalized dosing strategies in patients with elevated BMI.

Plasma apixaban concentrations and thrombin generation assay parameters in response to dose reduction for atrial fibrillation.

To investigate plasma apixaban concentrations and thrombin generation assay (TGA) parameters across different apixaban doses in atrial fibrillation patients who had dose-reduction criteria for apixaban. This observational study included 374 patients (mean age 75.6 ± 7.7 years, 54.8% female) with dose-reduction criteria for apixaban. The patients were divided into 3 groups: (i) on-label standard dose (5 mg twice daily, n =166); (ii) on-label reduced dose (2.5 mg twice daily, n =55); and (iii) off-label underdose (2.5 mg twice daily, n =153). Apixaban concentrations determined via the anti-Xa assay and TGA parameters were compared at trough levels. The off-label underdose group exhibited significantly lower apixaban trough concentrations than the on-label reduced-dose and standard-dose groups (56.7 ± 42.9 vs. 83.7 ± 70.4 vs. 129.9 ± 101.8 ng/mL, all P <.001). Less than 70% of all patients fell within the expected range of apixaban concentrations. Proportions exceeding the upper limit of the expected range were significantly lower in the off-label underdose group (1.3%) than in the on-label reduced-dose (9.1%, P =.005) and standard-dose (12.7%, P <.001) groups. The TGA parameters showed the on-label standard-dose group displaying the lowest thrombogenic profiles. Lower creatinine clearance was the most significant predictor of higher apixaban concentrations. Off-label underdosed apixaban resulted in lower apixaban concentrations than both on-label standard and reduced-dose regimens. A considerable proportion of the patients exhibited apixaban concentrations outside the expected range, suggesting the potential benefits of plasma concentration monitoring. Further studies are needed to compare dosages directly, investigate the impact of plasma apixaban concentration monitoring and validate the current dose-reduction criteria.

High occurrence of autoimmune and lymphoproliferative manifestations in adults with common variable immunodeficiency in southernTaiwan.

There are no reported case series of common variable immunodeficiency (CVID) from southern Taiwan. A 20-year review was performed in adult CVID from a southern Taiwan medical center. Patients with ages of 18 years or older were enrolled from May, 2003 to April, 2023. Twelve patients were identified, 8 females/4 males aged 23 to 68 (38.9±13.4) with one to 11 years (5.0±3.3) delay of diagnosis after disease onset. There were concomitant autoimmune disorders in 7 (58 %), splenomegaly in 10 (83%), lymphadenopathy in 4 (25%) and B-cell lymphoma in 2 (17%). All received intravenous immunoglobulin (IVIg) infusion with improved autoimmune-mediated arthritis in 2. Patients with higher IgG trough levels (above 500mg/dL) had a better survival than those with lower IgG trough levels. Adult CVID in southern Taiwan has a high occurrence of autoimmune and lymphoproliferative manifestations. Early diagnosis with IVIg infusion might improve the presentations.

Potential influence of interleukin-6 -174G/C gene polymorphism on kidney graft function and tacrolimus dose requirements: five-year follow-up

1. Introduction The study aimed to investigate the influence of interleukin (IL)-6 -174 G/C gene polymorphism on graft function (defined as estimated glomerular filtration rate, eGFR), as well as on the tacrolimus (Tac) pharmacokinetics during the five years after kidney transplantation. 2. Methods The study included 115 Caucasian kidney transplant recipients on Tac-based immunosuppression. The patients were followed between 6 and 60 post-transplantation months. Interleukin-6 and CYP3A5 genotyping were performed. 3. Results Patients carrying the IL-6 -174GG genotype had lower eGFR values compared to the patients with the IL-6 -174GC and −174CC genotypes at the 12th, 48th and 60th post-transplantation months. The linear regression analysis indicated that eGFR at the 6th post-transplantation month and IL-6 -174 G/C polymorphism are independent predictors of eGFR values in the late post-transplantation period. The IL-6 -174GG genotype carriers had lower dose-adjusted trough concentration (C0/D) of Tac compared to the IL-6 C allele carriers during the entire observation period (except at the 24th month), while this effect was independent of the CYP3A5 genotype within three years post-transplantation. 4. Conclusion Interleukin-6 genotyping could be an additional tool to categorise patients towards the risk of graft deterioration in the long-term post-transplantation period. The IL-6 genotyping could be supportive in genotype-guided dosing of Tac.

The Influence of High Body Mass Index (BMI > 35 kg/m2) on Apixaban Plasma Concentration in Patients with Atrial Fibrillation.

Apixaban, a direct oral anticoagulant is administered for stroke prevention in atrial fibrillation patients. Dosing adjustment is guided by renal function, age, and body weight. However, no data exist on its pharmacokinetics in patients with a body mass index (BMI) ≥ 35 kg/m2. The aim was to investigate the effects of BMI ≥35 kg/m2 on trough plasma concentrations of apixaban in patients with atrial fibrillation. This prospective study compared steady-state trough concentrations of apixaban in patients with a BMI ≥35 kg/m2 and patients with a BMI <35 kg/m2. Sixty patients were included. In patients receiving 5 mg apixaban twice daily, the median trough plasma concentration was 29% lower in patients with a BMI ≥35 kg/m2 than in those with a BMI <35 kg/m2 (148.9 ng/ml, interquartile range [IQR] 94.5-205.6, compared to 209.1 ng/ml, IQR 167-266.8 ng/ml, respectively; P = 0.044). However, median trough concentrations fell within the manufacturer's predicted range for effective steady-state apixaban exposure. A similar trend was observed with 2.5 mg apixaban twice daily, although statistical significance was not reached. Multivariate analysis revealed no correlation between BMI values and trough concentrations. BMI ≥35 kg/m2 patients exhibited lower apixaban trough concentrations, while remaining within the manufacturer's established range for effective steady-state apixaban, suggesting that dose adjustment is unnecessary for this specific patient group.

Drug-Drug Interaction Between Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine During Malaria Chemoprevention in Pregnant Women.

Co-administration of dihydroartemisinin-piperaquine (DP) and sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria in pregnancy (IPTp) may be superior in preventing adverse birth outcomes compared with either therapy alone, but potential drug-drug interactions require investigation. We conducted intensive and sparse pharmacokinetic (PK) studies in a subset of Ugandan women participating in a randomized controlled trial of monthly IPTp with SP vs. DP vs. DP + SP. Intensive PK sampling was performed from day 0 to 23 after dosing at 28 weeks gestation in 87 participants across treatment arms. Sparse sampling was performed on day 28 (trough) after dosing at 20 and 28 gestational weeks in additional 196 participants receiving SP vs. DP + SP. Intensive PK analysis demonstrated that compared with SP alone, co-administration of DP + SP was associated with lower maximal concentrations, the area under the concentration-time curves (AUC), and day 23 concentrations of sulfadoxine (25%, 25%, and 27%) and pyrimethamine (26%, 34%, and 32%) (P < 0.05 for all comparisons). Sparse PK results demonstrated participants co-administered DP + SP had lower trough concentrations after dosing at 20 and 28 gestational weeks for sulfadoxine (6%, P = 0.68 and 31%, P = 0.023, respectively) and pyrimethamine (18%, P = 0.032 and 33%, P < 0.001, respectively) compared with SP alone. Co-administration of DP + SP was associated with a 19% reduction in piperaquine AUC (P = 0.046), but no significant difference in other PK parameters compared with DP alone. In summary, co-administration of DP + SP was associated with significantly reduced SP exposure, with a greater magnitude during the third vs. second trimester. The clinical consequences of this interaction are yet unknown.

Age-Related Differences in Rejection Rates, Infections, and Tacrolimus Exposure in Pediatric Kidney Transplant Recipients in the CERTAIN Registry

IntroductionData on age-related differences in rejection rates, infectious episodes and tacrolimus exposure in pediatric kidney transplant recipients (pKTR) on a tacrolimus-based immunosuppressive regimen are scarce. MethodsWe performed a large-scale analysis of 802 pKTR from the CERTAIN registry from 40 centers in 14 countries. Inclusion criteria were a tacrolimus-based immunosuppressive regimen and at least two years of follow-up. The patient population was divided into three age groups (infants and young children <6 years, school-aged children 6-12 years, and adolescents >12 years) to assess age-related differences in outcome. ResultsMedian follow-up was 48 months (IQR, 36-72). Within the first 2 years post-transplant, infants and young children had a significantly higher incidence of infections (80.6% vs. 55.0% in adolescents, P<0.001) and a significantly higher number of cumulative hospital days (median 13 days vs. 7 days in adolescents, P < 0.001). Adolescents had a significantly higher rate of biopsy-proven acute rejection episodes in the first year post-transplant (21.7%) than infants and young children (12.6%, P=0.007). Infants and young children had significantly lower tacrolimus trough levels, lower tacrolimus concentration-to-dose ratios as an approximation for higher tacrolimus clearance, and higher tacrolimus intra-patient variability (all P < 0.01) than adolescents. ConclusionsThis largest study to date in European pKTR on a tacrolimus-based immunosuppressive regimen shows important age-related differences in rejection rates, infection episodes, tacrolimus exposure and clearance. These data suggest that immunosuppressive therapy in pKTR should be tailored and personalized according to the age-specific risk profiles of this heterogeneous patient population. The data may also serve as a benchmark for future studies with novel immunosuppressive drugs.

쌀가루의 물리화학적 특성에 대한 가수분해 농축잠두단백과 병아리콩가루의 영향

This study investigated the impact of hydrolyzed plant proteins on the physical, thermal, and rheological properties of rice flour (RF) for protein fortification for the elderly and general food systems. Faba bean protein concentrate and chickpea flour were first treated with polysaccharide hydrolyzed enzymes (control; CTFP and CTCF, respectively) and subsequentially with protease hydrolyzed enzymes (hydrolyzed protein material; HZFP and HZCF, respectively). The addition of CTFP and HZFP enhanced the swelling power of RF, whereas the CTCF and HZCF exhibited the opposite trends. Adding all controls and hydrolyzed protein materials to RF increased the solubility and gelatinization temperature and decreased the gelatinization enthalpy. The HZFP addition successfully developed the pasting viscosity of RF, whereas the others did not. The RF-HZFP mixture had a higher peak viscosity than RF but lower trough, breakdown, final, and setback viscosities. These findings suggest that the controls and hydrolyzed protein materials studied here could be used as sources for protein fortification of foods, particularly for the elderly, with minimal changes in textural and rheological characteristics, thereby contributing to the development of nutritious and palatable food products.

Treatment Algorithm for Surgical Correction of Lower Eyelid Bags and Tear Trough Deformity Based on Barton Grading System.

Facial rejuvenation procedures for lower eyelid bags and tear trough deformity have recently gained increasing attention. This study introduced a treatment algorithm tailored to the severity of tear trough deformity, categorized using the Barton grading system, to tackle this concern effectively. One hundred seventy-six patients with combined lower eyelid bags and tear trough deformity underwent lower lid blepharoplasty at our center between 2018 and 2023. Preoperative assessment utilized the Barton grading system to categorize the severity of tear trough deformity, guiding personalized surgical approaches for each patient. Postoperative outcomes, including satisfaction levels, complications, and tear trough deformity improvement, were evaluated. Following surgery, 175 out of 176 patients achieved a reduction to Barton grade level of 0. Postoperative satisfaction scores averaged 4.4, with a satisfaction rate of 96.6%. Complications were minimal, including mild postoperative ectropion in patients and single occurrences of postoperative hematoma, infection, insufficient improvement, and recurrence. Our treatment algorithm offers a straightforward and effective approach for addressing tear trough deformity and lower eyelid bags. Further research is warranted to validate these findings.

Cefepime trough levels and clinical outcomes in patients undergoing universal therapeutic drug monitoring: A prospective cohort study

BackgroundCefepime is an essential beta-lactam antibiotic for which therapeutic drug monitoring (TDM) is not performed routinely in many centers. Current literature on cefepime levels consists of retrospective reports of TDM applied selectively by clinicians, i.e., in the setting of suspected toxicity. In an effort to capture and define therapeutic plasma concentration thresholds, this prospective study applied TDM uniformly to consecutive inpatients with suspected or confirmed bacterial infections and observed their ensuing 30-day clinical course. MethodsThis single-center prospective observational study included adult patients hospitalized in the hematology, intermediate- or intensive-care units of Geneva University Hospitals between January 2019 and December 2021. Participants in steady state (receiving cefepime for ≥24 hours) uniformly underwent TDM at least once and thereafter were assessed for the primary and secondary outcomes of occurrence of adverse events and clinical response, respectively, through 30 days. ResultsAmong 151 included patients, 104 had at least one trough level. Most (95/104, 91%) experienced clinical success. Six (6%) experienced an adverse event possibly related to cefepime; no neurotoxicity was observed. Median trough level was 8.5 mg/L (IQR 5.8-13.3); trough levels of those with or without adverse events and those with or without clinical success did not differ significantly. Trough levels increased significantly with renal insufficiency and age. ConclusionCefepime TDM conducted uniformly in hospitalized patients with severe infections reveals lower trough levels than previously reported. Toxicity is rare and clinical effectiveness is high, such that the determination of a strict therapeutic range remains elusive.

Implications to basin evolution from the interpretation of superficial and buried geological features from remote sensing and magnetic data sets, Lower and Middle Benue Trough, Nigeria

The Lower and Middle Benue Trough is an intra-continental rifted basin with most rocks concealed by thick sediments and vegetation. Geological field mapping is very difficult resulting in high uncertainties. Remote sensing and geophysical techniques can assist in refining lithological boundaries and detecting buried geological features such as intrusive bodies, which can be very useful in interpreting the structural history of a basin. The main aim of our study is to re-process and interpret aeromagnetic and multispectral satellite datasets to understand the evolution of the Benue Trough. We used high-resolution aeromagnetic data and, Landsat 8 and ASTER data sets to interpret surface and near-surface lithologies, particularly igneous bodies, within the Benue Trough, Nigeria, with the aim of better constraining the basin evolution in time and space. A matched bandpass filter was applied to the aeromagnetic data to separate shallow/near-surface (residual) anomalies from deep (regional) anomalies. The result of the residual anomaly was further filtered by derivative-based filters to delineate surface/near-surface igneous bodies. The satellite remote sensing datasets were processed and enhanced, and diagnostic mineral spectral signatures related to geology were interpreted. A spectral angle mapping (SAM) supervised classification was used to map various lithologies and their boundaries. The delineated igneous bodies (volcanic rocks, plugs, dykes, bosses, and sills) are concentrated along the SE margin of the Trough where they intruded along a major NE-SW trend; but changes in the intrusion style are interpreted to relate to specific stages in the basin history. We suggest that the initial magma emplacement was controlled by structures mostly along the SE margin of an asymmetric basin, but the rifting locus later migrated towards the centre of the present basin.

Rod-Shaped Starch from Galanga: Physicochemical Properties, Fine Structure and In Vitro Digestibility.

This work investigated the physicochemical properties, structural characteristics, and digestive properties of two non-conventional starches extracted from Galanga: Alpinia officinarum Hance starch (AOS) and Alpinia galanga Willd starch (AGS). The extraction rates of the two starches were 22.10 wt% and 15.73 wt%, which is lower than widely studied ginger (Zingiber officinale, ZOS). But they contained similar amounts of basic constituents. AOS and AGS showed a smooth, elongated shape, while ZOS was an oval sheet shape. AOS and ZOS were C-type starches, and AGS was an A-type starch. AOS showed the highest crystallinity (35.26 ± 1.02%) among the three starches, possessed a higher content of amylose (24.14 ± 0.73%) and a longer amylose average chain length (1419.38 ± 31.28) than AGS. AGS starch exhibits the highest viscosity at all stages, while AOS starch shows the lowest pasting temperature, and ZOS starch, due to its high amylose content, displays lower peak and trough viscosities. Significant differences were also found in the physicochemical properties of the three starches, including the swelling power, solubility, thermal properties, and rheological properties of the three starches. The total content of resistant starch (RS) and slowly digestible starch (SDS) in AOS (81.05%), AGS (81.46%), and ZOS (82.58%) are considered desirable. These findings proved to be valuable references for further research and utilization of ginger family starch.

Gender- and Age-Related Characterization of Lower Eyelid Morphology: Three-Dimensional Analysis in a Chinese Population.

The lower eyelid region is a critical component of the face. It is essential to establish anthropometric reference values for the evaluation of aging, surgical planning and assessment of outcomes in periocular esthetic and rejuvenation procedures. This study aims to provide comprehensive anthropometric data on the Chinese lower eyelid region, into account factors such as sex and age, through three-dimensional imaging analysis. Three-dimensional facial images were obtained from 84 healthy Chinese individuals aged between 20-35 and 50-65 years, as well as eight patients aged between 20 and 35 who presented with eyelid bags. A total of 27 landmarks were identified, leading to the generation of corresponding 21 lines, 5 curves, 4 angles, 2 areas and 5 ratios. The measurements were compared among different age groups, genders and young patients with or without eyelid bags. Compared to females, males exhibited a more elongated palpebral fissure, lower tear trough and lid-cheek junction, smaller inner and outer canthus angles, as well as a larger area and proportion of the lower palpebral region. As age progressed, the height and width of the palpebral fissure and inner canthus angle decreased gradually, which was accompanied by sagging of the tear trough and lid-cheek junction, an increase in lower eyelid area and swelling of the lower eyelid. Young patients undergoing eyelid bags demonstrated larger and more swelling lower eyelid which held clinical significance for rejuvenation surgery. Males exhibited a higher proportion of the brow-eye unit occupied by the lower eyelid region compared to females. Elderly individuals displayed noticeable drooping of the tear trough and lid-cheek junction, accompanied by swelling in the lower palpebral region. These findings can serve as standard references for esthetic procedures and reconstructive periocular operations. This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to Table of Contents or online Instructions to Authors www.springer.com/00266.

Model-Informed Clinical Development of Once-Every-6-Month Injection of Paliperidone Palmitate in Patients with Schizophrenia: A Pharmacometric Bridging Approach (Part I).

A model-informed drug development (MIDD) approach was implemented for paliperidone palmitate (PP) 6-month (PP6M) clinical development, using pharmacokinetics and pharmacokinetic/pharmacodynamic model-based simulations. PP6M pharmacokinetics were simulated by extending the PP 3-month (PP3M) pharmacokinetic model to account for increased injection volume, and hence dose. Contribution of the MIDD approach to the design of the pivotal PP6M phase-3 study (PP6M/PP3M noninferiority study, NCT03345342) investigating schizophrenia relapse rates was twofold: (1) PP6M dose selection, and (2) hypothesis generation that lower trough concentrations (Ctrough) associated with PP6M, relative to PP3M, were not associated with lower efficacy, which was to be evaluated in the phase-3 study. Moreover, accompanied by an intense sampling scheme to adequately characterize paliperidone pharmacokinetics and to elucidate the potential relationship between concentration and safety/efficacy, the bridging strategy eliminated the need for additional phase-1/phase-2 clinical studies. Using a MIDD bridging strategy, PP6M doses were selected that, compared with PP3M, were expected to have a similar range of exposures and a noninferior relapse rate and safety profile. Clinical data from PP6M/PP3M noninferiority study confirmed that PP6M, compared with PP3M, had a similar range of exposures (T'jollyn etal. in Eur J Drug Metab Pharmacokinet 2024), as well as a noninferior relapse rate and safety profile (this manuscript). Consistency of the MIDD approach with observed clinical outcomes confirmed the hypothesis that lower Ctrough did not lead to increased relapse rates at the doses administered. Although higher paliperidone peak concentrations are achieved with corresponding doses of PP6M relative to PP3M in the phase-3 clinical study, types and incidences of treatment-related adverse events were comparable between PP6M and PP3M groups and no new safety concerns emerged for PP6M (Najarian etal. in Int J Neuropsychopharmacol 25(3):238-251, 2022).

Atrial arrhythmias following CAR-chimeric antigen receptor T-cell therapy: Incidence, risk factors and biomarker profile.

Recent reports have raised concerns about the association of chimeric antigen receptor T cell (CAR-T) with non-negligible cardiotoxicity, particularly atrial arrhythmias. First, we conducted a pharmacovigilance study to assess the reporting of atrial arrhythmias following CD19-directed CAR-T. Subsequently, to determine the incidence, risk factors and outcomes of atrial arrhythmias post-CAR-T, we compiled a retrospective single-centre cohort of non-Hodgkin lymphoma patients. Only commercial CAR-T products were considered. Atrial arrhythmias were nearly fourfold more likely to be reported after CAR-T therapy compared to all other cancer patients in the FAERS (adjusted ROR = 3.76 [95% CI 2.67-5.29]). Of the 236 patients in our institutional cohort, 23 (10%) developed atrial arrhythmias post-CAR-T, including 12 de novo arrhythmias, with most (83%) requiring medical intervention. Atrial arrhythmias frequently co-occurred with cytokine release syndrome and were associated with higher post-CAR-T infusion peak levels of IL-10, TNF-alpha and LDH, and lower trough levels of fibrinogen. In a multivariable analysis, risk factors for atrial arrhythmia were history of atrial arrhythmia (OR = 6.80 [2.39-19.6]) and using CAR-T product with a CD28-costimulatory domain (OR = 5.17 [1.72-18.6]). Atrial arrhythmias following CD19-CAR-T therapy are prevalent and associated with elevated inflammatory biomarkers, a history of atrial arrhythmia and the use of a CAR-T product with a CD28 costimulatory domain.

Influence of UGT2B7, UGT1A4 and ABCG2 Polymorphisms on the Pharmacokinetics and Therapeutic Efficacy of Lamotrigine in Patients with Epilepsy.

A substantial inter-individual variability has been observed in the pharmacokinetics of lamotrigine. The aim of the study was to investigate the impact of genetic polymorphism of the metabolizing enzymes (UGT2B7, UGT1A4) and transporter (ABCG2) on the pharmacokinetics and therapeutic efficacy of lamotrigine in patients with epilepsy. The genetic analysis of single-nucleotide polymorphisms was conducted using polymerase chain reaction sequence. High-performance liquid chromatography/tandem mass spectrometry was employed to measure the plasma concentrations of lamotrigine. The efficacy of lamotrigine was assessed by evaluating the reduction rate of epileptic seizure frequency. This study included a cohort of 331 patients who were treated with lamotrigine as monotherapy. A linear correlation was observed between the lamotrigine concentration and daily dose taken (r = 0.58, p < 2.2e-16). Statistically significant differences were found in both the median plasma concentration and dose-adjusted concentration (C/D ratio) when comparing the ineffective to the effective group (p < 0.05). Multivariate analysis showed that UGT1A4 rs2011425, ABCG2 rs2231142 polymorphisms and age had a significant relationship with the lamotrigine concentrations (p < 0.05). Age was a predictive factor for C/D ratio (p < 0.001). Lamotrigine concentration and weight were good predictive factors for effective seizure outcomes (odds ratio [OR] = 0.715, 95% CI 0.658-0.776, p < 0.001; OR = 0.926, 95% CI 0.901-0.951, p < 0.001, respectively). The cut-off values of lamotrigine trough concentrations for clinical outcomes in the age-related groups were determined as 2.49μg/ml (area under the receiver-operating characteristic curve [AUC]: 0.828, 95% CI 0.690-0.966), 2.70μg/ml (AUC: 0.805, 95% CI 0.745-0.866) and 3.25μg/ml (AUC: 0.807, 95% CI 0.686-0.928) for the adult group, adolescent group, and toddler and school-age group, respectively. UGT1A4 rs2011425 and ABCG2 rs2231142 were correlated with lamotrigine concentrations. Lower lamotrigine trough concentration was found in the ineffective group and the troughs were associated with seizure outcomes.

Transcutaneous lower eyelid blepharoplasty with micro-autologous fat transplantation harvested from orbital fat pads for lower eyelid aging treatment

The aging process of lower eyelids results in lower eyelid wrinkles, tear troughs, and eye bags. Many therapies have been described for treatment of lower eyelid aging, and transcutaneous blepharoplasty is often used for treating cases with eyebags and dermatochalasis. However, it may cause depression near the medial orbit resulting in a hollowed look. In the present study, we developed an innovative method transferring the herniated fatty tissue to volume loss area during the surgical procedure of transcutaneous lower eyelid blepharoplasty by means of micro-autologous fat transplantation harvested from resected orbital fat pads. Besides, we also analyze it efficacy and safety compared with traditional methods of transcutaneous lower eyelid blepharoplasty. We reviewed the records of the patients who underwent transcutaneous lower eyelid blepharoplasty with and without micro-autologous fat transplantation, for lower eyelid aging improvement. We used global aesthetic improvement scale, Hirmand's classification system, and Wrinkle Severity Rating Scale to evaluate the cosmetic outcome at 1week, 1month, and 3months after operation by two independent investigators. We found patients received transcutaneous lower eyelid blepharoplasty with autologous fat graft had significantly higher global aesthetic improvement scale and Wrinkle Severity Rating Scale improvement than those underwent transcutaneous lower eyelid blepharoplasty only in each evaluation timepoints. There was no significant difference of adverse effects between both surgical methods. The present study demonstrated the efficacy and safety of the lower eyelid blepharoplasty with micro-autologous fat transplantation harvesting from resected orbital fat pads.

Effect of cation valence on the retrogradation, gelatinization and gel characteristics of maize starch

This study aimed to examine the impact of trivalent, divalent, or monovalent cations dissolving into water and being mixed with maize starch to influence its retrogradation, gelatinization, and gel characteristics. The result of the analysis using a differential scanning calorimeter showed that all cations raised the peak of gelatinization temperature of maize starch, especially Al3+ or Fe3+, while trivalent cations reduced the enthalpy. The result of the analysis using a rapid viscosity analyzer showed that trivalent cation caused lower trough viscosity, final viscosity, and pasting temperature but higher breakdown viscosity of maize starch than monovalent or divalent cations. Confocal laser scanning microscopy showed that the cation promoted the destruction of gelatinized maize starch granules, especially Zn2+, Fe3+, or Al3+. Additionally, trivalent Fe3+ or Al3+ caused higher gel strength of maize starch. Generally, the cation with higher valence changed more retrogradation, gelatinization, and gel characteristics of maize starch.

Association between serum IgG concentrations and the incidence of infections in patients with chronic lymphocytic leukemia and secondary immunodeficiency under treatment with Privigen.

To investigate the association between serum immunoglobulin G (IgG) concentrations and the incidence of infections in patients with chronic lymphocytic leukemia (CLL) and secondary immunodeficiency receiving treatment with Privigen. Data was analyzed from a non-interventional study conducted in 31 centers in Germany and 1 in Austria. Adult CLL patients with hypogammaglobulinemia and recurrent infections were allowed to enter the study upon signing informed consent, if a prior decision for treatment with Privigen had been made. All infections requiring an antimicrobial treatment were subject to analysis. Patients were stratified according to their mean post-baseline serum IgG trough levels in a group with lower IgG trough levels (≤ 5.0 g/L), and a group with higher IgG trough levels (> 5.0 g/L). Overall, 89 patients and 840 treatment cycles were analyzed. Up to 11 treatment cycles (average duration 29 days) were documented in each patient. In the group with higher IgG trough levels (> 5.0 g/L, N = 72), significantly fewer infections were observed than in the group with lower IgG trough levels (≤ 5.0 g/L, N = 17), including fewer severe and serious infections. The Privigen dosage was a major determinant of the post-baseline serum IgG levels. Overall tolerability of Privigen was assessed as very good or good in 91% of patients. This analysis confirms the association of serum IgG trough levels with the incidence of infections and highlights the importance of careful monitoring of IgG levels during treatment of secondary immunodeficiencies in CLL patients.