Optimal Trough Research Articles

Optimal Trough Concentration of Tacrolimus in Pediatric Patients With Primary Nephrotic Syndrome.

The trough concentration (C0) of tacrolimus in children with nephrotic syndrome (NS) has rarely been explored, so its target level was based on transplant research. This study aimed to determine the optimal tacrolimus C0 in NS children. Data from primary NS children treated with tacrolimus at Wuhan Children's Hospital in the last 10 years were retrospectively collected. According to the cutoff C0 analyzed by receiver-operator characteristics (ROC) analysis, patients were divided into very low- (< 4 ng/mL), low- (4-5 ng/mL), medium- (5-7 ng/mL), and high-concentration (7-10 ng/mL) groups. A total of 196 patients were enrolled for primary outcome analysis. Compared to medium-concentration group, only the very low-concentration group obtained significant inferior primary outcomes, including overall remission rate, relapse-free survival rate, and relapse rate at 6 months. For secondary outcomes, the very low-concentration group experienced more frequent treatment failure in 12 months, whereas the high-concentration group suffered a higher risk of adverse events than the medium-concentration group. For steroid-resistant NS, very low- and low-concentration groups required longer time to achieve remission compared to medium-concentration group. For steroid-sensitive NS, the very low-concentration group suffered a higher relapse frequency than medium-concentration group. Lastly, the dose of tacrolimus required for children with different CYP3A5 genotypes with or without Wuzhi capsules was analyzed. In conclusion, tacrolimus may be targeted to C0 of 4-7 ng/mL during the first 6 months in children with NS. For steroid-resistant NS, C0 of 5-7 ng/mL can achieve a rapid remission.

Optimal Teicoplanin Trough Concentration With Therapeutic Drug Monitoring in Children: A Systematic Review and Meta-analysis.

Teicoplanin is used to treat serious Gram-positive bacterial infections. However, the optimal trough concentrations for pediatric patients remain unclear owing to the lack of monitoring guidelines. This study aimed to determine the optimal teicoplanin trough concentration for treating Gram-positive bacterial infections in children. A systematic review was conducted using 4 databases. Stepwise cutoffs within the range of 10-30 mcg/mL were used for efficacy and safety. Studies were included if they reported treatment success rates and/or all-cause mortality, nephrotoxicity, hepatotoxicity, and thrombocytopenia according to the trough concentration. The meta-analysis included 12 studies involving 830 pediatric patients. Teicoplanin cutoff values of 10, 15, 20, and 30 mcg/mL were reported in 9, 8, 9, and 2 studies, respectively. Trough concentrations <10 mcg/mL significantly reduced the treatment success rate, with an odds ratio of 0.07 and a 95% confidence interval ranging from 0.01 to 0.40. The overall treatment success rate was 50.0% versus 95.7% observed at concentrations ≥10 mcg/mL. However, no significant difference was observed at the 15-, 20-, and 30-mcg/mL cutoffs, when compared with lower concentrations. Trough concentrations <20 mcg/mL were associated with a decreased risk of nephrotoxicity (odds ratio = 0.21; 95% confidence interval, 0.08-0.55). However, hepatotoxicity and thrombocytopenia showed no significant associations with trough concentration ranges between 10 and 30 mcg/mL. Although further prospective studies are required for validation, the authors' findings suggest that 10- to 20-mcg/mL teicoplanin is the optimal trough concentration for enhanced clinical success and reduced toxicity in pediatric patients.

Optimum tacrolimus trough levels for enhanced graft survival and safety in kidney transplantation: a retrospective multicenter real-world evidence study.

The current study aimed to determine the optimal tacrolimus trough levels for balancing graft survival and patient safety following kidney transplantation. We conducted a retrospective cohort study involving 11,868 kidney transplant recipients from five medical centers. The association between tacrolimus exposures (periodic mean trough level, coefficient of variability, time in therapeutic range) and composite allograft outcome (de novo donor specific antibody, biopsy-proven rejection, kidney dysfunction, and graft failure), as well as safety outcomes (severe infection, cardiovascular events, malignancy, and mortality) were assessed. Data were sourced from Clinical Data Warehouses and analyzed using advanced statistical methods, including Cox marginal structural models with inverse probability treatment weighting. Tacrolimus levels of 5.0-7.9ng/mL and 5.0-6.9ng/mL during the 2-12 month and 12-72 month post-transplantation periods, respectively, were associated with reduced risks of composite allograft outcomes. During the first post-transplant year, the adjusted hazard ratios (aHR) for composite allograft outcomes were: 0.69 (95% CI 0.55-0.85, P<0.001) for 5.0-5.9ng/mL; 0.81 (95% CI 0.67-0.98, P=0.033) for 6.0-6.9ng/mL; and 0.73 (95% CI 0.60-0.89, P=0.002) for 7.0-7.9ng/mL (compared to levels ≥8.0ng/mL). For the 6-year composite outcomes, aHRs were 0.68 (95% CI 0.53-0.87, P=0.002) for 5.0-5.9ng/mL and 0.65 (95% CI 0.50-0.85, P=0.001) for 6.0-6.9ng/mL. These optimal ranges showed reduced rates of severe infection (6y), malignancy (6y), and mortality (1y). This multicenter study provides robust evidence for optimal tacrolimus trough levels during the periods 2-12 and 12-72 months following kidney transplantation.

Rare bleeding disorders: Advances in management

Inherited factor coagulation deficiencies and vascular bleeding disorders, associated with bleeding of various severity, are often classified as rare bleeding disorders (RBDs). These include inherited fibrinogen disorders, inherited platelet function disorders (IPFD) and hereditary haemorrhagic telangiectasia (HHT). In the last decades, there have been large increases in knowledge on the epidemiology, genetics, physiopathology, clinical features, and diagnosis of RBDs, but improvements in management have been more limited and remain challenging. The treatment mainstay of RBDs is based only on replacement of a few available coagulation factor concentrates or cryoprecipitates. There is growing interest in therapeutic agents that enhance coagulation or inhibiting anticoagulant pathways in RBDs. In severe IPFD, the optimal platelet transfusion strategy is not yet established. Moreover, data is scarce on the effectiveness and safety of desmopressin and/or antifibrinolytic drugs often used for milder IPFD treatment. The best fibrinogen replacement strategy (prophylaxis vs. on demand) in afibrinogenemia is still debated. Similarly, the optimal trough fibrinogen target level for treatment of acute bleeding, and the role of fibrinogen replacement during pregnancy in mild hypofibrinogenemia and dysfibrinogenemia, have not been properly evaluated. The therapeutic arsenal in HHT includes antifibrinolytics and a series of antiangiogenic agents whose potential efficacy has been tested in small studies or are under investigation for treatment of bleeding. However, there is need to address several issues, including the optimal dosing strategies, the potential emergent toxicity of longer-term use, and the impact of systemic antiangiogenic treatment on visceral arteriovenous malformations.

Ustekinumab Drug Levels and Outcomes in Inflammatory Bowel Disease.

Data regarding the utility of therapeutic drug monitoring with ustekinumab (UST) are sparse. Our aim was to determine the correlation of UST levels with outcomes in a cohort of patients with inflammatory bowel disease (IBD). This was a multicenter, retrospective study of all patients with IBD who received UST from January 1, 2014 to March 1, 2022. The primary outcomes were the correlation of UST level with clinical remission (per physician global assessment), endoscopic healing [the absence of ulcers/erosions in Crohn's disease (CD) and Mayo endoscopic score ≤1 for ulcerative colitis (UC)], and normal serum C-reactive protein (CRP) (≤5mg/L). Secondary outcomes included defining optimal UST trough levels associated with favorable outcomes. A total of 71 patients (74.6% with CD; 57.7% female) were included. The median age was 39.5 years [interquartile range (IQR): 26 to 52] and 12.6% were on combination therapy with immunomodulators. Median UST trough levels were significantly higher in patients who achieved endoscopic healing at 5.4µg/mL versus 3.5µg/mL (P=0.035) and normal CRP at 5.5µg/mL versus. 3.1µg/mL (P=0.002). A cutoff UST level of 4.8µg/mL yielded the highest area under the curve (AUC) of 0.73 (95% CI: 0.61-0.80) to predict a normal CRP followed by a cutoff of 3.5µg/mL which yielded an AUC of 0.66 (95% CI: 0.52-0.81) to predict endoscopic healing. UST trough levels were significantly higher in patients who achieved a normal CRP and endoscopic healing. A cutoff UST level of 4.8µg/mL reliably predicted CRP normalization.

P493 Do antiTNF or Ustekinumab trough levels correlate with joint extraintestinal manifestations activity in Inflammatory bowel disease patients?

Abstract Background Inflammatory spondyloarthritis(SpA) are the most common extraintestinal manifestations (EIM) associated to inflammatory bowel disease (IBD), with a prevalence of 20-50% for axial SpA(axSpA) and 5-20% for peripheral(pSpA). AntiTNF is the optimal therapy in axSpA intolerant or refractory to NSAIDs, also effective in pSpA. An optimal trough level has not been yet established in this clinical setting. Aim, to evaluate the correlation between antiTNF and UST trough levels and joint EIM activity in IBD patients. Methods Prospective, multicenter,cohort study. IBD patients diagnosed with articular EIM under antiTNF or Ustekinumab(UST) for at least 6 months were included. Blood samples were obtained just before administering the drug(trough levels), and a simultaneous evaluation by a rheumatologist and a gastroenterologist, was performed. Definitions: inactive AxSp=ASDAS-CRP&amp;lt;1.3 and BASDAI&amp;lt;2, inactive pSp=arthritis, enthesitis and dactylitis=0, active AxSp=ASDAS-CRP &amp;gt;2.1 and BASDAI&amp;gt;4, active pSp= artritis, entesitis o dactilitis &amp;gt; 0. Aim, to evaluate the correlation between antiTNF and UST trough levels and joint EIM activity in IBD patients. Results A total of 135 patients were included: mean age 51 ± 15, 59 (43.7%)women), 80% CD. 60(44.4%) patients presented axSpA, 50(37%) pSpA and 25(18.5%) mixed. 12(8.9%) had active IBD. Table 1 summarizes the patients' main demographic and clinical characteristics distributed by SpA activity. Fifty-three(39%) were on infliximab (IFX), 61(45.2%), on adalimumab (ADA) and 22 (16.3%) on UST treatment. NSAIDs treatment(12.7% vs 3.1%, p&amp;lt;0.05), higher fecal calprotectin(FC)(486 ± 709 vs 228.2 ± 297, p&amp;lt;0.05), and the prior use of biologics(33.8% vs 17.6%, p&amp;lt;0.05) were more frequent among active vs inactive SpA patients. No differences between IFX(7.05 ± 4.16 vs 5.79± 4.05, p=ns), ADA(7.98 ± 4.20 vs 9.51 ± 6.15 p=ns) and UST levels(3.39 ± 3.47 vs 3.08 ±2.69, p=ns), were found between active and inactive SpA patients, even when were distributed by type of SpA(axSpA/mixed and pSpA). Body mass index(b:-0,29, p=0.01)FC(b:-0,28, p=0.01), and intensified therapy(b:-0,28, p=0.01) were associated to higher IFX levels in the whole SpA cohort. Patients with axSpA or mixed were articular active more frequently than pSpA patients(82% vs 18%, p &amp;lt;0.05). IBD activity was correlated to articular activity only among pSpA patients(2% active IBD in inactive pSpA vs 20% active IBD in active pSpA patients, p=0.03). Conclusion AntiTNF and UST trough levels are not correlated to joint activity in patients with IBD and SpA. In our study more than 80% of patients with active SpA were inactive regarding IBD. Only pSpA patients presented correlation between IBD and articular activities.

Switching from intravenous to subcutaneous infliximab and vedolizumab in patients with inflammatory bowel disease: impact on trough levels, day hospital visits, and medical expenses

Objective Subcutaneous (SC) infliximab (IFX) and vedolizumab (VDZ) have recently become available. We aimed to examine the impact of switching from intravenous (IV) to SC IFX and VDZ in patients with inflammatory bowel disease (IBD) on costs, the day hospital burden, trough levels, and clinical outcomes. Methods Our study comprised the cohort of IBD patients receiving IV IFX or VDZ at our hospital in 2022. We evaluated costs, day hospital visits, trough levels, biochemical markers, relapse rates, and self-report outcomes until Jun 30th 2023. Results Of 114 patients, 18 continued IV therapy, 80 were switched to SC therapy, and 16 were inductions. Eighty-eight (90%) remained in steroid-free remission with no difference between the IV or SC groups. The mean IFX trough level changed from 8.2 ± 4.5 µg/ml to 14.5 ± 5.9 µg/ml, p < 0.001, and the VDZ trough level from 14.7 ± 7.1 mg/ml to 26.5 ± 13.8 mg/ml, p < 0.001. The average yearly costs of infusions and injections per patient were 2 580 € and 7 482 € for IFX and 15 990 € and 13 101 € for VDZ. The annual reduction of day hospital visits was 6,9 per patient. Conclusions IV and SC IFX and VDZ are equally effective in maintaining remission in IBD, but SC administration reduces day hospital visits and results in higher trough levels. SC VDZ is less and SC IFX more expensive than IV therapy. Further studies are needed to assess optimal dosing and separate trough levels for SC therapy.

Optimal tacrolimus trough levels and allograft outcomes in kidney transplant recipients: insights from a multicenter real-world study in South Korea

Optimal tacrolimus trough levels and allograft outcomes in kidney transplant recipients: insights from a multicenter real-world study in South Korea

Model-informed precision dosing in vancomycin treatment.

Introduction: While vancomycin remains a widely prescribed antibiotic, it can cause ototoxicity and nephrotoxicity, both of which are concentration-associated. Overtreatment can occur when the treatment lasts for an unnecessarily long time. Using a model-informed precision dosing scheme, this study aims to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model for vancomycin to determine the optimal dosage regimen and treatment duration in order to avoid drug-induced toxicity. Methods: The data were obtained from electronic medical records of 542 patients, including 40 children, and were analyzed using NONMEM software. For PK, vancomycin concentrations were described with a two-compartment model incorporating allometry scaling. Results and discussion: This revealed that systemic clearance decreased with creatinine and blood urea nitrogen levels, history of diabetes and renal diseases, and further decreased in women. On the other hand, the central volume of distribution increased with age. For PD, C-reactive protein (CRP) plasma concentrations were described by transit compartments and were found to decrease with the presence of pneumonia. Simulations demonstrated that, given the model informed optimal doses, peak and trough concentrations as well as the area under the concentration-time curve remained within the therapeutic range, even at doses smaller than routine doses, for most patients. Additionally, CRP levels decreased more rapidly with the higher dose starting from 10days after treatment initiation. The developed R Shiny application efficiently visualized the time courses of vancomycin and CRP concentrations, indicating its applicability in designing optimal treatment schemes simply based on visual inspection.

Ustekinumab trough levels in children with Crohn's disease refractory to anti-tumor necrosis factor agents: a prospective case series of off-label use.

Background: Ustekinumab is used off-label in pediatric Crohn's disease refractory to anti-tumor necrosis factor. Data on optimal dosing, target trough levels, and potential benefit of therapeutic drug monitoring in children treated with ustekinumab are limited. Materials and Methods: We describe a series of six adolescents who consented to be treated with ustekinumab. We measured their trough levels, C-reactive protein, and fecal calprotectin before every administration. Results: Standard adult dosing was effective to achieve biochemical remission (fecal calprotectin < 250mg/kg) in one patient and clinical remission (resolution of symptoms) in another. The other four patients failed to respond on standard dosing and underwent intravenous re-induction and interval shortening to increase ustekinumab trough levels. This resulted in biochemical remission in one patient and clinical remission in another, suggesting an exposure-response relationship. The remaining two patients had no therapeutic benefit, and ustekinumab was discontinued. Conclusion: In this report, we show that ustekinumab can induce remission in pediatric patients with anti-tumor necrosis factor refractory Crohn's disease. It is worth escalating the dose before abandoning the drug as ineffective. Prospective studies in children are needed to determine long-term efficacy of ustekinumab, usefulness of therapeutic drug monitoring strategies, and, if applicable, optimal target trough levels.

Exploration of the optimal GS-441524 trough concentration for treating COVID-19

Remdesivir (RDV) is the cornerstone for treating coronavirus disease 2019 (COVID-19). The active metabolite of RDV, GS-441524 (a nucleoside analog), has high inter-individual variability in plasma concentration; however, its concentration-response relationship is still unclear. This study investigated the target GS-441524 trough concentration for symptom improvement in COVID-19 pneumonia. This single-center, retrospective, observational study included COVID-19 pneumonia patients (≥15 years) who were administered RDV for ≥3 days from May 2020 to August 2021 at Saiseikai Futsukaichi Hospital. To determine the cut-off value of GS-441524 trough concentration on day 3, the achievement of the National Institute of Allergy and Infectious Disease Ordinal Scale (NIAID-OS) ≤3 after RDV administration was evaluated using the cumulative incidence function (CIF) with the Gray test and time-dependent receiver operating characteristic (ROC) analysis. Multivariate logistic regression analysis was performed to determine the factors influencing GS-441524 target trough concentrations. Our analysis comprised 59 patients. The CIF revealed that GS-441524 trough concentration ≥70 ng/mL was associated with the achievement of NIAID-OS ≤3 (p = 0.047), which was significant based on the time-dependent ROC analysis. Factors influencing GS-441524 trough concentration ≥70 ng/mL included a decrease in eGFR (adjusted odds ratio [aOR] 0.96, 95% confidence interval [95% CI] 0.92-0.99, p = 0.027) and BMI ≥25 kg/m2 (aOR 0.26, 95% CI 0.07-0.86, p = 0.031). GS-441524 trough concentration ≥70 ng/mL is a predictor of efficacy in COVID-19 pneumonia. The presence of lower eGFR or BMI ≥25 kg/m2 was associated with achieving GS-441524 trough concentration ≥70 ng/mL.

Patients With Inflammatory Bowel Diseases and Higher Visceral Adipose Tissue Burden May Benefit From Higher Infliximab Concentrations to Achieve Remission.

In patients with inflammatory bowel diseases (IBDs), high visceral adipose tissue (VAT) burden is associated with a lower response to infliximab, potentially through alterations in volume distribution and/or clearance. Differences in VAT may also explain the heterogeneity in target trough levels of infliximab associated with favorable outcomes. The aim of this study was to assess whether VAT burden may be associated with infliximab cutoffs associated with efficacy in patients with IBD. We conducted a prospective cross-sectional study of patients with IBD receiving maintenance infliximab therapy. We measured baseline body composition parameters (Lunar iDXA), disease activity, trough levels of infliximab, and biomarkers. The primary outcome was steroid-free deep remission. The secondary outcome was endoscopic remission within 8 weeks of infliximab level measurement. Overall, 142 patients were enrolled. The optimal trough levels of infliximab cutoffs associated with steroid-free deep remission and endoscopic remission were 3.9 mcg/mL (Youden Index [J]: 0.52) for patients in the lowest 2 VAT % quartiles (<1.2%) while optimal infliximab level cutoffs associated with steroid-free deep remission for those patients in the highest 2 VAT % quartiles was 15.3 mcg/mL (J: 0.63). In a multivariable analysis, only VAT % and infliximab level remained independently associated with steroid-free deep remission (odds ratio per % of VAT: 0.3 [95% confidence interval: 0.17-0.64], P < 0.001 and odds ratio per μg/mL: 1.11 [95% confidence interval: 1.05-1.19], P < 0.001). The results may suggest that patients with higher visceral adipose tissue burden may benefit from achieving higher infliximab levels to achieve remission.

ALPS like: Trekking Sirolimus and its Fallouts

A three-year-old male presented to our multispecialty clinic with recurrent fever without periodicity, neutropenia, diffuse lymphadenopathy, and splenomegaly. Family history was notable for two maternal cousins with hypogammaglobulinemia and neutropenia. Pertinent labs include elevated CD3 positive, double negative cells (7.7%, 156 cells/mcl), elevated IL-10 (85.6 pg/mL); and elevated IL-18 (3145 pg/mL). Rheumatologic studies returned unremarkable (ANA was weakly positive, with extracted nuclear antigen antibody panel within normal limits). Abdominal ultrasound revealed splenomegaly (14 cm). Whole genome sequencing for the patient and parents was negative, including no diagnostic abnormalities in the FAS, FASLG or CASP10 genes.The patient was diagnosed with probable ALPS, per the 2009 revised ALPS criteria (Oliveira et al, Blood, 2010). He was started on colchicine for fevers but was transitioned to sirolimus several weeks later due to lack of clinical improvement. Mirroring a prior study that evaluated sirolimus for children with ALPS, sirolimus was initiated at a dose of 2.3 mg/m2, targeting goal trough levels 5–15 ng/mL (Bride et al. Blood, 2016). Sirolimus trough levels are depicted in Table 1 and Figure 1. [Display omitted] At follow up 3 months later, the patient’s CD3 positive, double negative T cells normalized (0.2%, 3 cells/mcl), splenomegaly improved (10.7 cm), lymphadenopathy was no longer palpable, and cytokine levels normalized. Despite consecutive subtherapeutic sirolimus trough levels preceding the 3-month evaluation, probable ALPS markers improved.Sirolimus has caused toxicity. Baseline lipid panel prior to sirolimus therapy demonstrated elevated triglycerides and low HDL, likely related to ALPS (Sriram et al, Case Reports Immunol, 2016). While HDL improved, total cholesterol and LDL increased and triglycerides remain elevated. He has developed hypertension while on sirolimus.These findings demonstrate that sirolimus trough alone may not predict clinical response. Given the excellent correlation between trough levels and area under the concentration-time curve (AUC) for sirolimus (Stenton et al. Clin Pharmacokinetics 2005), it is unlikely that AUC sirolimus measurements would either be of clinical benefit or better explain the patient’s clinical response. This patient’s excellent clinical response despite multiple subtherapeutic sirolimus trough levels suggests that further research to determine the optimal sirolimus trough range may be indicated.

P713 Proactive therapeutic infliximab monitoring during induction phase in inflammatory bowel disease

Abstract Background Therapeutic drug monitoring (TDM) of infliximab (IFX) in patients with Crohn’s disease (CD) and ulcerative colitis (UC) is increasingly used in clinical routine, although proactive TDM is still controversial. Nevertheless, disease activity and drug clearance are higher at the induction phase leading to an increased risk of inadequate drug exposure and treatment failure. The aim of the study was to evaluate the efficacy of the implementation of an early proactive TDM strategy, comparing clinical remission (CR) and biochemical remission (BR) at week 14 and 52, and endoscopic improvement (EI) between two groups. Methods Retrospective cohort study conducted in an Inflammatory Bowel Disease (IBD) unit of a tertiary care hospital. Biologic-naïve patients diagnosed of CD or UC who initiated IFX from 2019 to 2021 (p-TDM group) and from 2016 to 2019 (no-TDM group) were included. In the p-TDM group, proactive IFX trough levels and antidrug antibodies were measured since week 2 and dose adjustment since week 6 was performed using a previously validated population pharmacokinetic model (Fasanmade et al. Clinical Therapeutics 2011). In the no-TDM group, dose escalation was performed considering symptoms, blood, or stool results. CR was defined as Harvey-Bradshaw Index &amp;lt;5 in CD and partial Mayo clinic score &amp;lt;3 in UC. BR was stablished as fecal calprotectin (FCP) &amp;lt;150 mcg/g or c-reactive protein &amp;lt;0.5 mg/dL. EI was defined as lack of ulcerations in CD and Mayo endoscopic score 0-1 in UC. A combined variable to evaluate objective remission (OR) at week 52 was defined as: FCP &amp;lt;150 mcg/g or EI in UC, and EI or radiologic improvement (MRI) in CD. Moreover, surgery, hospitalization and treatment discontinuation rates were compared between both groups. Results 30 patients were included in each group: 13 UC, 16 CD and 1 IBD unclassified. There were no statistical differences in baseline characteristic between groups (table 1). Outcomes at week 14 and 52 are shown in table 2. At week 14, CR rate was significantly higher in p-TDM than in no-TDM (86.7% vs 56.7%, p=0.01). Although BR rate at week 14 was numerically higher in p-TDM, it did not achieve statistical significance (61.1% in p-TDM vs 50.0% in no-TDM, p=0.59). However, limitations in blood and stool collection were considerable at this timepoint. During first year, hospitalizations tend to be fewer in p-TDM group. There were no statistically differences in CR and BR or in EI between groups at week 52. Although OR rate was higher in p-TDM than in no-TDM, it did not reach statistical significance (60.9% vs 33.3%, p=0.06). Conclusion Proactive TDM during induction phase, especially in naïve patients, could be a useful tool to obtain optimal IFX trough levels and to classify correctly primary failure.

Physician awareness and understanding of primary immunodeficiency disorders: a web-based study in Japan

Primary immunodeficiencies (PIDs)/Inborn errors of immunity (IEI) consist of a complex genetic group of disorders that cause susceptibility to infections, inflammation, immune dysregulation, autoimmunity, and malignancy. One of the key steps to reach an early diagnosis is improving knowledge of PID among the medical community. In this study, a web-based survey was conducted among 355 Japanese physicians, consisting of 121 pediatricians, 116 hematologists, and 118 general internal medicine physicians, to assess their awareness and knowledge about the diagnostic flow of PID. One of the major problems this study identified was the unawareness of optimal IgG trough levels among the physicians, while around half the physicians knew about the symptoms of PID. Results from the hypothetical case study revealed that over 70% of physicians considered PID after obtaining the past medical history of patients and 75.2% of physicians showed interest in gaining more knowledge about PID. The survey findings revealed that proper questioning to understand the exact medical history of patients may lead to basic immunological examination. There is a need to improve knowledge about PID, e.g., the ‘10 warning signs of PID’ and ‘4 stages of testing for PID’, and to motivate physicians to ensure earlier diagnosis of PID.

Effects of feed trough positioning height on growth performance, feed loss, feeding environment, and behavior of geese

In the traditional feeding pattern of geese, the feed trough will be placed on the ground for a long time and hurts the living environment. This research aimed to investigate the effect of 4 different feed trough positioning heights on growth performance, blood parameters, feed loss, water consumption, feeding environment, and behavior of geese and determine the optimal trough positioning height for 28 to 70-d geese. A total of one hundred ninty-two 28-d male Yuzhou white geese were allocated randomly to 4 groups with 6 replicate pens per group according to the trough positioning height (on the ground [D], one-third [L], two-thirds [M], and the same height of geese's beak above the ground [H], respectively). The results show that the growth performance and blood biochemical parameters have no significant difference among groups (P > 0.05). The average daily feed loss and water consumption presented the lowest value in group H (P < 0.01). The hygienic condition index of the feed and feed trough increased as trough positioning height. Feed from group H had a higher cleanliness score than other groups (P < 0.001). The count of microbes (total bacteria, Staphylococcus aureus, and Escherichia coli) on the surface of the feed trough from group H was lower than other groups (P < 0.001). Geese from group H had shorter daily feeding and drinking time than other groups (P < 0.05). Overall, these data indicate the same trough positioning height with geese's beaks could lower feed loss, and water consumption and improve hygienic conditions without damage to growth performance and will be the optimal choice for geese.

Toward optimization of cyclosporine concentration target to prevent acute graft‐versus‐host disease following myeloablative allogeneic stem cell transplant

Despite the common use of cyclosporine (CsA) for acute graft-versus-host disease (aGVHD) prophylaxis following allogeneic stem cell transplant, the optimal CsA trough target remains unknown. Here, we report on outcomes of adult patients following myeloablative conditioning to identify an optimal CsA trough target and characterize the most relevant timeframe post-transplant for CsA trough targeting to minimize aGVHD. We retrospectively reviewed 399 consecutive patients who underwent first peripheral blood allogeneic stem cell transplant for hematological malignancies between January 2009 and December 2018. In the unadjusted and adjusted analyses, the incidence of grades 2-4 aGVHD was significantly higher among patients with an average CsA trough concentration <250mcg/L compared to patients with an average CsA trough concentration ≥250mcg/L during days 15-28 post-transplant (31.5% versus 18.8%, P = 0.037), with an odds ratio (OR) of 1.97 (95% confidence interval 1.04-3.71). In contrast, no correlations between CsA trough concentration and relapse, non-relapse mortality and overall survival was found. In conclusion, early post-transplant CsA trough concentrations are an important factor in the prophylaxis against aGVHD. Our findings suggest that CsA trough concentrations should be maximized between days 15-28 post-myeloablative transplant.

Ustekinumab trough levels predicting laboratory and endoscopic remission in patients with Crohn\u2019s disease

BackgroundsOptimal concentration of ustekinumab (UST) predicting endoscopic remission has not been fully investigated in Crohn’s disease (CD). We aimed to identify the optimal UST trough levels predicting clinical, laboratory and endoscopic remission in CD patients.MethodsTwenty-eight patients with CD were enrolled and investigated (27 patients by enteroscopy and 1 by colonoscopy). The endoscopic activity was assessed using the scoring system that applied the Rutgeerts score to observed intestine. Serum UST trough levels and anti-UST antibodies (AUAs) levels were determined by in-house immunoassays.ResultsEndoscopic activity was negatively correlated with serum UST trough levels (Spearman’s rank correlation coefficient (ρ) = − 0.66, P = 0.0001) and serum albumin levels (ρ = − 0.60, P = 0.0007). The endoscopic activity was positively and significantly correlated with CRP (ρ = 0.59, P = 0.0009) and ESR (ρ = 0.44, P = 0.033). There was no significant association between the endoscopic score and AUA levels and/or Crohn’s disease activity index (CDAI). Serum UST trough levels and albumin levels were significantly higher in the endoscopic remission group (scores of 0 and 1) than in the non-endoscopic remission group (UST trough, mean 3.3 vs. 1.8 μg/mL). No significant difference was observed in AUAs between the endoscopic remission and non-remission groups. Receiver operation curve (ROC) analysis revealed that the optimal cutoff value of UST trough levels predicting normal CRP and serum albumin levels was 1.7 μg/mL for each, and the optimal cutoff value predicting endoscopic remission was 2.0 μg/mL (AUC: 0.80, 95% CI 0.64–0.96).ConclusionAchievement of endoscopic remission requires higher UST trough levels than required for normalization of CRP and serum albumin levels.

Expert opinion on current and future prophylaxis therapies aimed at improving protection for people with hemophilia A.

The next frontier in hemophilia A management has arrived. However, questions remain regarding the broader applicability of new and emerging hemophilia A therapies, such as the long-term safety and efficacy of non-factor therapies and optimal regimens for individual patients. With an ever-evolving clinical landscape, it is imperative for physicians to understand how available and future hemophilia A therapies could potentially be integrated into real-life clinical practice to improve patient outcomes. Against this background, nine hemophilia experts from Central European countries participated in a pre-advisory board meeting survey. The survey comprised 11 multiple-choice questions about current treatment practices and future factor and non-factor replacement therapies. The survey questions were developed to reflect current unmet needs in hemophilia management reflected in the literature. The experts also took part in a follow-up advisory board meeting to discuss the most important unmet needs for hemophilia management as well as the pre-meeting survey results. All experts highlighted the challenge of maintaining optimal trough levels with prophylaxis as their most pressing concern. Targeting trough levels of ≥30–50 IU/L or even higher to achieve less bleeding was highlighted as their preferred strategy. However, the experts had an equal opinion on how this could be achieved (i.e., more efficacious non-factor therapies or factor therapy offering broader personalization possibilities such as targeting trough levels to individual pharmacokinetic data). In summary, our study favors personalized prophylaxis to individual pharmacokinetic data rather than a "one-size-fits-all" approach to hemophilia A management to maintain optimal trough levels for individual patients.

Therapeutic Drug Monitoring of Anti-Thymocyte Globulin in Allogeneic Stem Cell Transplantation: Proof of Concept.

Anti-thymocyte globulin (ATG), a polyclonal antibody, is used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-vs.-host-disease (GvHD) and graft failure (GF). Overexposure to ATG leads to poor early T-cell recovery, which is associated with viral infections and poor survival. Patients with severe inflammation are at high risk for GF and GvHD, and may have active infections warranting swift T-cell recovery. As ATG exposure may be critical in these patients, individualized dosing combined with therapeutic drug monitoring (TDM) may improve outcomes. We describe the individualized dosing approach, an optimal sampling scheme, the assay to measure the active fraction of ATG, and the workflow to perform TDM. Using a previously published population pharmacokinetic (PK) model, we determine the dose to reach optimal exposures associated with low GvHD and rejection, and at the same time promote T-cell recovery. Based on an optimal sampling scheme, peak and trough samples are taken during the first 3 days of once-daily dosing. The fraction of ATG able to bind to T-cells (active ATG) is analyzed using a bio-assay in which Jurkat cells are co-cultured with patient’s plasma and the binding is quantified using flow cytometry. TDM is performed based on these ATG concentrations on the third day of dosing; subsequent doses can be adjusted based on the expected area under the curve. We show that individualized ATG dosing with TDM is feasible. This approach is unique in the setting of antibody treatment and may result in better immune reconstitution post-HCT and subsequently better survival chances.