Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals.

Vaccine-mediated immunity often relies on the generation of protective antibodies and memory B cells, which commonly stem from germinal center (GC) reactions. An in-depth comparison of the GC responses elicited by SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals has not yet been performed due to the challenge of directly probing human lymph nodes. Herein, through a fine-needle aspiration-based approach, we profiled the immune responses to SARS-CoV-2 mRNA vaccines in lymph nodes of healthy individuals and kidney transplant recipients (KTXs). We found that, unlike healthy subjects, KTXs presented deeply blunted SARS-CoV-2-specific GC B cell responses coupled with severely hindered T follicular helper cell, SARS-CoV-2 receptor binding domain-specific memory B cell, and neutralizing antibody responses. KTXs also displayed reduced SARS-CoV-2-specific CD4 and CD8 T cell frequencies. Broadly, these data indicate impaired GC-derived immunity in immunocompromised individuals and suggest a GC origin for certain humoral and memory B cell responses following mRNA vaccination.

Dielectric Characterization of H2O and CO2 Uptake by Polyethylenimine Films.

The absorption of CO2 by polyethylenimine polymer (PEI) materials is of great interest in connection with proposed carbon capture technologies, and the successful development of this technology requires testing methods quantifying the amount of CO2, H2O, and reaction byproducts under operating conditions. We anticipate that dielectric measurements have the potential for quantifying both the extent of CO2 and H2O absorption within the PEI matrix material as well as insights into subsequent reaction byproducts that can be expected to occur in the presence of moisture. The complexity of the chemistry involved in this reactive binding process clearly points to the need for the use of additional spectroscopic techniques to better resolve the multiple components involved and to validate the model-dependent findings from the dielectric measurements. Here, we employed noncontact resonant microwave cavity instrumentation operating at 7.435 GHz that allows for the precise determination of the complex dielectric permittivity of CO2 films exposed to atmospheres of controlled relative humidity (RH), and N2:CO2 compositions. We find that the addition of CO2 leads to a considerable increase in dielectric loss of the PEI film relative to loss measured in nitrogen (N2) atmosphere across the same RH range. We attribute this effect to a reaction between CO2 and PEI generating a charged dielectrically active species contributing to the dielectric loss in the presence of moisture. Possible reaction mechanisms accounting for these observations are discussed, including the formation of carbamate-ammonium pairs and ammonium cations stabilized by bicarbonate anions that have sufficient local mobility to be dielectrically active in the investigated microwave frequency range. Understanding of these reaction mechanisms and the development of tools to quantify the amount of reactive byproducts are expected to be critical for the design and optimization of carbon capture materials.

Starvation selection reduces and delays larval ecdysone production and signaling.

Previous studies have shown that selection for starvation resistance in Drosophila melanogaster results in delayed eclosion and increased adult fat stores. It is assumed that these traits are caused by the starvation selection pressure, but its mechanism is unknown. We found that our starvation-selected (SS) population stores more fat during larval development and has extended larval development and pupal development time. Developmental checkpoints in the third instar associated with ecdysteroid hormone pulses are increasingly delayed. The delay in the late larval period seen in the SS population is indicative of reduced and delayed ecdysone signaling. An enzyme immunoassay for ecdysteroids (with greatest affinity to the metabolically active 20-hydroxyecdysone and the α-ecdysone precursor) confirmed that the SS population had reduced and delayed hormone production compared with that of fed control (FC) flies. Feeding third instar larvae on food supplemented with α-ecdysone partially rescued the developmental delay and reduced subsequent adult starvation resistance. This work suggests that starvation selection causes reduced and delayed production of ecdysteroids in the larval stage and affects the developmental delay phenotype that contributes to subsequent adult fat storage and starvation resistance.

A survey of solid organ transplant recipient attitudes and concerns regarding contraception and pregnancy.

INTRODUCTION: Many women who are solid organ transplant (SOT) recipients wish to have children after transplantation. Contraception is an important component of post-transplant planning and care, given the increased risk associated with post-transplant pregnancies. We sought to understand patient attitudes and concerns about post-transplant contraception and pregnancy. METHODS: Following a comprehensive literature review, our team developed a survey that was administered to female SOT recipients of childbearing age. We used descriptive and inferential statistics to characterize participant views RESULTS: A total of 243 transplant recipients completed the survey (80.7% response rate). The mean age of respondents was 37.5 years (±8.1 years), 66.7% were kidney recipients, and 40.7% were within the first year after transplant. The most common concerns among respondents included fetal and maternal health complications. Participants generally did not agree that transplant recipients should be advised to avoid pregnancy. There was strong support for shared decision-making about pregnancy after transplantation CONCLUSION: Understanding patient perspectives can help transplant providers make better care recommendations and support patient autonomy in reproductive decisions post-transplant. Given that there are some differences in views by transplant type, individualized conversations between patients and providers are needed.

Outcomes in kidney transplant recipients treated with immediate-release tacrolimus capsules versus extended-release tacrolimus capsules: A cohort study.

INTRODUCTION: Prior randomized trials and observational studies have generally reported similar outcomes in kidney transplant recipients (KTRs) treated with immediate-release tacrolimus (IR-TAC) versus extended-release tacrolimus (ER-TAC). However, many of these previous studies focused on patients with low immunological risks, had small sample sizes and brief follow-up periods, and excluded outcomes associated with graft loss, such as chronic rejection. METHODS: To address these limitations, we conducted a cohort study of 848 KTRs at a single transplantation center who had generally high immunological risks and were treated with either IR-TAC capsules (589 patients, 65.9%) or ER-TAC capsules (289 patients, 34.1%). All patients received their designated maintenance immunosuppressive regimen for at least 3 months post-transplantation. Afterwards, tacrolimus formulation was at the discretion of each patient's transplant nephrologist. For the two treatment groups, we compared the hazards of experiencing a composite outcome of acute or chronic antibody-mediated rejection (AMR), acute or chronic T-cell-mediated rejection, de novo DSA, and/or graft loss over a 3-year period starting at 3 months post-transplantation. RESULTS: In a multivariable Cox proportional hazards regression model, KTRs treated with IR-TAC capsules had an increased hazard of experiencing the composite outcome when compared to patients treated with ER-TAC capsules; however, this result was not significant (adj HR 1.24, 95% CI .92-1.68, p = .163). Similar results were obtained with inverse probability of treatment weighting (IPTW) using a propensity score (adj HR 1.25, 95% CI .93-1.68, p = .146). CONCLUSION: These findings suggest that when compared to IR-TAC capsules, ER-TAC capsules do not reduce the hazard of poor outcomes in KTRs with generally high immunological risks.

Should responder analyses be conducted on continuous outcomes?

Continuous outcomes are often dichotomized to classify trial subjects as responders or nonresponders, with the difference in rates of response between treatment and control defined as the "responder effect." In this article, we caution that dichotomization of continuous interval outcomes may not be best practice. Defining clinical benefit or harm for continuous interval outcomes as the difference between the means of treatment and control, that is, the "continuous treatment effect," we examine the case where treatment and control outcomes are normally distributed and differ only in location. For this case, continuous treatment effects may be considered clinically relevant if they exceed a prespecified minimum clinically important difference. In contrast, using minimum clinically important differences as dichotomization thresholds will not ensure clinically relevant responder effects. For example, in some situations, increasing the threshold may actually relax the criterion for effectiveness by increasing the calculated responder effect. Using responder effects to quantitatively assess benefit or risk of investigational drugs for continuous interval outcomes presents interpretational challenges. In particular, when the dichotomization threshold is halfway between the treatment and control outcome means, the responder effect is at a maximum with a magnitude monotonically related to the number of standard deviations between the mean outcomes of treatment and control. Large responder effect benefits may therefore reflect clinically unimportant continuous treatment effects amplified by small standard deviations, and small responder effect risks may reflect either clinically important continuous treatment effects minimized by large standard deviations, or selection of a dichotomization threshold not providing maximum responder effect.

Statistical methods for handling missing data to align with treatment policy strategy.

The International Council for Harmonization (ICH) E9(R1) addendum recommends choosing an appropriate estimand based on the study objectives in advance of trial design. One defining attribute of an estimand is the intercurrent event, specifically what is considered an intercurrent event and how it should be handled. The primary objective of a clinical study is usually to assess a product's effectiveness and safety based on the planned treatment regimen instead of the actual treatment received. The estimand using the treatment policy strategy, which collects and analyzes data regardless of the occurrence of intercurrent events, is usually utilized. In this article, we explain how missing data can be handled using the treatment policy strategy from the authors' viewpoint in connection with antihyperglycemic product development programs. The article discusses five statistical methods to impute missing data occurring after intercurrent events. All five methods are applied within the framework of the treatment policy strategy. The article compares the five methods via Markov Chain Monte Carlo simulations and showcases how three of these five methods have been applied to estimate the treatment effects published in the labels for three antihyperglycemic agents currently on the market.

A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1.

The ability to quickly discover reliable hits from screening and rapidly convert them into lead compounds, which can be verified in functional assays, is central to drug discovery. The expedited validation of novel targets and the identification of modulators to advance to preclinical studies can significantly increase drug development success. Our SaXPyTM ("SAR by X-ray Poses Quickly") platform, which is applicable to any X-ray crystallography-enabled drug target, couples the established methods of protein X-ray crystallography and fragment-based drug discovery (FBDD) with advanced computational and medicinal chemistry to deliver small molecule modulators or targeted protein degradation ligands in a short timeframe. Our approach, especially for elusive or "undruggable" targets, allows for (i) hit generation; (ii) the mapping of protein-ligand interactions; (iii) the assessment of target ligandability; (iv) the discovery of novel and potential allosteric binding sites; and (v) hit-to-lead execution. These advances inform chemical tractability and downstream biology and generate novel intellectual property. We describe here the application of SaXPy in the discovery and development of DNA damage response inhibitors against DNA polymerase eta (Pol η or POLH) and apurinic/apyrimidinic endonuclease 1 (APE1 or APEX1). Notably, our SaXPy platform allowed us to solve the first crystal structures of these proteins bound to small molecules and to discover novel binding sites for each target.

MRI of the live fish brain at 3 Tesla: Feasibility, technique and interspecies anatomic variations.

Advances in aquatic animal medicine and continued growth of the fish hobbyist and aquaculture communities have led to a developing interest in antemortem diagnostic imaging of aquatic species. The aims of this prospective, pilot study were to determine whether advanced neuroimaging can be safely achieved in live fish using clinically available equipment, to optimize imaging parameters, and to develop a comparative MRI atlas of a few fish species of economic or research value. Two each of channel catfish (Ictalurus punctatus), koi (Cyprinus rubrofuscus), and grass carp (Ctenopharyngodon idella) of at least 30 cm in length were individually anesthetized for 3 Tesla (3T) magnetic resonance imaging (MRI) of the brain. All fish achieved an adequate anesthetic level for prolonged immobilization during imaging. Diagnostic quality images were obtained for all subjects; however, the spatial resolution was maximized with larger fish. Imaging protocols were optimized for standard neuroimaging sequences. Additionally, inversion times for fluid-attenuation inversion recovery (FLAIR) sequences were adapted to the naturally high protein content of fish pericerebral fluid. Following imaging, the fish successfully recovered from anesthesia, were humanely euthanized, and were immediately processed to assess brain histopathology. Necropsy confirmed the sex and health status of each fish. A limited comparative MRI atlas was created of the brains of these species for clinical reference. Findings from the current study supported the use of 3T MRI as an adjunct diagnostic test for fish with suspected neurologic disease and provided a limited anatomic atlas of the teleost brain for use as a reference.

Association of donor hepatitis C virus infection status and risk of BK polyomavirus viremia after kidney transplantation.

Kidney transplantation (KT) from deceased donors with hepatitis C virus (HCV) into HCV-negative recipients has become more common. However, the risk of complications such as BK polyomavirus (BKPyV) remains unknown. We assembled a retrospective cohort at four centers. We matched recipients of HCV-viremic kidneys to highly similar recipients of HCV-aviremic kidneys on established risk factors for BKPyV. To limit bias, matches were within the same center. The primary outcome was BKPyV viremia ≥1000 copies/ml or biopsy-proven BKPyV nephropathy; a secondary outcome was BKPyV viremia ≥10 000 copies/ml or nephropathy. Outcomes were analyzed using weighted and stratified Cox regression. The median days to peak BKPyV viremia level was 119 (IQR 87-182). HCV-viremic KT was not associated with increased risk of the primary BKPyV outcome (HR 1.26, p = .22), but was significantly associated with the secondary outcome of BKPyV ≥10 000 copies/ml (HR 1.69, p = .03). One-year eGFR was similar between the matched groups. Only one HCV-viremic kidney recipient had primary graft loss. In summary, HCV-viremic KT was not significantly associated with the primary outcome of BKPyV viremia, but the data suggested that donor HCV might elevate the risk of more severe BKPyV viremia ≥10 000 copies/ml. Nonetheless, one-year graft function for HCV-viremic recipients was reassuring.

Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma.

Severe asthma is associated with the production of interleukin 17A (IL-17A). The exact role of IL-17A in severe asthma and the factors that drive its production are unknown. Here we demonstrate that IL-17A mediated severe airway hyperresponsiveness (AHR) in susceptible strains of mice by enhancing IL-13-driven responses. Mechanistically, we demonstrate that IL-17A and AHR were regulated by allergen-driven production of anaphylatoxins, as mouse strains deficient in complement factor 5 (C5) or the complement receptor C5aR mounted robust IL-17A responses, whereas mice deficient in C3aR had fewer IL-17-producing helper T cells (T(H)17 cells) and less AHR after allergen challenge. The opposing effects of C3a and C5a were mediated through their reciprocal regulation of IL-23 production. These data demonstrate a critical role for complement-mediated regulation of the IL-23-T(H)17 axis in severe asthma.

Tolerability of mycophenolate mofetil in elderly kidney transplant recipients: A retrospective cohort study.

BACKGROUND: Optimal immunosuppression in elderly kidney transplant recipients (KTRs) is not well defined, with mycophenolate mofetil (MMF) being poorly tolerated. Study aim was to compare MMF dose reduction incidence and reason(s) in elderly vs. nonelderly KTRs in the 1st year after transplant with a protocol dose of 1 g/day. METHODS: In this single-center retrospective study, first or repeat KTRs receiving rabbit antithymocyte globulin (rATG), MMF 1 g/day, tacrolimus, and prednisone, were stratified by age [≥60 (elderly) or <60 years (nonelderly)]. Primary outcome was MMF dose reduction incidence in the first year. Secondary outcomes included dose reduction rationale, 1-year patient and graft survival, graft function, rejection, infection, hospital presentation, and time to dose reduction. Of 335 KTRs, dose reduction incidence was significantly greater in the elderly group (66% and 54%, p = 0.04), though this did not remain significant when adjusted for sex, race, and valganciclovir use. Most common rationale was leukopenia in the elderly group and CMV in the nonelderly group. There were no significant differences in secondary outcomes. CONCLUSIONS: Mycophenolate mofetil 1 g/day was poorly tolerated in both elderly and nonelderly KTRs receiving lymphocyte-depleting induction with a high incidence of dose reductions; however, no short-term adverse graft outcomes were identified.

Synchronous Telehealth Yoga and Cognitive Processing Group Therapies for Women Veterans with Posttraumatic Stress Disorder: A Multisite Randomized Controlled Trial Adapted for COVID-19.

Background: Providing care over telehealth grew slowly until the COVID-19 pandemic. Since the onset of the COVID-19 pandemic, providing mental health care was readily adapted to virtual means; however, clinical trial research is nascent in adapting methods and procedures to the virtual world. Methods: We present protocol modifications to pivot a multisite randomized controlled trial study, conducted at Southeastern and Pacific Northwestern Veterans Affairs Health Care Systems, from being conducted in-person to virtually, following the onset of the COVID-19 pandemic. We measured outcomes of posttraumatic stress disorder (PTSD) symptoms and psychophysiological markers of stress among female Veterans with PTSD secondary to military sexual trauma. We collected qualitative data about provider and participant experiences with telehealth. Results: Across sites, 200 participants were consented (48 virtually), 132 were randomized (28 to virtual groups), and 117 completed data collection and treatment (69 completed all or some data collection or treatment virtually). Conclusions: The pivots made for this study were in response to the COVID-19 pandemic and offer innovative procedures leveraging technology and contributing to the broader landscape of conducting research virtually. Clinical Trials Number: NCT02640690.

Approach to Cystic Lesions in the Abdomen and Pelvis, with Radiologic-Pathologic Correlation.

Cystic lesions found in and around the peritoneal cavity can often be challenging to diagnose owing to significant overlap in imaging appearance between the different entities. When the cystic lesion can be recognized to arise from one of the solid abdominal organs, the differential considerations can be more straightforward; however, many cystic lesions, particularly when large, cannot be clearly associated with one of the solid organs. Cystic lesions arising from the mesentery and peritoneum are less commonly encountered and can be caused by relatively rare entities or by a variant appearance of less-rare entities. The authors provide an overview of the classification of cystic and cystic-appearing lesions and the basic imaging principles in evaluating them, followed by a summary of the clinical, radiologic, and pathologic features of various cystic and cystic-appearing lesions found in and around the peritoneal cavity, organized by site of origin. Emphasis is given to lesions arising from the mesentery, peritoneum, or gastrointestinal tract. Cystic lesions arising from the liver, spleen, gallbladder, pancreas, urachus, adnexa, or soft tissue are briefly discussed and illustrated with cases to demonstrate the overlap in imaging appearance with mesenteric and peritoneal cystic lesions. When approaching a cystic lesion, the key imaging features to assess include cyst content, locularity, wall thickness, and presence of internal septa, solid components, calcifications, or any associated enhancement. While definitive diagnosis is not always possible with imaging, careful assessment of the imaging appearance, location, and relationship to adjacent structures can help narrow the differential diagnosis. Online supplemental material is available for this article. ©RSNA, 2021.

DFT Analysis of Organotin Catalytic Mechanisms in Dehydration Esterification Reactions for Terephthalic Acid and 2,2,4,4-Tetramethyl-1,3-cyclobutanediol.

Polyesters synthesized from 2,2,4,4-tetramethyl-1,3-cyclobutanediol (TMCD) and terephthalic acid (TPA) are improved alternatives to toxic polycarbonates based on bisphenol A. In this work, we use ωB97X-D/LANL2DZdp calculations, in the presence of a benzaldehyde polarizable continuum model solvent, to show that esterification of TMCD and TPA will reduce and subsequently dehydrate a dimethyl tin oxide catalyst, becoming ligands on the now four-coordinate complex. This reaction then proceeds most plausibly by an intramolecular acyl-transfer mechanism from the tin complex, aided by a coordinated proton donor such as hydronium. These findings are a key first step in understanding polyester synthesis and avoiding undesirable side reactions during production.

Stability and sub-cellular localization of DNA polymerase ß is regulated by interactions with NQO1 and XRCC1 in response to oxidative stress.

Protein-protein interactions regulate many essential enzymatic processes in the cell. Somatic mutations outside of an enzyme active site can therefore impact cellular function by disruption of critical protein-protein interactions. In our investigation of the cellular impact of the T304I cancer mutation of DNA Polymerase ß (Polß), we find that mutation of this surface threonine residue impacts critical Polß protein-protein interactions. We show that proteasome-mediated degradation of Polß is regulated by both ubiquitin-dependent and ubiquitin-independent processes via unique protein-protein interactions. The ubiquitin-independent proteasome pathway regulates the stability of Polß in the cytosol via interaction between Polß and NAD(P)H quinone dehydrogenase 1 (NQO1) in an NADH-dependent manner. Conversely, the interaction of Polß with the scaffold protein X-ray repair cross complementing 1 (XRCC1) plays a role in the localization of Polß to the nuclear compartment and regulates the stability of Polß via a ubiquitin-dependent pathway. Further, we find that oxidative stress promotes the dissociation of the Polß/NQO1 complex, enhancing the interaction of Polß with XRCC1. Our results reveal that somatic mutations such as T304I in Polß impact critical protein-protein interactions, altering the stability and sub-cellular localization of Polß and providing mechanistic insight into how key protein-protein interactions regulate cellular responses to stress.

In patients with ASCVD and elevated LDL-C with maximal statin therapy, inclisiran reduced LDL-C levels at 18 months.

SOURCE CITATION: Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382:1507-19. 32187462.

Kidney transplantation and donation in the transgender population: A single-institution case series.

The medical needs of the transgender population are increasingly recognized within the US health care system. Hormone therapy and gender-affirming surgery present distinct anatomic, hormonal, infectious, and psychosocial issues among transgender kidney transplant donors and recipients. We present the first reported experience with kidney transplantation and donation in transgender patients. A single-center case series (January 2014-December 2018) comprising 4 transgender kidney transplant recipients and 2 transgender living donors was constructed and analyzed. Experts in transplant surgery, transplant psychiatry, transplant infectious disease, pharmacy, and endocrinology were consulted to discuss aspects of care for these patients. Four transgender patients identified as male-to-female and 2 as female-to-male. Three of 6 had gender-affirming surgeries prior to transplant surgery, 1 of whom had further procedures posttransplant. Additionally, 4 patients were on hormone therapy. All 6 had psychiatric comorbidities. The 4 grafts have done well, with an average serum creatinine of 1.45 mg/dL at 2 years (range 1.01-1.85 mg/dL). However, patients encountered various postoperative complications, 1 of which was attributable to modified anatomy. Thus, transgender kidney transplant patients can present novel challenges in regard to surgical considerations as well as pre- and posttransplant care. Dedicated expertise is needed to optimize outcomes for this population.

Use of Dietary Supplements in Living Kidney Donors: A Critical Review.

Dietary supplement use is high among US adults, with the intention by users to promote overall health and wellness. Kidney donors, who are selected based on their overall good health and wellness, can have high utilization rates of dietary supplements. We provide a framework for the evaluation of living kidney donors and use of dietary supplements. In this review, dietary supplements will include any orally administered dietary or complementary nutritional products, but excluding micronutrients (vitamins and minerals), food, and cannabis. Use of dietary supplements can influence metabolic parameters that mask future risk for chronic illness such as diabetes and hypertension. Dietary supplements can also alter bleeding risk, anesthesia and analgesic efficacy, and safety in a perioperative period. Finally, postdonation monitoring of kidney function and risk for supplement-related nephrotoxicity should be part of a kidney donor educational process. For practitioners evaluating a potential kidney donor, we provide a list of the most commonly used herbal supplements and the effects on evaluation in a predonation, perioperative donation, and postoperative donation phase. Finally, we provide recommendations for best practices for integration into a comprehensive care plan for kidney donors during all stages of evaluation. We recommend avoidance of dietary supplements in a kidney donor population, although there is a paucity of data that identifies true harm. Rather, associations, known mechanisms of action, and common sense suggest that we avoid use in this population.

Chronopharmacokinetics and Food Effects of Single-Dose LCP-Tacrolimus in Healthy Volunteers.

BACKGROUND: A modified-release version of tacrolimus, LCP-tacrolimus (LCPT; Envarsus XR, Veloxis Pharmaceuticals, Cary, NC), has been licensed in the United States for prophylaxis of organ rejection in de novo kidney transplant patients. As tacrolimus has a narrow therapeutic window, the impact of circadian patterns on LCPT drug exposure, including food and chronopharmacokinetic effects, needs to be elucidated to optimize dosing. METHODS: Two randomized, crossover, phase 1 studies were conducted in healthy volunteers. The first assessed the effect of morning versus evening dosing on the pharmacokinetic profile of LCPT 2 mg; the second assessed the effect of food on the pharmacokinetic profile of LCPT 5 mg. In both, blood samples were drawn from participants for up to 144 hours after administration of a single LCPT dose. RESULTS: No significant differences were observed between evening and morning dosing in peak blood concentration (4.4 versus 4.0 ng/mL; P = 0.27), area under the time-concentration curve (AUC) from time 0 to time of the last concentration (89.1 versus 102.6 ng/mL; P = 0.20), AUC from time 0 to infinity (99.7 versus 114.3 ng·h/mL; P = 0.18), AUC from 0 to 24 hours post-dose (AUC0-24; 49.4 versus 51.6 ng·h/mL; P = 0.56), time to reach maximum blood concentration (median, 6.0 versus 6.0 hours; P = 0.91), total clearance (arithmetic mean = 21.5 versus 19.5 L/h; P = 0.50), or terminal half-life (arithmetic mean = 26.8 versus 28.1 hours; P = 0.26). After a high-calorie meal in the morning, the AUC0-24 reduced by 54% (ratio of geometric means = 45.6%; P < 0.0001) and peak blood concentration reduced by 22% (ratio of geometric means = 78.4%; P = 0.0006). However, the terminal half-life did not differ between fasted and fed states (33.3 versus 34.8 hours; P = 0.16), implying that these differences occurred because of altered bioavailability rather than modified clearance. CONCLUSIONS: For LCPT, no chronopharmacokinetic effects were observed, whereas food significantly reduced the 24-h exposure and the peak blood concentration.