Model-Informed Precision Dosing of Tacrolimus: A Systematic Review of Population Pharmacokinetic Models and a Benchmark Study of Software Tools.

BACKGROUND AND OBJECTIVE: Tacrolimus is an immunosuppressant commonly administered after solid organ transplantation. It is characterized by a narrow therapeutic window and high variability in exposure, demanding personalized dosing. In recent years, population pharmacokinetic models have been suggested to guide model-informed precision dosing of tacrolimus. We aimed to provide a comprehensive overview of population pharmacokinetic models and model-informed precision dosing software modules of tacrolimus in all solid organ transplant settings, including a simulation-based investigation of the impact of covariates on exposure and target attainment. METHODS: We performed a systematic literature search to identify population pharmacokinetic models of tacrolimus in solid organ transplant recipients. We integrated selected population pharmacokinetic models into an interactive software tool that allows dosing simulations, Bayesian forecasting, and investigation of the impact of covariates on exposure and target attainment. We conducted a web survey amongst model-informed precision dosing software tool providers and benchmarked publicly available tools in terms of models, target populations, and clinical integration. RESULTS: We identified 80 population pharmacokinetic models, including 44 one-compartment and 36 two-compartment models. The most frequently retained covariates on clearance and distribution parameters were cytochrome P450 3A5 polymorphisms and body weight, respectively. Our simulation tool, hosted at https://lpmx.shinyapps.io/tacrolimus/ , allows thorough investigation of the impact of covariates on exposure and target attainment. We identified 15 model-informed precision dosing software tool providers, of which ten offer a tacrolimus solution and nine completed the survey. CONCLUSIONS: Our work provides a comprehensive overview of the landscape of available tacrolimus population pharmacokinetic models and model-informed precision dosing software modules. Our simulation tool allows an interactive thorough exploration of covariates on exposure and target attainment.

Dynamics and Evolution of Donor-derived Cytomegalovirus Infection in 3 Solid Organ Transplant Recipients With the Same Multiorgan Donor.

BACKGROUND: Cytomegalovirus (CMV) infection poses a significant risk to immunosuppressed transplant recipients, manifesting through primary infection, reinfection, or reactivation. METHODS: We analyzed the emergence of drug resistance in CMV infection in 3 patients who were later found to have received an allograft from a shared, deceased donor. The seronegative transplant recipients developed symptomatic CMV infections after bowel/pancreas, kidney, or lung transplantation. Prospective Sanger sequencing was used to identify mutations in the viral DNA polymerase (DP) and protein kinase (PK). DP and PK variants were retrospectively quantified by targeted next-generation sequencing. The impact of the novel DP-A505G substitution on drug susceptibility was assessed using a recombinant virus. Whole-genome sequencing of clinical CMV samples was enabled through target DNA enrichment. RESULTS: The DP-A505G substitution was found in all patient samples and could be associated with a natural polymorphism. A subsequent review of the patients' clinical histories revealed that they had all received organs from a single donor. The CMV infection exhibited divergent evolution among the patients: patient 1 developed resistance to ganciclovir and foscarnet because of 2 DP mutations (V715M and V781I), patient 2 showed no genotypic resistance, and patient 3 developed ganciclovir (PK-L595S) and maribavir resistance (PK-T409M). Interpatient variation across the entire CMV genome was minimal, with viral samples clustering in phylogenetic analysis. CONCLUSIONS: All 3 transplant recipients were infected with the same donor-derived CMV strain and readily developed different drug susceptibility profiles. This underscores the importance of judicious antiviral drug use and surveillance in preventing antiviral resistance emergence.

Intestinal Permeability in Disorders of Gut-Brain Interaction: From Bench to Bedside.

Intestinal barrier function lies at a critical interface of a range of peripheral and central processes that influence disorders of gut-brain interactions (DGBI). Although rigorously tested, the role of barrier dysfunction in driving clinical phenotype of DGBI remains to be fully elucidated. In vitro, in vivo, and ex vivo strategies can test various aspects of the broader permeability and barrier mechanisms in the gut. Luminal mediators of host, bacterial, and dietary origin can influence the barrier function and a disrupted barrier can also influence the luminal milieu. Critical to our understanding is how barrier dysfunction is influenced by stress and other comorbidities that associate with DGBI and the crosstalk between barrier and neural, hormonal, and immune responses. Additionally, the microbiome's significant role in the communication between the brain and gut has led to the integrative model of a microbiome gut-brain axis with reciprocal interactions between brain networks and networks composed of multiple cells in the gut, including immune cells, enterochromaffin cells, gut microbiota and the derived luminal mediators. This review highlights the techniques for assessment of barrier function, appraises evidence for barrier dysfunction in DGBI including mechanistic studies in humans, as well as provides an overview of therapeutic strategies that can be used to directly or indirectly restore barrier function in DGBI patients.

Physiological and Psychological Factors Contribute to Real-Time Esophageal Symptom Reporting in Patients With Refractory Reflux.

INTRODUCTION: Real-time symptom reporting during ambulatory reflux monitoring plays a key role in the evaluation of esophageal symptoms, although the underlying processes are poorly understood. We aim to identify the psychological and physiological factors associated with real-time reflux symptom reporting and symptom-reflux association parameters. METHODS: Adult patients with refractory reflux symptoms completed psychosocial questionnaires and standard 24-hour pH-impedance monitoring. A hurdle-Poisson model evaluated the association between psychological and physiological (proton pump inhibitor [PPI] use, total number of reflux episodes) variables on real-time symptom frequency, assessed through a button press within 2 minutes of experiencing a symptom. Logistic regression assessed the variables associated with symptom association probability (SAP) and symptom index classification (positive/negative). Complementary machine learning analyses with 8-fold cross-validation further identified variables associated with symptom frequency and sought to optimize SAP classification performance. RESULTS: Both psychological (pain-related anxiety, depressive symptoms, trait anxiety) and physiological (total number of reflux episodes, off PPI during testing) variables were associated with symptom frequency. The total number of reflux episodes and being studied off PPI were significantly associated with a higher likelihood of being classified as SAP or symptom index positive. The best-performing model in the machine learning analysis demonstrated a poor job of correctly classifying patients as SAP positive/negative (misclassification rate = 41.4%). DISCUSSION: Real-time reflux symptom reporting is a multifactorial process, with both psychological and physiological processes contributing to different aspects of the reflux disease experience. Findings build on questionnaire-based research to underscore the importance of including psychological processes in our understanding of esophageal symptom reporting.

Operational recommendations for the implementation of home parenteral nutrition program of care according to the guidelines of the European society for clinical nutrition and metabolism.

Home parenteral nutrition (HPN) is a complex therapy, which requires dedicated facilities and expertise. However, the management and provision of HPN differs significantly between countries and between HPN centers within countries. These differences lead to heterogeneity in the quality of care received by patients, with variable impact on the appropriateness, safety, and effectiveness of HPN, and resultant variability in the quality of life that a patient may expect. The European Society for Clinical Nutrition and Metabolism (ESPEN) have published guidelines on the appropriate and safe provision of HPN, with an associated practical version describing a short and precise way to implement the guidelines' recommendations in clinical practice. This educational paper suggests means of implementation of evidence supported HPN guidelines, using "operational recommendations" applitngto healthcare professionals, administrators and stakeholders, with the ultimate aim of enhancing equity of patient access to an appropriate and safe HPN program of care.

Eosinophil Depletion as a Potential Therapeutic Strategy in Acute and Chronic Intestinal Inflammation Based on a Dextran Sulfate Sodium Colitis Model.

BACKGROUND: A role for eosinophils in intestinal inflammation and fibrosis in the context of inflammatory bowel disease has been suggested, yet the precise nature, whether causal or secondary remains debated. Hence, it remains unclear whether targeting eosinophils should be further explored as a treatment option in inflammatory bowel disease. METHODS: Acute and chronic dextran sulfate sodium colitis was induced in wild-type C57BL/6 mice. Eosinophils were depleted by anti-CCR3 injections before colitis induction in a chronic model and after colitis onset in an acute model in order to investigate the impact of eosinophil depletion on pre-existing colitis. Inflammation was assessed using the disease activity index, macroscopic damage, and histological disease activity score. In the chronic model, fibrosis was assessed by examining colon weight/length ratio, collagen deposition through Martius Scarlet Blue staining, hydroxyproline assay, and COL1A1 expression. Protein and gene expression were assessed using the Meso Scale Discovery platform and real-time quantitative polymerase chain reaction. RESULTS: In the acute and chronic colitis model, eosinophil depletion resulted in reduced disease activity and faster recovery, as observed via the total area under the curve of the disease activity index (P = .004 and P = .02, respectively), macroscopic damage score (P = .009 and P = .08, respectively), and histological disease activity score (P = .09 and P = .002, respectively). In the acute model, the accelerated recovery was accompanied by an increase in interleukin (IL)-10 (P = .03) and a decrease in IL-4 (P = .03) and IL-6 (P = .009). Colon weight/length ratio and collagen deposition were not affected by eosinophil depletion. CONCLUSIONS: Eosinophil depletion prevents and decreases intestinal inflammation in a preclinical dextran sulfate sodium model without affecting fibrosis. These results pave the way for exploring eosinophil depletion as a novel treatment modality in addressing intestinal inflammation.

This study investigated the effect of eosinophil depletion on intestinal inflammation and fibrosis in a dextran sulfate sodium colitis model. Our findings suggest a proinflammatory role for eosinophils and therefore warrant further investigation into eosinophil targeting as a treatment option for inflammatory bowel disease patients.

DOMINO trial post hoc analysis: evaluation of the diet effects on symptoms in IBS subtypes.

Background: Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction characterized by recurrent abdominal pain related to defecation and/or associated to a change in bowel habits. According to the stool type, four different IBS subtypes can be recognized, constipation predominant (IBS-C), diarrhea predominant (IBS-D), mixed (IBS-M), and undefined (IBS-U). Patients report that their IBS symptoms are exacerbated by food. Thus, it is important to find a nutritional approach that could be effective in reducing IBS symptoms. Objective: The present work is a post hoc analysis of the previously published DOMINO trial. It aimed to evaluate the effects of a self-instructed FODMAP-lowering diet smartphone application on symptoms and psychosocial aspects in primary care IBS stratifying the results for each IBS subtypes. Design: Post hoc analysis. Methods: Two hundred twenty-two primary care IBS patients followed a FODMAP-lowering diet for 8 weeks with the support of a smartphone application. Two follow-up visits were scheduled after 16 and 24 weeks. IBS-Symptoms Severity Score (IBS-SSS), quality of life (QoL), and adherence and dietary satisfaction were evaluated. Results: After 8 weeks, IBS-SSS improved in all IBS subtypes (p < 0.0001). Physician Health Questiionnaire (PHQ-15) improved only in IBS-D (p = 0.0006), whereas QoL improved both in IBS-D (p = 0.01) and IBS-M (p = 0.005). Conclusion: This post hoc analysis showed that the app is useful in all IBS subtypes; thus, it could be used as an effective tool by both general practitioners and patients to manage symptoms in primary care. Trial registration: Ethical Commission University Hospital of Leuven reference number: S59482. Clinicaltrial.gov reference number: NCT04270487.

What is already known about this subject? The low FODMAP (fermentable oligo-, di-, and monosaccharides and polyols) diet has shown efficacy for controlling IBS (irritable bowel syndrome) symptoms in small controlled trials in tertiary care patients. As this approach requires several visits with an experienced dietitian, it seems less suitable for primary care. What are the new findings? The benefit of the FODMAP lowering app was already present at 4 weeks and persisted during follow-up until 24 weeks. How might it impact on clinical practice in the foreseeable future? Given its superiority to standard first-line pharmacotherapy, and its ease of use, a FODMAP lowering app has the potential to become the preferred first-line treatment for primary care IBS.

The effect of sparkling water on the systemic pharmacokinetics of paracetamol in older adults.

Paracetamol absorption kinetics show considerable variability in older adults, complicating the development of effective dosing regimens in the advanced-age population. In previous research, sparkling water has been shown to influence absorption-related processes. This study aimed to apply these findings to older adults and investigate the impact of sparkling water on absorption-related variability and early exposure. To this end, fourteen volunteers, with a median age of 72.5, were enrolled in a small-scale, randomised, controlled clinical trial with a cross-over design. A single immediate-release 500 mg paracetamol tablet was administered with sparkling or still water. Venous blood samples were collected regularly over 8 hours and analysed using HPLC-UV. Reduced variability of absorption-related parameters and a trend towards higher early exposure were observed in the sparkling water group, as demonstrated by a 1.6-fold increased AUC0-30min, a 2-fold reduced geometric coefficient of variation (GCV) for AUC0-30min, and a reduced median [interquartile range] Tmax of 25.0 [20.0-30.0] min compared to 30.0 [25.0-45.0] min. Based on our findings, sparkling water as a real-life dosing condition might improve paracetamol absorption kinetics and early exposure in the advanced-age population.

Redefining Histological Cell Counts Using a Standardized Method: The Leuven Intestinal Counting Protocol.

INTRODUCTION: The diagnosis of eosinophilic gastrointestinal diseases is largely based on mucosal eosinophil counts, but thresholds and normal ranges beyond the esophagus are debated, calling for much-needed methodological standardization. We aimed to develop a standardized workflow for duodenal cell quantification and estimate duodenal eosinophil and mast cell numbers in healthy controls. METHODS: Software-based histological cell quantification using free-sized or fixed-sized regions was developed and applied to digitized hematoxylin and eosin (H&E)-stained slides from 58 individuals (healthy controls [HCs] and patients with functional dyspepsia). Intraclass correlation coefficients (ICCs) compared inter-rater reliability between software-based and microscopic quantification. Reproducibility of the software-based method was validated in an independent cohort of 37 control and functional dyspepsia subjects. Eosinophil identification on H&E staining was compared to immunohistochemistry (IHC). Normal eosinophil (H&E) and mast cell (cKit) ranges were determined in 70 adult HCs. RESULTS: Eosinophil quantification on digitized slides demonstrated excellent (ICC = 0.909) and significantly improved reproducibility over microscopic evaluation (ICC = 0.796, P = 0.0014), validated in an independent cohort (ICC = 0.910). Duodenal eosinophils were more abundant around crypts than in villi ( P < 0.0001), while counts were similar on matched H&E- and IHC-stained slides ( P = 0.55). Mean ± SD (95th percentile) duodenal eosinophils and mast cells in HC were 228.8/mm 2 ± 94.7 (402.8/mm 2 ) and 419.5/mm 2 ± 132.2 (707.6/mm 2 ), respectively. DISCUSSION: We developed and validated a standardized approach to duodenal histological cell quantification, generalizable to various mucosal cell types. Implementation of software-based quantification identified 400 eosinophils/mm 2 and 700 mast cells/mm 2 as thresholds for abnormal duodenal infiltration.

Characterization of luminal contents from the fasted human proximal colon.

To treat colonic diseases more effectively, improved therapies are urgently needed. In this respect, delivering drugs locally to the colon is a key strategy to achieve higher local drug concentrations while minimizing systemic side effects. Understanding the luminal environment is crucial to efficiently develop such targeted therapies and to predict drug disposition in the colon. In this clinical study, we collected colonic contents from an undisturbed fasted proximal colon via colonoscopy and characterized their composition with regard to drug disposition. Colonic pH, osmolality, protein content, bile salts, lipids, phospholipids and short-chain fatty acids were investigated in 10 healthy volunteers (8 male and 2 female, age 19-25). The unique environment of the proximal colon was reflected in the composition of the sampled luminal fluids and the effect of the microbiota could be observed on the pH (median 6.55), the composition of bile salts (majority deconjugated and secondary), and the abundance of short-chain fatty acids. At the same time, an increase in phospholipid concentration, osmolality and total protein content compared to reported ileal values was seen, likely resulting from desiccation. Lipids could only be found in low quantities and mainly in the form of cholesterol and free fatty acids, showing almost complete digestion and absorption by the time luminal contents reach the colon. All characteristics also displayed the considerable intersubject variability found in different regions of the gastrointestinal tract. This study contributes to an improved understanding of the luminal conditions in the proximal colon and facilitates the development of new predictive tools to study colonic drug absorption.

New insights in immunomodulation for intestinal transplantation.

Tolerance is the Holy Grail of solid organ transplantation (SOT) and remains its primary challenge since its inception. In this topic, the seminal contributions of Thomas Starzl at Pittsburgh University outlined foundational principles of graft acceptance and tolerance, with chimerism emerging as a pivotal factor. Immunologically, intestinal transplantation (ITx) poses a unique hurdle due to the inherent characteristics and functions of the small bowel, resulting in increased immunogenicity. This necessitates heavy immunosuppression (IS) while IS drugs side effects cause significant morbidity. In addition, current IS therapies fall short of inducing clinical tolerance and their discontinuation has been proven unattainable in most cases. This underscores the unfulfilled need for immunological modulation to safely reduce IS-related burdens. To address this challenge, the Leuven Immunomodulatory Protocol (LIP), introduced in 2000, incorporates various pro-tolerogenic interventions in both the donor to the recipient, with the aim of facilitating graft acceptance and improving outcome. This review seeks to provide an overview of the current understanding of tolerance in ITx and outline recent advances in this domain.

Fibrostricturing Crohn's Disease Is Marked by an Increase in Active Eosinophils in the Deeper Layers.

INTRODUCTION: Approximately 50% of patients with Crohn's disease (CD) develop intestinal strictures necessitating surgery. The immune cell distribution in these strictures remains uncharacterized. We aimed to identify the immune cells in intestinal strictures of patients with CD. METHODS: During ileocolonic resections, transmural sections of terminal ileum were sampled from 25 patients with CD and 10 non-inflammatory bowel disease controls. Macroscopically unaffected, fibrostenotic, and inflamed ileum was collected and analyzed for immune cell distribution (flow cytometry) and protein expression. Collagen deposition was assessed through a Masson Trichrome staining. Eosinophil and fibroblast colocalization was assessed through immunohistochemistry. RESULTS: The Masson Trichrome staining confirmed augmented collagen deposition in both the fibrotic and the inflamed regions, though with a significant increased collagen deposition in the fibrotic compared with inflamed tissue. Distinct Th1, Th2, regulatory T cells, dendritic cells, and monocytes were identified in fibrotic and inflamed CD ileum compared with unaffected ileum of patients with CD as non-inflammatory bowel disease controls. Only minor differences were observed between fibrotic and inflamed tissue, with more active eosinophils in fibrotic deeper layers and increased eosinophil cationic protein expression in inflamed deeper layers. Last, no differences in eosinophil and fibroblast colocalization were observed between the different regions. DISCUSSION: This study characterized immune cell distribution and protein expression in fibrotic and inflamed ileal tissue of patients with CD. Immunologic, proteomic, and histological data suggest inflammation and fibrosis are intertwined, with a large overlap between both tissue types. However strikingly, we did identify an increased presence of active eosinophils only in the fibrotic deeper layers, suggesting their potential role in fibrosis development.

Patients' and caregivers' perspective on challenges and outcomes with tube feeding: Analysis of home enteral nutrition survey data.

BACKGROUND: Given the growing use of home enteral nutrition (HEN), assessing the experience of consumers and caregivers is crucial to understanding the real-world subjective and objective challenges of administering HEN. METHODS: After obtaining institutional review board approval, a survey was distributed to HEN consumers and caregivers between January 16, 2020, and July 16, 2021. Data collected included information regarding demographics, primary diagnosis, tube and connectors, HEN regimen, and overall HEN experience. RESULTS: A total of 884 individuals responded to the survey: 673 (76.1%) responses by caregivers and 211 (23.9%) responses by patients. The study cohort included 566 (64%) children and 318 (36%) adults. The leading primary diagnosis of participants was developmental delay and motility disorder for children and adults, respectively. Low-profile gastric tubes were the most used (75.7% of children and 30.3% of adults). Notably, legacy connectors were utilized for more patients (46.7% children, 52.6% adults) compared to ISO-80369-3 connectors (38.9% children, 29.7% adults). HEN complications were prevalent, including enteral tube site infections and other tube-related complications, including clogging and kinking. CONCLUSION: This real-world data reveals that HEN complications remain prevalent. Additionally, despite introducing ISO-80369-3 connectors many years ago, most patients continue to use legacy tubes with a significant lack of knowledge about ISO-80369-3 connectors. The survey results guide HEN providers to focus on several areas to reduce complications.

Multilevel Analysis of the Neovascularization and Integration Process of a Nonvascularized Rectus Fascia Transplantation.

Background: Failure to close the abdominal wall after intestinal transplantation (ITx) or multivisceral Tx remains a surgical challenge. An attractive method is the use of nonvascularized rectus fascia (NVRF) in which both layers of the donor abdominal rectus fascia are used as an inlay patch without vascular anastomosis. How this graft integrates over time remains unknown. The study aims to provide a multilevel analysis of the neovascularization and integration process of the NVRF. Methods: Three NVRF-Tx were performed after ITx. Clinical, radiological, histological, and immunological data were analyzed to get insights into the neovascularization and integration process of the NVRF. Moreover, cryogenic contrast-enhanced microfocus computed tomography (microCT) analysis was used for detailed reconstruction of the vasculature in and around the NVRF (3-dimensional histology). Results: Two men (31- and 51-y-old) and 1 woman (49-y-old) underwent 2 multivisceral Tx and 1 combined liver-ITx, respectively. A CT scan showed contrast enhancement around the fascia graft at 5 days post-Tx. At 6 weeks, newly formed blood vessels were visualized around the graft with Doppler ultrasound. Biopsies at 2 weeks post-Tx revealed inflammation around the NVRF and early fibrosis. At 6 months, classical 2-dimensional histological analysis of a biopsy confirmed integration of the fascia graft with strong fibrotic reaction without signs of rejection. A cryogenic contrast-enhanced microCT scan of the same biopsy revealed the presence of microvasculature, enveloping and penetrating the donor fascia. Conclusions: We showed clinical, histological, and microCT evidence of the neovascularization and integration process of the NVRF after Tx.

Breaking the Barrier: The Role of Gut Epithelial Permeability in the Pathogenesis of Hypertension.

PURPOSE OF THE REVIEW: To review what intestinal permeability is and how it is measured, and to summarise the current evidence linking altered intestinal permeability with the development of hypertension. RECENT FINDINGS: Increased gastrointestinal permeability, directly measured in vivo, has been demonstrated in experimental and genetic animal models of hypertension. This is consistent with the passage of microbial substances to the systemic circulation and the activation of inflammatory pathways. Evidence for increased gut permeability in human hypertension has been reliant of a handful of blood biomarkers, with no studies directly measuring gut permeability in hypertensive cohorts. There is emerging literature that some of these putative biomarkers may not accurately reflect permeability of the gastrointestinal tract. Data from animal models of hypertension support they have increased gut permeability; however, there is a dearth of conclusive evidence in humans. Future studies are needed that directly measure intestinal permeability in people with hypertension.

The Leuven Prolonged Acute Stress Test (L-PAST): A novel paradigm to induce a subjective and glucocorticoid stress response for at least ninety minutes.

Laboratory stress tests typically administer stress acutely, ranging from 3 to 15 minutes. However, everyday stressors usually last longer than ten minutes (e.g., examination stressors, work stressors, and social stressors. Moreover, in some studies, it may be relevant to induce stress for a longer period to affect certain psychological or physiological parameters. To this end, we developed a novel stress test that intends to induce psychosocial stress for 90 minutes. The Leuven Prolonged Acute Stress Test (L-PAST) combines physical (hand immersion in cold water), cognitive (mental arithmetic), and psychosocial (social evaluation and feelings of failure) stress elements of two well-known laboratory stress tests, the Maastricht Acute Stress Test (MAST) and the Montreal Imaging Stress Test (MIST). Fifty healthy women were subjected to both the L-PAST and a sham (control) test in a randomized and counterbalanced manner. The stress response was determined by salivary cortisol measurements and assessment of subjective stress ratings at regular time points during the time preceding the stress period (5 min), the stress period (90 min), and the recovery period (35 min). Cognitive reactivity to failure and subjective pain levels were also assessed at various time points. The childhood trauma questionnaire (CTQ) and the perceived stress scale (PSS) were administered prior to the testing phase. As expected, linear mixed models revealed that the stress response was significantly higher during the L-PAST as indicated by a significant time point by condition interaction effect for both the cortisol response (F(10,450)=12.21, p < 0.0001, ηp2=0.11) and the subjective stress response (F(13,637)=13.98, p < 0.0001, ηp2 = 0.12). Moreover, there was a significant time point by condition interaction effect for cognitive reactivity to failure (F(13,637) = 7.97, p < 0.0001, ηp2 = 0.07) and subjective pain (F(13,637) = 38.52, p < 0.0001, ηp2 = 0.27), indicating that the levels were higher during the L-PAST at most stress induction time points. Lastly, higher CTQ scores were associated with higher subjective pain levels during the L-PAST (F(1,44)=6.05, p = 0.02). Collectively, our results confirm the efficacy of the L-PAST in inducing a prolonged subjective as well as cortisol stress response.

Celiac disease: Hope for new treatments beyond a gluten-free diet.

BACKGROUND & AIMS: Celiac disease (CD) is a chronic inflammatory disease of the small intestine induced and maintained by gluten ingestion in susceptible individuals. Current treatment consists of strict adherence to a lifelong gluten-free diet (GFD) which is considered safe and effective in the large majority of patients. However, since adherence to a GFD is difficult and has a negative impact on quality of life, an increasing interest in other treatment options has emerged. Moreover, in some individuals a GFD is not sufficiently effective, necessitating alternative treatments. METHODS: By performing a systematic search, we constructed a detailed narrative review. Only treatment options considered relevant and conducted in a phase I, II or III clinical trial were included. RESULTS: Based on the pathophysiology of CD, four major therapeutic approaches can be distinguished: firstly, by focusing on intraluminal gluten detoxification before absorption occurs, secondly, by modulating intestinal permeability and preventing paracellular uptake, thirdly, by enhancing immunological tolerance to gluten and finally, by regulating gluten auto-immunity. CONCLUSIONS: Despite significant efforts, no treatment has yet completed a phase III clinical trial. Future studies will likely focus on the use of supplemental drugs in conjunction to a GFD, with ALV003 and ZED-1227 currently being the most promising therapeutic options.

Added Value of 13C Analysis in Breath Tests in H2-Negative Subjects to Diagnose Lactose Malabsorption: A Proof of Concept Study.

INTRODUCTION: Diagnosing lactose malabsorption is usually based on hydrogen excretion in breath after a lactose challenge. However, a proportion of subjects with lactose malabsorption will not present a rise in hydrogen. Measuring excretion of methane or stable isotope labeled 13CO2 after ingestion of 13C-lactose has been proposed to mitigate this problem. OBJECTIVE: The aim of the study was to assess the performance of measuring methane and 13CO2 in individuals with normal hydrogen excretion compared to a genetic lactase non-persistence test. METHODS: Individuals referred for lactose breath testing and healthy controls were included. Participants received 13C-enriched lactose, performed breath testing, and underwent genotyping for a marker of lactase non-persistence (13910C*T). Using genotype as gold standard, the performance of measuring methane and 13CO2 excretion was assessed. RESULTS: 151 subjects participated in the study, 50 of which presented a lactase non-persistent genotype. Of these, 72% were correctly diagnosed through hydrogen excretion of ≥ 20 ppm above baseline. In subjects with normal hydrogen excretion, cumulative 13C excretion had an area under the curve (AUC) of the receiver operating characteristics (ROC) curve of 0.852. Sensitivity was 93% and specificity was 51% for the current cutoff of 14.5%. The optimal cutoff was 12.65% (sensitivity 93%, specificity 70%). The ROC curve of peak methane had an AUC of 0.542 (sensitivity of 14%, specificity of 91% for cutoff ≥ 10 ppm). CONCLUSIONS: In individuals with genetically demonstrated lactase non-persistence and negative hydrogen breath test, the use of 13C-lactose with measurement of 13CO2 excretion and hydrogen is a well-performing test to detect the lactose malabsorption and performs better than methane in our cohort.