Evaluation of Genetic Variants Associated with the Risk of Thiopurine-Related Pancreatitis: A Case Control Study from ENEIDA Registry.

INTRODUCTION: Risk factors for developing pancreatitis due to thiopurines in patients with inflammatory bowel disease (IBD) are not clearly identified. Our aim was to evaluate the predictive pharmacogenetic risk of pancreatitis in IBD patients treated with thiopurines. METHODS: We conducted an observational pharmacogenetic study of acute pancreatitis events in a cohort study of IBD patients treated with thiopurines from the prospectively maintained ENEIDA registry biobank of GETECCU. Samples were obtained and the CASR, CEL, CFTR, CDLN2, CTRC, SPINK1, CPA1, and PRSS1 genes, selected based on their known association with pancreatitis, were fully sequenced. RESULTS: Ninety-five cases and 105 controls were enrolled; a total of 57% were women. Median age at pancreatitis diagnosis was 39 years. We identified 81 benign variants (50 in cases and 67 in controls) and a total of 35 distinct rare pathogenic and unknown significance variants (10 in CEL, 21 in CFTR, 1 in CDLN2, and 3 in CPA1). None of the cases or controls carried pancreatitis-predisposing variants within the CASR, CPA1, PRSS1, and SPINK1 genes, nor a pathogenic CFTR mutation. Four different variants of unknown significance were detected in the CDLN and CPA1 genes; one of them was in the CDLN gene in a single patient with pancreatitis and 3 in the CPA1 gene in 5 controls. After the analysis of the variants detected, no significant differences were observed between cases and controls. CONCLUSION: In patients with IBD, genes known to cause pancreatitis seem not to be involved in thiopurine-related pancreatitis onset.

Should Inflammatory Bowel Disease Clinicians Provide Their Patients with e-Health Resources? Patients' and Professionals' Perspectives.

Introduction: The internet is emerging as a source of information for patients with inflammatory bowel disease (IBD). However, it is not always reliable and may cause anxiety. We aim to assess patients' information habits and patients' and professionals' perceptions of a national website integrated as an educational resource for the IBD unit. Methods: Patients aged 18-65 years, comfortable with the internet, and attending follow-ups at participating IBD units (March-June 2019) and their professionals were invited to evaluate a recommended website through an online survey. Results: Three hundred eighty-nine patients and 95 professionals completed the survey. The internet (n = 109; 27.4%) was the second preferred source of information after the health care team (n = 229; 57.5%). Eighty percent of patients searched the internet for information on their disease and 28.6% did so at least once a week (n = 114), especially newly diagnosed ones (<2 years). Patients valued a website recommended by their professional (n = 379; 95.2%) and endorsed by the National Working Group (n = 377; 94.7%). They would attend online educational initiatives on the website (n = 279; 70.1%) and complete periodical surveys to improve its usefulness (n = 338; 84.9%). According to IBD professionals, this type of website is the best patient source of supplementary information (n = 76; 80%) and they "prescribe" it to most patients (67.0 ± 25.2%), especially the newly diagnosed patients (52.7 ± 26.5%). It effectively integrates routine face-to-face education (n = 95; 100%). Conclusions: Patients of IBD units, especially newly diagnosed ones, appreciate a trusted e-Health resource to back up professional information. The favorable opinion of patients and professionals will allow its use in training interventions.

Huge fecaloma in a rectum ampulla resolved with conservative treatment using a carbonated soft drink.

Colonic impaction due to a fecaloma is a very frequent complication in patients with chronic constipation. Most cases respond to conservative measures such as digital disimpaction or treatment with oral laxatives and enemas. However, in some cases fecalomas could be refractory to these treatments requiring aggressive measures such as endoscopic or surgical removal. Even more, there are a few cases of death reported as a complication of a fecaloma refractory to usual treatments. We report, for the first time, a case of a patient with a huge fecaloma refractory to oral laxative and enemas resolved conservatively with a single irrigation of a carbonated soft drink through a rectal probe.

Portal hypertension hemorrhage secondary to a stomal varicose vein in a patient with two consecutive thrombosis of a transjugular intrahepatic portosystemic shunt (TIPS).

Less than 5% of patients with liver cirrhosis (LC) with portal hypertension (PH) develop atypical shunt (in regions other than the esophagus or the stomach). Within this group are varices associated with a stoma, for example the ones associated with an uretero-ileostomy which are infrequent. They are a diagnostic and therapeutic challenge, as they can cause hemorrhages due to PH. We present a clinical case about stoma varicose bleeding as the latest guidelines for the management of PH do not mention them or their treatment due to their low incidence.

Non-pharmacologic direct cost of a simplified strategy with glecaprevir/pibrentasvir for 8 weeks in naïve non-cirrhotic patients with hepatitis C implemented in clinical practice. The Just SIMPLE Study.

BACKGROUND AND OBJECTIVE: The emergence of highly tolerable, effective, and shorter duration direct-acting antivirals (DAAs) regimens offers the opportunity to simplify hepatitis C virus management but medical costs are unknown. Thus, we aimed to determine the direct medical costs associated with a combo-simplified strategy (one-step diagnosis and low monitoring) to manage HCV infection within an 8-week glecaprevir/pibrentasvir (GLE/PIB) regimen in clinical practice in Spain. PATIENTS AND METHODS: Healthcare resources and clinical data were collected retrospectively from medical charts of 101 eligible patients at 11 hospitals. Participants were adult, treatment naïve subjects with HCV infection without cirrhosis in whom a combo-simplified strategy with GLE/PIB for 8 weeks were programmed between Apr-2018 and Nov-2018. RESULTS: The GLE/PIB effectiveness was 100% (CI95%: 96.2-100%) in the mITT population and 94.1% (CI95%: 87.5-97.8%) in the ITT population. Three subjects discontinued the combo-simplified strategy prematurely, none of them due to safety reasons. Five subjects reported 8 adverse events, all of mild-moderate intensity. Combo-simplified strategy mean direct costs were 754.35±103.60€ compared to 1689.42€ and 2007.89€ of a theoretical 12-week treatment with 4 or 5 monitoring visits, respectively; and 1370.95€ and 1689.42€ of a theoretical 8-week with 3 or 4 monitoring visits, respectively. Only 4.9% of the subjects used unexpected health care resources. CONCLUSIONS: 8-week treatment with GLE/PIB combined with a combo simplified strategy in real-life offers substantial cost savings without affecting the effectiveness and safety compared to traditional approaches.

Isolation and characterization of urine microvesicles from prostate cancer patients: different approaches, different visions.

BACKGROUND: Because of their specific and biologically relevant cargo, urine extracellular vesicles (EVs) constitute a valuable source of potential non-invasive biomarkers that could support the clinical decision-making to improve the management of prostate cancer (PCa) patients. Different EV isolation methods differ in terms of complexity and yield, conditioning, as consequence, the analytical result. METHODS: The aim of this study was to compare three different isolation methods for urine EVs: ultracentrifugation (UC), size exclusion chromatography (SEC), and a commercial kit (Exolute® Urine Kit). Urine samples were collected from 6 PCa patients and 4 healthy donors. After filtered through 0.22 µm filters, urine was divided in 3 equal volumes to perform EVs isolation with each of the three approaches. Isolated EVs were characterized by spectrophotometric protein quantification, nanoparticle tracking analysis, transmission electron microscopy, AlphaScreen Technology, and whole miRNA Transcriptome. RESULTS: Our results showed that UC and SEC provided better results in terms of EVs yield and purity than Exolute®, non-significant differences were observed in terms of EV-size. Interestingly, luminescent AlphaScreen assay demonstrated a significant enrichment of CD9 and CD63 positive microvesicles in SEC and UC methods compared with Exolute®. This heterogeneity was also demonstrated in terms of miRNA content indicating that the best correlation was observed between UC and SEC. CONCLUSIONS: Our study highlights the importance of standardizing the urine EV isolation methods to guaranty the analytical reproducibility necessary for their implementation in a clinical setting.

Consequences and management of COVID-19 on the care activity of an Inflammatory Bowel Disease Unit.

INTRODUCTION: COVID-19 has altered the usual practice of medicine and the state of emergency declared in Spain on March 14th has considerably changed the activity of inflammatory bowel disease (IBD) units. The aim of this study was to evaluate the consequences of COVID-19 on the IBD Unit's activity and provide information on restructuring with available resources. METHODS: an observational study was performed in a referral hospital in Madrid (Spain). Type of appointment, loss of follow-up, hospital admission, treatment changes, endoscopic activity, surgeries and blood tests were evaluated between March 15th and May 15th, 2020. This data was compared with the usual activity a year before. RESULTS: among the 510 patients included, 476 (93.33 %) received had a remote consultation, representing an increase of 92.38 % compared with the previous year (0.95 %). There was a loss of follow-up in 26 patients (5.1 %) vs 15 (3.58 %) the previous year. A total of 60 (35.09 %) blood tests, 64 (76.19 %) endoscopies and all scheduled surgeries were suspended. Besides, 484 (94.9 %) patients remained adherent vs 417/419 (99.5 %) in the pre-pandemic period and 48 (9.41 %) reported symptoms of an IBD flare. Thirty-nine (7.6 %) patients developed symptoms suggestive of COVID-19. CONCLUSION: a large number of tests and on-site outpatient visit consultations were suspended. However, a rapid adaptation to telemedicine allowed these patients to be closely followed up. Although it was possible to maintain therapeutic compliance, with a loss to follow-up slightly higher than the previous year, suspensions and delays of tests could have significant negative consequences in the long term.

Comparison of original and biosimilar infliximab (CTP-13) in biologic-naïve patients with Crohn's disease and ulcerative colitis: a retrospective, multicenter real-life study in Spain.

PURPOSE: biosimilar infliximab (CTP-13) has been recently approved for the treatment of several immune-mediated inflammatory disorders, including inflammatory bowel disease (IBD). Comparative studies between this biosimilar and original infliximab in the real clinical practice are scarce. The objective of this study was to compare short and long-term safety and efficacy of original (O) and biosimilar infliximab (B-IFX) in biologic-naïve, IBD patients in the real life clinical practice. METHODS: a retrospective, multicentric study was performed in five Spanish hospitals. Consecutive IBD, biologic-naïve patients from an historic cohort who initiated O-IFX from January 2013 were compared with biologic-naïve patients, who started treatment with B-IFX since its approval in January 2015. The evaluation of efficacy was assessed after the induction phase, at week 14 and week 54 of treatment. Time to dose escalation or treatment persistence of both O-IFX and B-IFX was also considered. The appearance of serious adverse events was recorded. RESULTS: two hundred and thirty-nine IBD biologic-naïve patients who started with O-IFX or B-IFX were included: 153 patients were diagnosed with Crohn's disease (95 treated with O- and 58 treated with B-IFX) and 86 with ulcerative colitis (40 received O- and 46 received B-IFX). At weeks 14 and 54, both O-IFX and B-IFX groups reached a similar clinical response and remission rates. Time to dose escalation, treatment persistence and safety profile were comparable between both groups. CONCLUSIONS: this long-term real-life experience provides additional evidence of the similarity of O- and B-IFX CTP-13 in terms of efficacy and safety in IBD patients.

Etched-cavity GaSb laser diodes on a MOVPE GaSb-on-Si template.

We report on 2.3-µm etched-cavity GaSb-based laser diodes (LDs) epitaxially integrated on on-axis (001)Si and benchmarked against their cleaved facet counterparts. The LDs were grown in two steps. First, a GaSb-on-Si template was grown by metal-organic vapor phase epitaxy (MOVPE) before the growth of the LD heterostructure by molecular-beam epitaxy. Different etched-facet geometries operate in continuous wave well above room temperature, and their performance are similar to those of cleaved-cavity LDs. These results show that etching mirrors is a viable route to form laser cavities in the GaSb technology and that MOVPE GaSb-on-Si templates are a suitable platform for optoelectronic devices overgrowth.

Systolic High-Pitch Coronary CT Angiography for Evaluation of the Coronary Arteries in Heart Transplant Recipients.

OBJECTIVE. The purpose of this study was to evaluate the feasibility, image quality, and radiation dose of high-pitch coronary CT angiography (CCTA) in orthotopic heart transplant (OHT) recipients. SUBJECTS AND METHODS. Twenty-two consecutive OHT recipients (16 men, six women; median age, 66.5 years [interquartile range, 51.3-70.3 years]; median heart rate, 91 beats/min [interquartile range, 79.3-97.3 beats/min]) underwent CCTA with a third-generation dual-source CT scanner in high-pitch mode to rule out coronary allograft vasculopathy. Data acquisition was triggered at 30% of the R-R interval. Two independent observers blindly assessed image quality on a per-segment, per-vessel, and per-patient basis using a 4-point scale (4, excellent; 1, not evaluative). Scores 2-4 indicated diagnostic quality. Studies were compared with previously performed retrospective ECG-gated examinations, when available. Interobserver agreement on the image quality was assessed with kappa statistics. Radiation dose was recorded. RESULTS. A total of 322 coronary segments were evaluated. Diagnostic image quality was observed in 97.5% of the segments. Interobserver agreement for image quality assessment was very good on a per-patient (κ = 0.82), per-vessel (κ = 0.83), and per-segment basis (κ = 0.89). The median per-patient image quality score was 4.0 (3.0-4.0) for the entire coronary tree. A comparison of image quality scores between high-pitch and retrospective ECG-gated CCTA examinations showed no significant differences, but the estimated mean radiation dose was significantly lower for the high-pitch mode (median dose-length product, 31.6 mGy × cm [interquartile range, 23.1-38.8 mGy × cm] vs 736.5 mGy × cm [interquartile range, 655.5-845.7 mGy × cm], p < 0.001). CONCLUSION. Performing single-heartbeat high-pitch CCTA during the systolic phase of the cardiac cycle in OHT recipients results in diagnostic image quality in coronary angiograms at very low radiation dose.

Recent Advances in Astaxanthin Micro/Nanoencapsulation to Improve Its Stability and Functionality as a Food Ingredient.

Astaxanthin is a carotenoid produced by different organisms and microorganisms such as microalgae, bacteria, yeasts, protists, and plants, and it is also accumulated in aquatic animals such as fish and crustaceans. Astaxanthin and astaxanthin-containing lipid extracts obtained from these sources present an intense red color and a remarkable antioxidant activity, providing great potential to be employed as food ingredients with both technological and bioactive functions. However, their use is hindered by: their instability in the presence of high temperatures, acidic pH, oxygen or light; their low water solubility, bioaccessibility and bioavailability; their intense odor/flavor. The present paper reviews recent advances in the micro/nanoencapsulation of astaxanthin and astaxanthin-containing lipid extracts, developed to improve their stability, bioactivity and technological functionality for use as food ingredients. The use of diverse micro/nanoencapsulation techniques using wall materials of a different nature to improve water solubility and dispersibility in foods, masking undesirable odor and flavor, is firstly discussed, followed by a discussion of the importance of the encapsulation to retard astaxanthin release, protecting it from degradation in the gastrointestinal tract. The nanoencapsulation of astaxanthin to improve its bioaccessibility, bioavailability and bioactivity is further reviewed. Finally, the main limitations and future trends on the topic are discussed.

The Harvey-Bradshaw Index Adapted to a Mobile Application Compared with In-Clinic Assessment: The MediCrohn Study.

Objectives: Mobile apps are useful tools in e-health and self-management strategies in disease monitoring. We evaluated the Harvey-Bradshaw index (HBI) mobile app self-administered by the patient to see if its results agreed with HBI in-clinic assessed by a physician. Methods: Patients were enrolled in a 4-month prospective study with clinical assessments at months 1 and 4. Patients completed mobile app HBI and within 48 h, HBI was performed by a physician (gold standard). HBI scores characterized Crohn's disease (CD) as remission <5 or active ≥5. We determined agreement per item and total HBI score and intraclass correlation coefficients (ICCs). Bland-Altman plot was performed. HBI changes in disease activity from month 1 to month 4 were determined. Results: A total of 219 patients were enrolled. All scheduled assessments (385 pairs of the HBI questionnaire) showed a high percentage of agreement for remission/activity (92.4%, κ = 0.796), positive predictive value (PPV) for remission of 98.2%, and negative predictive value of 76.7%. High agreement was also found at month 1 (93.15%, κ = 0.82) and month 4 (91.5%, κ = 0.75). Bland-Altman plot was more uniform when the HBI mean values were <5 (remission). ICC values were 0.82, 0.897, and 0.879 in all scheduled assessments, 1 and 4 months, respectively. Conclusions: We found a high percentage of agreement between patients' self-administered mobile app HBI and in-clinic physician assessment to detect CD activity with a remarkably high PPV for remission. The mobile app HBI might allow a strict control of inflammation by remote monitoring and flexible follow-up of CD patients. Reduction of sanitary costs could be possible.

Implementation of massive sequencing in the genetic diagnosis of hereditary cancer syndromes: diagnostic performance in the Hereditary Cancer Programme of the Valencia Community (FamCan-NGS).

BACKGROUND: Approximately 5 to 10% of all cancers are caused by inherited germline mutations, many of which are associated with different Hereditary Cancer Syndromes (HCS). In the context of the Program of Hereditary Cancer of the Valencia Community, individuals belonging to specific HCS and their families receive genetic counselling and genetic testing according to internationally established guidelines. The current diagnostic approach is based on sequencing a few high-risk genes related to each HCS; however, this method is time-consuming, expensive and does not achieve a confirmatory genetic diagnosis in many cases. This study aims to test the level of improvement offered by a Next Generation Sequencing (NGS) gene-panel compared to the standard approach in a diagnostic reference laboratory setting. METHODS: A multi-gene NGS panel was used to test a total of 91 probands, previously classified as non-informative by analysing the high-risk genes defined in our guidelines. RESULTS: Nineteen deleterious mutations were detected in 16% of patients, some mutations were found in already-tested high-risk genes (BRCA1, BRCA2, MSH2) and others in non-prevalent genes (RAD51D, PALB2, ATM, TP53, MUTYH, BRIP1). CONCLUSIONS: Overall, our findings reclassify several index cases into different HCS, and change the mutational status of 14 cases from non-informative to gene mutation carriers. In conclusion, we highlight the necessity of incorporating validated multi-gene NGS panels into the HCSs diagnostic routine to increase the performance of genetic diagnosis.

Isolation of microsatellite loci for the endangered vermetid gastropod Dendropoma lebeche using Illumina MiSeq next generation sequencing technology.

Dendropoma petraeum, considered the primary vermetid reef-building species in the Mediterranean, has recently been shown to be a species complex of at least four cryptic species. These species have highly restricted, non-overlapping distributions, causing concern for their conservation status. To better study the genetic diversity of these populations, we selected one of these species, Dendropoma lebeche (Templado et al. in Mediterr Mar Sci 17(1):13-31, 2016), which is restricted to the western Mediterranean, for microsatellite marker development using Illumina MiSeq. We provide an initial survey of 29 polymorphic microsatellite loci for D. lebeche. Genetic analyses identified 2-11 alleles per locus across the 30 samples examined. Observed and expected heterozygosities ranged from 0.067 to 0.800 and 0.064 to 0.770, respectively. None of the loci deviated from Hardy-Weinberg equilibrium or showed signs of being under selective pressure. Significant linkage disequilibrium was found between two loci. We also show the cross-species amplification of these microsatellite markers in the other three species of the complex, the Tyrrhenian-Sicilian lineage, D. cristatum (Biondi, 1859), the Levantine lineage, D. anguliferum (Monterosato, 1878) and Dendropoma sp. found along the Ionian-Aegean coasts, suggesting their potential utility for future phylogenetic and evolutionary studies.

Adalimumab Maintenance Treatment in Ulcerative Colitis: Outcomes by Prior Anti-TNF Use and Efficacy of Dose Escalation.

BACKGROUND: The impact of prior anti-TNF use on "real-life" outcomes of adalimumab therapy in ulcerative colitis (UC) is not well known. AIM: To compare the influence of prior anti-TNF use on the outcomes of adalimumab maintenance treatment in UC patients. We also assessed the effectiveness of adalimumab dose escalation. METHODS: This retrospective multicenter cohort study included consecutive UC who advanced to an adalimumab maintenance regimen. Patients in whom adalimumab was discontinued prior to week eight of treatment were excluded. The co-primary efficacy endpoints were the cumulative probabilities of adalimumab failure-free survival and colectomy-free survival. We also assessed the need for and the effectiveness of adalimumab dose escalation. RESULTS: Of 184 UC on maintenance treatment with adalimumab, 116 (63%) had previous anti-TNF use. After a median follow-up of 23 months (interquartile range 13-49), 112 patients (60%) maintained corticosteroid-free clinical response. Sixty-nine patients (37%) had adalimumab failure, and 22 (12%) needed colectomy. Anti-TNF-naïve patients had significantly lower adjusted rates of adalimumab failure (hazard ratio [HR] 0.65; p < 0.001), adalimumab dose escalation (HR 0.35; p = 0.002), and need for colectomy (HR 0.26; p < 0.004). Seventy-six patients (41%) needed dose escalation after secondary loss of response, and 47% of these regained response after escalation. Short-term response after escalation was identified as a significant predictor of colectomy avoidance (HR 0.53; p = 0.007). CONCLUSIONS: In this "real-life" cohort of UC patients on maintenance treatment with adalimumab, anti-TNF-naïve patients had significantly better long-term outcomes. Adalimumab dose escalation enabled recovery of response in nearly half of patients.

Vulvar metastatic Crohn disease: clinical, histopathological and ultrasonographic findings.

Metastatic Crohn disease (MCD) is an unusual type of cutaneous Crohn disease characterized by skin lesions separated from the lesions of the gastrointestinal tract. The diagnosis of MCD is essentially histological,showing noncaseating granulomas in the dermis and subcutaneous fat tissue. We report a case of MCD with vulvar involvement and clinical, histopathological, and ultrasonographic findings of this disease.

[Impact of the incorporation of a nurse in an inflammatory bowel disease unit]. / Impacto de la incorporación de la enfermera a una unidad de enfermedad inflamatoria intestinal.

INTRODUCTION: Multidisciplinary units are needed because of the growing complexity and volume of patients with inflammatory bowel disease (IBD). OBJECTIVES: To evaluate the healthcare, economic and research impact of incorporating a nurse into the IBD unit of the Puerta de Hierro Majadahonda University Hospital. METHODS: We prospectively recorded the activity carried out by the nurse of the IBD unit from March 2010 to December 2014. RESULTS: During this period, healthcare demand progressively increased, with 1,558 patients being attended by our unit. The healthcare provided by the nurse included 5,293 electronic mails and 678 telephone calls. We estimated that this activity represented a saving of 3,504 in-person medical consultations and 852 accident and emergency department visits. Other activities consisted of monitoring treatments with biological and non-biological agents (8,371 laboratory tests), extraction of 342 blood samples, follow-up of 1047 diagnostic tests and consultations with other medical specialties, health education in self-administration of drugs in 114 patients, the performance of 158 granulocyte apheresis procedures, and participation in 25 research projects. CONCLUSION: The incorporation of a specialised nurse in an IBD unit had major economic, healthcare and research benefits.

Surviving the Messinian Salinity Crisis? Divergence patterns in the genus Dendropoma (Gastropoda: Vermetidae) in the Mediterranean Sea.

Four genetically distinct clades were recently described under the name Dendropoma petraeum, a Mediterranean endemic vermetid gastropod. The aim of this work is to date the processes that drove to the diversification within this taxon and to relate them to the corresponding historical events occurred in the Mediterranean Sea. Sequences from mitochondrial and nuclear markers were obtained from specimens collected in 29 localities spanning over 4000km across the entire distribution range of D. petraeum species complex. The phylogenetic and coalescent-based analyses confirmed the four well-supported and largely differentiated lineages of D. petraeum, clearly delimited geographically along a west-east axis within the Mediterranean Sea: Western, Tyrrhenian-Sicilian, Ionian-Aegean and Levantine lineages. Divergence time estimates, obtained using a range of known substitution rates for other marine gastropods, indicated two main stages of diversification. In the first period (between 9.5 and 4.5mya), the ancestral D. petraeum diverged into the current four lineages. The most recent period occurred between 3.72 and 0.66mya in the late Pliocene-early Pleistocene, and included the main within-lineage diversification events. Therefore, if the divergence time between the major lineages of Dendropoma in the Mediterranean actually predated or coincided with the Messinian Salinity Crisis, then they should have survived to this dramatic period within the Mediterranean, as supported by Bayes Factors model comparison. Conversely, if the divergence started after the crisis, congruent with the idea that no true marine organism survived the Messinian Salinity Crisis, then our results indicate substitution rates of Dendropoma much higher than usual (5.16% per million years for COI, 3.04% for 16S). More recent climate changes seem to have conditioned the demographic history of each lineage differently. While Western and Tyrrhenian-Sicilian lineages both underwent an increase in their effective population sizes from 1.5 to 0.6mya coinciding with a long interglacial period, the Ionian-Aegean and Levantine lineages showed constant effective population sizes since 2-2.5mya, suggesting that these eastern lineages might represent small and relict populations surviving the subsequent Quaternary glaciations in isolated refugia.

Cysteamine (Cystagon®) adherence in patients with cystinosis in Spain: successful in children and a challenge in adolescents and adults.

BACKGROUND: Cysteamine has improved survival and prognosis in cystinosis. Increasing numbers of patients reach adulthood and face new challenges such as compliance that wanes over time. The aim of this study was to evaluate adherence to cysteamine treatment in a group of cystinotic patients in Spain in an attempt to identify potential therapy pitfalls and improve the overall care of affected individuals. Despite the impact of cysteamine on prognosis, there is a paucity of data regarding adherence. METHOD: Thirty-four cystinotic patients (21 male) 38% ≥18 years were enrolled in a voluntary, anonymous survey. Replies were obtained from patients (15/34), mothers (11/34), fathers (4/34) and both parents (4/34). RESULTS: Patient age (median and interquartile range) at diagnosis was 1 year (0.57-1), and patient age at Cystagon® initiation was also 1 year (0.8-1.8). Sixteen (47%) were kidney transplant (KTx) recipients; six were retransplanted. Age at first KTx 10 years (8.7-13.7). Patient understanding of multiorgan involvement in cystinosis: 4.1 organs reported; eye 97% and kidney 91%. Cysteamine was given by mother (100%) and father (83%) in <11 year olds, or self-administered (94%) in ≥11 year olds. Four daily doses in 89% versus 56% in <11 year olds or ≥11 year olds, with fixed schedule in 94% versus 50% in <11 or ≥11 year olds and progressive loss of reminders over time. Furthermore, 44% complained of unpleasant smell. Motivation for treatment compliance was 100% versus 40% in <11 versus ≥11 year olds, respectively. Disease impact in patients <18 years is as follows: school (29%), social (14%), 'feeling different' (10%); in patients ≥18 years: 'feeling different' (62%), professional (39%) and job absenteeism (31%). Referring physician: paediatric nephrologist (94%) and nephrologist (63%) in <11 versus ≥11 year olds. Ophthalmological follow-up: 83% versus 38% in <11 versus ≥11 year olds. Patient opinion of physician expertise: paediatric nephrologist (94%) and nephrologist (44%). New treatment options (65%) and better information (42%) were demanded to improve adherence. CONCLUSION: Treatment with Cystagon is effective in young patients. However, adherence diminishes over time in adolescents and adults despite disease impact. Strategies such as better information on the disease, patient self-care promotion and facilitated transition to adult healthcare services are required to improve compliance and the clinical management of cystinosis.

Infliximab Dose Escalation as an Effective Strategy for Managing Secondary Loss of Response in Ulcerative Colitis.

BACKGROUND: The outcomes of infliximab dose escalation in ulcerative colitis (UC) have not been well evaluated. AIMS: To assess the short- and long-term outcomes of infliximab dose escalation in a cohort of patients with UC. METHODS: This was a multicenter, retrospective, cohort study. All consecutive UC patients who had lost response to infliximab maintenance infusions and who underwent infliximab dose escalation were included. Post-escalation short-term clinical response and remission were evaluated. In the long term, the cumulative probabilities of infliximab failure-free survival and colectomy-free survival were calculated. Predictors of short-term response and event-free survival were estimated using logistic regression analysis and Cox proportional hazard regression analysis. RESULTS: Seventy-nine patients were included. Fifty-four patients (68.4%) achieved short-term clinical response and 41 patients (51.9%) entered in clinical remission. After a median follow-up of 15 months [interquartile range (IQR) 8-26], 33 patients (41.8%) had infliximab failure. Patients with short-term response had a significantly lower adjusted rate of infliximab failure [hazard ratio (HR) 0.24, 95% confidence interval (CI) 0.12-0.49; p < 0.001]. During a median follow-up of 24 months (IQR 13-34), 9 patients (11.4%) needed colectomy. Short-term response was identified as a predictor of colectomy avoidance (HR 0.14; 95% CI 0.03-0.69; p < 0.007). CONCLUSIONS: In UC patients who lost response to infliximab during maintenance, infliximab dose escalation enabled recovery of short-term response in nearly 70% of patients. In the long term, 58% of patients maintained sustained clinical benefit, and 9 of 10 avoided colectomy. Short-term response was associated with an 86% reduction in the relative risk of colectomy.