Determinants of and interventions for Proton Pump Inhibitor prescription behavior: A systematic scoping review.

BACKGROUND: Proton Pump Inhibitors (PPI) are frequently prescribed. Long-term use is associated with side-effects and patients often lack a valid indication. Inappropriate PPI prescribing thus needs to be addressed. This review aims to scope 1) what determinants are studied as reasons for PPI prescribing, 2) what strategies are used for changing PPI (de)prescribing, and 3) whether important determinants are addressed in these interventions. METHODS: We searched eight databases for papers on determinants of physician PPI prescribing. Studies were included if they were conducted in a Western country and focused on oral PPIs for an adult population. By following the Behaviour Change Wheel, we extracted information regarding PPI prescribing behavior, behavioral determinants and intervention strategies. FINDINGS: We included 74 papers. Most focused on the determinants knowledge and beliefs about consequences. The latter was consistently related to PPI prescribing. Results for knowledge were mixed. Most interventions used education or enablement (e.g., algorithms, quality check improvements, involvement of pharmacists) as strategies. Enablement consistently improved PPI prescribing, while results for education were mixed. INTERPRETATION: There is an overemphasis on reflective processes in studies on PPI prescribing. Future research should comprehensively identify behavioral determinants, focusing on reflective and impulsive processes, such that interventions can address the most important determinants.

The cost-effectiveness of physician assistants/associates: A systematic review of international evidence.

BACKGROUND: The global utilization of the physician assistant/associate (PA) is growing. Their increasing presence is in response to the rising demands of demographic changes, new developments in healthcare, and physician shortages. While PAs are present on four continents, the evidence of whether their employment contributes to more efficient healthcare has not been assessed in the aggregate. We undertook a systematic review of the literature on PA cost-effectiveness as compared to physicians. Cost-effectiveness was operationalized as quality, accessibility, and the cost of care. METHODS AND FINDINGS: Literature to June 2021 was searched across five biomedical databases and filtered for eligibility. Publications that met the inclusion criteria were categorized by date, country, design, and results by three researchers independently. All studies were screened with the Risk of Bias in Non-randomised Studies-of Interventions (ROBIN-I) tool. The literature search produced 4,855 titles, and after applying criteria, 39 studies met inclusion (34 North America, 4 Europe, 1 Africa). Ten studies had a prospective design, and 29 were retrospective. Four studies were assessed as biased in results reporting. While most studies included a small number of PAs, five studies were national in origin and assessed the employment of a few hundred PAs and their care of thousands of patients. In 34 studies, the PA was employed as a substitute for traditional physician services, and in five studies, the PA was employed in a complementary role. The quality of care delivered by a PA was comparable to a physician's care in 15 studies, and in 18 studies, the quality of care exceeded that of a physician. In total, 29 studies showed that both labor and resource costs were lower when the PA delivered the care than when the physician delivered the care. CONCLUSIONS: Most of the studies were of good methodological quality, and the results point in the same direction; PAs delivered the same or better care outcomes as physicians with the same or less cost of care. Sometimes this efficiency was due to their reduced labor cost and sometimes because they were more effective as producers of care and activity.

Translation initiation factor eIF2Bε promotes Wnt-mediated clonogenicity and global translation in intestinal epithelial cells.

Modulation of global mRNA translation, which is essential for intestinal stem cell function, is controlled by Wnt signaling. Loss of tumor supressor APC in stem cells drives adenoma formation through hyperactivion of Wnt signaling and dysregulated translational control. It is unclear whether factors that coordinate global translation in the intestinal epithelium are needed for APC-driven malignant transformation. Here we identified nucleotide exchange factor eIF2Bε as a translation initiation factor involved in Wnt-mediated intestinal epithelial stemness. Using eIF2BεArg191His mice with a homozygous point mutation that leads to dysfunction in the enzymatic activity, we demonstrate that eIF2Bε is involved in small intestinal crypt formation, stemness marker expression, and secreted Paneth cell-derived granule formation. Wnt hyperactivation in ex vivo eIF2BεArg191His organoids, using a GSK3ß inhibitor to mimic Apc driven transformation, shows that eIF2Bε is essential for Wnt-mediated clonogenicity and associated increase of the global translational capacity. Finally, we observe high eIF2Bε expression in human colonic adenoma tissues, exposing eIF2Bε as a potential target of CRC stem cells with aberrant Wnt signaling.

Physician Assistants and Nurse Practitioners in Primary Care Plus: A Systematic Review.

INTRODUCTION: Shifting specialist care from the hospital to primary care/community care (also called primary care plus) is proposed as one option to reduce the increasing healthcare costs, improve quality of care and accessibility. The aim of this systematic review was to get insight in primary care plus provided by physician assistants or nurse practitioners. METHODS: Scientific databases and reference list were searched. Hits were screened on title/abstract and full text. Studies published between 1990-2018 with any study design were included. Risk of bias assessment was performed using QualSyst tool. RESULTS: Search resulted in 5.848 hits, 15 studies were included. Studies investigated nurse practitioners only. Primary care plus was at least equally effective as hospital care (patient-related outcomes). The number of admission/referral rates was significantly reduced in favor of primary care plus. Barriers to implement primary care plus included obtaining equipment, structural funding, direct access to patient-data. Facilitators included multidisciplinary collaboration, medical specialist support, protocols. CONCLUSIONS AND DISCUSSION: Quality of care within primary care plus delivered by nurse practitioners appears to be guaranteed, at patient-level and professional-level, with better access to healthcare and fewer referrals to hospital. Most studies were of restricted methodological quality. Findings should be interpreted with caution.

An activity analysis of Dutch hospital-based physician assistants and nurse practitioners.

BACKGROUND: The physician assistant (PA) and the nurse practitioner (NP) were introduced into The Netherlands in 2001 and 1997 respectively. By the second decade, national policies had accelerated the acceptance and development of these professions. Since 2015, the PA and NP have full practice authority as independent health professionals. The aim of this research was to gain a better understanding of the tasks and responsibilities that are being shifted from Medical Doctors (MD) to PAs and NPs in hospitals. More specifically in what context and visibility are these tasks undertaken by hospital-based PAs and NPs in patient care. This will enable them to communicate their worth to the hospital management. STUDY DESIGN: A descriptive, non-experimental research method design was used to collect and analyze both quantitative and qualitative data about the type of tasks performed by a PA or NP. Fifteen medical departments across four hospitals participated. METHODS: The patient scheduling system and hospital information system were probed to identify and characterize a wide variety of clinical tasks. The array of tasks was further verified by 108 interviews. All tasks were divided into direct and indirect patient care. Once the tasks were cataloged, then MDs and hospital managers graded the PA- or NP-performed tasks and assessed their contributions to the hospital management system. FINDINGS: In total, 2883 tasks were assessed. Overall, PAs and NPs performed a wide variety of clinical and administrative tasks, which differed across hospitals and medical specialties. Data from interviews and the hospital management systems revealed that over a third of the tasks were not properly registered or attributed to the PA or NP. After correction, it was found that the NP and PA spent more than two thirds of their working time on direct patient care. CONCLUSIONS: NPs and PAs performed a wide variety of clinical tasks, and the consistency of these tasks differed per medical specialty. Despite the fact that a large part of the tasks was not visible due to incorrect administration, the interviews with MDs and managers revealed that the use of an NP or PA was considered to have an added value at the quality of care as well to the production for hospital-based medical care in The Netherlands.

Effects of growth stage and growing degree day accumulations on triticale forages: 2. In vitro disappearance of neutral detergent fiber.

The use of winter triticale (X Triticosecale Wittmack) in dairy-cropping systems has expanded greatly in recent years, partly because of its value as a forage crop but also to improve land stewardship by providing winter ground cover. Our objectives were to use 2-pool and 3-pool nonlinear models to characterize in vitro disappearance of neutral detergent fiber (NDF) and then describe the relationship between estimated parameters from those models with plant growth stage or growing degree days (GDD) >5°C for winter triticale forages harvested during 2016 and 2017 in Marshfield, Wisconsin. Forages were harvested from replicated field plots each year at growth stages ranging from stem elongation to soft dough. All NDF analyses included use of sodium sulfite and heat-stable α-amylase with residual fiber corrected for contaminant ash (asNDFom). Nonlinear 3-pool models for in vitro disappearance of asNDFom that included fast (Bfast) and slow (Bslow) disappearance pools as well as an associated disappearance rate for each (Kdfast and Kdslow, respectively) were easily fitted provided that a single discrete lag time was applied to both Bfast and Bslow pools to reduce the number of parameters to be estimated. An unresolved issue related to fitting 3-pool decay models was the incomplete recovery of asNDFom from immature triticale forages at 0 h, which was partially resolved with 2 approaches that produced similar estimates of Kdfast and Kdslow. Most parameters obtained from 2- and 3-pool decay models for asNDFom could be related to growth stage or GDD using polynomial regression techniques, often with high coefficients of determination (R2). For 3-pool models of asNDFom disappearance, Bslow increased with plant maturity, but the associated Kdslow ranged narrowly from 0.011 to 0.015/h and could not be related to growth stage or GDD by quartic, cubic, quadratic, or linear regression models. Despite different cultivars coupled with substantial differences in precipitation across years, single endpoint estimates of in vitro disappearance of asNDFom after 24, 30, or 48 h of incubation were closely related (R2 ≥ 0.906) to growth stage and GDD by linear or quadratic regression models that were generally similar across production years. Typical recommendations for harvesting triticale at boot stage to facilitate the planting of a double crop are strongly supported by the extensive 30-h in vitro disappearance of asNDFom at that growth stage, which was 63.1 and 64.8% of asNDFom during 2016 and 2017, respectively.

Systematic review with meta-analysis: anxiety and depression in children and adolescents with inflammatory bowel disease.

BACKGROUND: The co-existence of psychological problems and paediatric inflammatory bowel disease (IBD) is receiving increasing attention. Most studies investigated anxiety and depression, with prevalence rates varying from 0% to 50%. A systematic review is necessary to provide clear insight into the prevalence of anxiety and depression in paediatric IBD. AIM: To systematically evaluate available data on the prevalence of anxiety and depressive symptoms and disorders in paediatric IBD (aged 6-18 years). METHODS: Comprehensive searches were performed in Embase, Medline Ovid, Web of Science, Cochrane, PubMed, PsychInfo Ovid, and Google scholar for studies published from 1994 to 2017. Pooled prevalence rates were calculated using inverse variance heterogeneity models. Meta-regression was used to study if disease type, disease activity and gender influence prevalence. RESULTS: Twenty-eight studies (N = 8107, mean age: 14.3) were identified. Pooled prevalence estimates were 16.4% (95% confidence interval [CI] 6.8%-27.3%) for anxiety symptoms and 4.2% (95% CI 3.6%-4.8%) for anxiety disorders. Pooled prevalence estimates were 15.0% (95% CI 6.4%-24.8%) for depressive symptoms and 3.4% (95% CI 0%-9.3%) for depressive disorders. Meta-regression showed no influence of disease type or gender on these prevalence rates, but studies with a higher percentage of active disease had a higher rate of depressive symptoms. CONCLUSIONS: The described pooled prevalence of anxiety and depressive symptoms is lower than in adult IBD. However, due to varying instruments/cut-offs for measuring symptoms and few studies investigating disorders, the results should be interpreted with caution. Cross-cultural use of the same instruments is needed to gain better insight into prevalence rates.

Effects of growth stage and growing degree day accumulations on triticale forages: 1. Dry matter yield, nutritive value, and in vitro dry matter disappearance.

The use of triticale (X Triticosecale Wittmack) in dairy-cropping systems has expanded greatly in recent years, partly to improve land stewardship by providing winter ground cover. Our objective was to establish relationships relating indices of nutritive value with growth stage or accumulated growing degree days >5°C for triticale forages grown in central Wisconsin. Replicated 3.7-m × 9.1-m plots were established following removal of corn for silage (fall 2015) and soybeans (fall 2016) and then harvested at various growth stages the following spring. Plants were assigned a numerical growth stage based on a linear staging system suitable for use as an independent regression variable. Response variables [e.g., dry matter (DM) yield, indices of nutritive value, and parameters from in vitro DM disappearance kinetics] were regressed on growth stage and growing degree days using linear, quadratic, cubic, or quartic models. For spring 2016, the mean DM yield at the boot stage (3,804 kg of DM/ha) was only 30% of that observed at the soft dough stage of growth (12,642 kg of DM/ha). Although yields were reduced during spring 2017, primarily due to spring flooding, the relationship between respective yields at these growth stages was similar (1,453 vs. 5,399 kg of DM/ha). Regressions of DM yield (kg/ha) on growth stage for 2016 were explained by a cubic model (Y = 0.0663x3 - 9.44x2 + 595x - 9,810) compared with a simple linear response for 2017 (Y = 103x - 3,024); in both cases, coefficients of determination were very high (R2 ≥ 0.934). Many nutritional and in vitro DM disappearance characteristics were affected by the juxtaposition and balance of 2 generally competing factors: (1) increased concentrations of structural plant fiber coupled with concurrent lignification as plants matured and (2) the accumulation of highly digestible carbohydrate during seed head development. A comparison of respective energy yields between the boot and soft dough stages of growth for 2016 (2,488 vs. 8,141 kg of total digestible nutrients/ha) and 2017 (1,033 vs. 3,520 kg of total digestible nutrients/ha) suggests that yields of energy are greater at soft dough stage and are mostly driven by DM yield. An informed harvest management decision for lactating cows may still favor a boot-stage harvest because of superior nutritional characteristics, a need to plant double-cropped corn expeditiously, or both. Harvest timing of triticale forages for other livestock classes would appear to be more flexible, but prioritizing a subsequent double crop may reduce the effects on DM yield to a secondary consideration.

Clinical disease activity is associated with anxiety and depressive symptoms in adolescents and young adults with inflammatory bowel disease.

BACKGROUND: Youths with inflammatory bowel disease (IBD) are at risk for developing anxiety and depressive symptoms with a reported 20%-50% prevalence rate. AIMS: This prospective study aimed to: (1) describe the prevalence and severity of anxiety and depressive symptoms in a large Dutch cohort of young IBD patients, and (2) identify demographic and clinical risk factors for anxiety and depression. METHODS: IBD patients (n = 374; 10-25 years) were screened for anxiety, depression and quality of life using validated age-specific questionnaires. Patients with elevated scores for anxiety and/or depressive symptoms received a diagnostic interview assessing psychiatric disorders. Demographic and clinical characteristics were retrieved from medical charts. Multiple logistic regression analysis was performed to identify risk factors for anxiety and/or depression. RESULTS: Patients (mean age 18.9 years, 44.1% male, Crohn's disease 60.4%) had disease in remission (75.4%), or mild, moderate and severe clinical disease activity in, respectively, 19.8%, 2.7% and 2.1%. Mild anxiety/depressive symptoms were present in 35.2% and severe symptoms in 12.4% of patients. Elevated symptoms of either anxiety (28.3%), depression (2.9%) or both (15.8%) were found and did not differ between adolescents (10-17 years) and young adults (18-25 years). Active disease significantly predicted depressive symptoms (odds ratio (OR): 4.6 [95% confidence interval [CI]: 2.4-8.8], P < 0.001). Female gender (OR: 1.7 [95% CI: 1.1-2.7]), active disease (OR: 1.9 [95% CI: 1.1-3.2]) and a shorter disease duration (OR: 1.3 [95% CI: 0.6-1.0) (all P < 0.025) significantly predicted anxiety and/or depressive symptoms. CONCLUSIONS: Considering the high prevalence of anxiety and depressive symptoms, psychological screening is recommended in young IBD patients. Screening facilitates early recognition and psychological treatment. Female patients and patients with active disease are the most vulnerable.

Physiological augmentation of esophageal distension pressure and peristalsis during conditions of increased esophageal emptying resistance.

BACKGROUND: Abdominal compression has been implemented as a provocative maneuver in high-resolution impedance manometry (HRIM) to "challenge" normal esophageal physiology with the aim of revealing abnormal motor patterns which may explain symptoms. In this study, we measured the effects of abdominal compression on esophageal functioning utilizing novel pressure-impedance parameters and attempted to identify differences between healthy controls and globus patients. METHODS: Twenty-two healthy volunteers (aged 23-32 years, 41% female) and 22 globus patients (aged 23-72 years, 68% female) were evaluated with HRIM using a 3.2-mm water perfused manometric and impedance catheter. All participants received 10 × 5 mL liquid swallows; healthy controls also received 10 × 5 mL liquid swallows with abdominal compression created using an inflatable cuff. All swallows were analyzed to assess esophageal pressure topography (EPT) and pressure-flow metrics, indicative of distension pressure, flow timing and bolus clearance were derived. KEY RESULTS: The effect of abdominal compression was shown as a greater contractile vigor of the distal esophagus by EPT and higher distension pressure based on pressure-flow metrics. Age and body mass index also increased contractile vigor and distension pressure. Globus patients were similar to controls. CONCLUSIONS AND INTERFERENCES: Intrabolus pressure and contractile vigor are indicative of the physiological modulation of bolus transport mechanisms. Provocative testing by abdominal compression induces changes in these esophageal bolus dynamics.

Risk factors for proximal disease extension and colectomy in left-sided ulcerative colitis.

OBJECTIVE: The primary objective of this study was to assess proximal disease extension of ulcerative colitis (UC) over time, with disease behaviour pattern and risk factors for proximal disease extension and colectomy as secondary aims. METHODS: All cumulative incident cases diagnosed with UC at the Academic Medical Center between January 1990 and December 2009 were studied. The cumulative risk of colectomy was calculated by Kaplan-Meier analysis. The Cox proportional hazards regression was used to identify risk factors associated with proximal disease extension and colectomy. RESULTS: In total, 506 UC patients were included with a median age of 33 years (IQR 23-41) at diagnosis. Ninety-five (18.8%) patients underwent colectomy during follow-up. Median follow-up was 10 years (IQR 5-15). Initial disease extent was evaluable in 416 patients, of whom 142 (34.1%) had proctitis, 155 (37.3%) left-sided colitis and 119 (28.6%) pancolitis. Proximal disease extension was observed in 120 (28.8%) patients during follow-up (51 proctitis to left-sided colitis, 39 proctitis to extensive colitis and 30 left-sided to extensive colitis). Disease behaviour was evaluable in 378 patients, of whom 244 (64.6%) had less than one relapse per year. Younger age at diagnosis (HR 0.98, 95% CI 0.96-0.99) and continuous active disease (HR 2.18, 95% CI 1.27-3.73) were independent risk factors for proximal disease extension. The cumulative risk of colectomy did not change over time between patients diagnosed before and after the year 2000 (p = 0.341). Continuous active disease (HR 7.05, 95% CI 4.23-11.77), systemic steroids (HR 3.25, 95% CI 1.37-7.71) and cyclosporine treatment (HR 2.80, 95% CI 1.66-4.72) were independent risk factors for colectomy, whereas proctitis at diagnosis (HR 0.43, 95% CI 0.22-0.86) carried a lower risk. CONCLUSION: In one-third of UC patients, left-sided disease at diagnosis will extend proximally during 10 years of follow-up. Proximal disease extension was not a risk factor for colectomy, but the risk of colectomy is rather determined by continuous disease activity, and use of systemic steroids and cyclosporine.

Profoundly Expanded T-cell Clones in the Inflamed and Uninflamed Intestine of Patients With Crohn's Disease.

BACKGROUND AND AIM: T cells are key players in the chronic intestinal inflammation that characterises Crohn's disease. Here we aim to map the intestinal T-cell receptor [TCR] repertoire in patients with Crohn's disease, using next-generation sequencing technology to examine the clonality of the T-cell compartment in relation to mucosal inflammation and response to therapy. METHODS: Biopsies were taken from endoscopically inflamed and uninflamed ileum and colon of 19 patients with Crohn's disease. From this cohort, additional biopsies were taken after 8 weeks of remission induction therapy from eight responders and eight non-responders. Control biopsies from 11 patients without inflammatory bowel disease [IBD] were included. The TCRß repertoire was analysed by next-generation sequencing of biopsy RNA. RESULTS: Both in Crohn's disease patients and in non-IBD controls, a broad intestinal T-cell repertoire was found, with a considerable part consisting of expanded clones. Clones in Crohn's disease were more expanded [p = 0.008], with the largest clones representing up to as much as 58% of the total repertoire. There was a substantial overlap of the repertoire between inflamed and uninflamed tissue and between ileum and colon. Following therapy, responders showed larger changes in the T-cell repertoire than non-responders, although a considerable part of the repertoire remained unchanged in both groups. CONCLUSIONS: The intestinal T-cell repertoire distribution in Crohn's disease is different from that in the normal gut, containing profoundly expanded T-cell clones that take up a large part of the repertoire. The T-cell repertoire is fairly stable regardless of endoscopic mucosal inflammation or response to therapy.

Suppression of anti-drug antibodies to infliximab or adalimumab with the addition of an immunomodulator in patients with inflammatory bowel disease.

BACKGROUND: Loss of response to anti-tumour necrosis factor (TNF) therapy in patients with inflammatory bowel disease (IBD) is often caused by anti-drug antibody formation with neutralisation of drug effect. Addition of an immunomodulator has been suggested to reduce immunogenicity, leading to regained response. AIM: To investigate whether addition of an immunomodulator to anti-TNF monotherapy could lead to anti-drug antibody suppression and regained clinical response in IBD patients. METHODS: We retrospectively collected measurements of infliximab or adalimumab serum concentrations and anti-drug antibodies to identify anti-drug positive patients with loss response who were given an immunomodulator. RESULTS: Anti-drug antibodies against infliximab and adalimumab were detected in 98/376 (26%) and in 61/226 (27%) patients, respectively. Immunomodulators were given to 17/159 patients. Clinical response was recaptured in 6/10 patients receiving a thiopurine and in all (7/7) patients receiving methotrexate. In 7/8 patients on infliximab, serum concentrations increased (median 2.84 µg/mL; IQR: 1.19-4.98) and in 6/9 patients on adalimumab (median 3.10 µg/mL; IQR: 1.45-4.45). This was accompanied by a decrease in anti-drug antibodies to undetectable levels (median 11 months for both anti-TNF agents). In 23 patients, no immunomodulator was added but anti-TNF interval was shortened (17/23) or dosage was increased (6/23), which resulted in a clinical response in 10/17 and 2/6 patients, respectively. CONCLUSION: In 77% of IBD patients with loss of response due to immunogenicity, addition of immunomodulator resulted in undetectable anti-drug antibody levels, increased serum drug concentrations and regained clinical response. This strategy should be considered in this patient population before switching to other agents.

The ATG16L1 risk allele associated with Crohn's disease results in a Rac1-dependent defect in dendritic cell migration that is corrected by thiopurines.

Thiopurines are commonly used drugs in the therapy of Crohn's disease, but unfortunately only show a 30% response rate. The biological basis for the thiopurine response is unclear, thus hampering patient selection prior to treatment. A genetic risk factor associated specifically with Crohn's disease is a variant in ATG16L1 that reduces autophagy. We have previously shown that autophagy is involved in dendritic cell (DC)-T-cell interactions and cytoskeletal regulation. Here we further investigated the role of autophagy in DC cytoskeletal modulation and cellular trafficking. Autophagy-deficient DC displayed loss of filopodia, altered podosome distribution, and increased membrane ruffling, all consistent with increased cellular adhesion. Consequently, autophagy-deficient DC showed reduced migration. The cytoskeletal aberrations were mediated through hyperactivation of Rac1, a known thiopurine target. Indeed thiopurines restored the migratory defects in autophagy-deficient DC. Clinically, the ATG16L1 risk variant associated with increased response to thiopurine treatment in patients with Crohn's disease but not ulcerative colitis. These results suggest that the association between ATG16L1 and Crohn's disease is mediated at least in part through Rac1 hyperactivation and subsequent defective DC migration. As this phenotype can be corrected using thiopurines, ATG16L1 genotyping may be useful in the identification of patients that will benefit most from thiopurine treatment.

Induction of endoplasmic reticulum stress by deletion of Grp78 depletes Apc mutant intestinal epithelial stem cells.

Intestinal epithelial stem cells are highly sensitive to differentiation induced by endoplasmic reticulum (ER) stress. Colorectal cancer develops from mutated intestinal epithelial stem cells. The most frequent initiating mutation occurs in Apc, which results in hyperactivated Wnt signalling. This causes hyperproliferation and reduced sensitivity to chemotherapy, but whether these mutated stem cells are sensitive to ER stress induced differentiation remains unknown. Here we examined this by generating mice in which both Apc and ER stress repressor chaperone Grp78 can be conditionally deleted from the intestinal epithelium. For molecular studies, we used intestinal organoids derived from these mice. Homozygous loss of Apc alone resulted in crypt elongation, activation of the Wnt signature and accumulation of intestinal epithelial stem cells, as expected. This phenotype was however completely rescued on activation of ER stress by additional deletion of Grp78. In these Apc-Grp78 double mutant animals, stem cells were rapidly lost and repopulation occurred by non-mutant cells that had escaped recombination, suggesting that Apc-Grp78 double mutant stem cells had lost self-renewal capacity. Although in Apc-Grp78 double mutant mice the Wnt signature was lost, these intestines exhibited ubiquitous epithelial presence of nuclear ß-catenin. This suggests that ER stress interferes with Wnt signalling downstream of nuclear ß-catenin. In conclusion, our findings indicate that ER stress signalling results in loss of Apc mutated intestinal epithelial stem cells by interference with the Wnt signature. In contrast to many known inhibitors of Wnt signalling, ER stress acts downstream of ß-catenin. Therefore, ER stress poses a promising target in colorectal cancers, which develop as a result of Wnt activating mutations.

[Transition from paediatric to adult care: management of adolescents with inflammatory bowel disease]. / Transitie van kinder- naar volwassenenzorg.

The transfer of adolescent patients with inflammatory bowel disease (IBD) to adult gastroenterology services is often troublesome. Failed transition can have adverse effects on the course of disease. We present two cases of adolescent IBD patients and their transition process. We identify requirements for successful transition and discuss potential barriers. We illustrate and emphasise that the medical teams on each side (paediatric and adult), as well as the patient and the parents should actively participate in the process of transition. The medical team should, preferably during a local transition clinic, regularly evaluate disease knowledge and self-management skills of the patient and make an individual transition plan to fill the gaps in knowledge and/or skills. Patients should be willing to learn to become more independent and parents should be stimulated to create an environment so that their child can actually try to become more independent. Lastly, we present the Rotterdam model for transition of IBD patients.

The Link between the Appendix and Ulcerative Colitis: Clinical Relevance and Potential Immunological Mechanisms.

The human appendix has long been considered as a vestigial organ, an organ that has lost its function during evolution. In recent years, however, reports have emerged that link the appendix to numerous immunological functions in humans. Evidence has been presented for an important role of the appendix in maintaining intestinal health. This theory suggests that the appendix may be a reservoir or 'safe house' from which the commensal gut flora can rapidly be reestablished if it is eradicated from the colon. However, the appendix may also have a role in the development of inflammatory bowel disease (IBD). Several large epidemiological cohort studies have demonstrated the preventive effect of appendectomy on the development of ulcerative colitis, a finding that has been confirmed in murine colitis models. In addition, current studies are examining the possible therapeutic effect of an appendectomy to modulate disease course in patients with ulcerative colitis. This literature review assesses the current knowledge about the clinical and immunological aspects of the vermiform appendix in IBD and suggests that the idea of the appendix as a vestigial remnant should be discarded.

Oral tolerance is inefficient in neonatal mice due to a physiological vitamin A deficiency.

Increased risk of allergy during early life indicates deficient immune regulation in this period of life. To date, the cause for inefficient neonatal immune regulation has never been elucidated. We aimed to define the ontogeny of oral tolerance and to identify necessary conditions specific for this stage of life. Ovalbumin (OVA) was administered orally to mice through breast milk and efficiency of systemic tolerance to OVA was assessed in adulthood using a model of allergic airway inflammation. Oral tolerance induction was fully efficient starting third week of life. Inefficiency in neonates was a consequence of abnormal antigen transfer across the gut barrier and retinaldehyde dehydrogenase expression by mesenteric lymph node CD103(+) neonatal dendritic cells, resulting in inefficient T-cell activation. Neonates' serum retinol levels were three times lower than in adult mice, and vitamin A supplementation was sufficient to rescue neonatal defects and allow tolerance induction from birth. The establishment of oral tolerance required the differentiation of Th1 lymphocytes in both vitamin A-supplemented neonates and 3-week-old unsupplemented mice. This knowledge should guide the design of interventions for allergy prevention that are adapted to the neonatal stage of life such as vitamin A supplementation.

Effects of cultivar and grazing initiation date on fall-grown oat for replacement dairy heifers.

Fall-grown oat has shown promise for extending the grazing season in Wisconsin, but the optimum date for initiating grazing has not been evaluated. Our objectives for this project were (1) to assess the pasture productivity and nutritive value of 2 oat cultivars [Ogle and ForagePlus (OG and FP, respectively)] with late-September (EG) or mid-October (LG) grazing initiation dates; and (2) to evaluate growth performance by heifers grazing these oat forages compared with heifers reared in confinement (CON). A total of 160 gravid Holstein heifers (80 heifers/yr) were assigned to 10 research groups (8 heifers/group). Mean initial body weight was 509±40.5 kg in 2013 and 517±30.2 kg in 2014. Heifer groups were assigned to specific pastures arranged as a 2×2 factorial of oat cultivars and grazing initiation dates. Grazing heifer groups were allowed to strip-graze oat pastures for 6 h daily before returning to the barn, where they were offered a forage-based basal total mixed ration. Main effects of oat cultivar and sampling date interacted for forage characteristics in 2013, but not in 2014. During 2013, oat forage mass increased until early November before declining in response to freezing weather conditions, thereby exhibiting linear and quadratic effects of sampling date, regardless of oat cultivar. Similar trends over time were observed in 2014. For 2013, the maximum forage mass was 5,329 and 5,046 kg/ha for FP and OG, respectively, whereas the mean maximum forage mass for 2014 was 4,806 kg/ha. ForagePlus did not reach the boot stage of growth during either year of the trial; OG matured more rapidly, reaching the late-heading stage during 2013, but exhibited only minor maturity differences from FP in 2014. For 2013, average daily gain for CON did not differ from grazing heifer groups (overall mean=0.63 kg/d); however, average daily gain from FP was greater than OG (0.68 vs. 0.57 kg/d), and greater from EG compared with LG (0.82 vs. 0.43 kg/d). For 2013, advantages in average daily gain for heifers grazing FP pastures were likely related to the greater energy density of FP oat throughout the fall that reached a maximum of 68.8% total digestible nutrients on November 27 compared with only 63.7% for OG on October 10. During 2014, average daily gain from CON exceeded all grazing heifer groups (0.81 vs. 0.57 kg/d), and average daily gain from EG again exceeded LG (0.70 vs. 0.44 kg/d). These results suggest that delaying grazing until mid-October will consistently suppress heifer growth performance, particularly if rapidly maturing cultivars are used.