How achievable are STRIDE-II treatment targets in real-world practice and do they predict long-term treatment outcomes?

Objective: The second iteration of the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) initiative recommends use of the Simple Endoscopic Score for Crohn's disease (SES-CD) as a treatment target for patients with CD. We aimed to assess whether the STRIDE-II endoscopic endpoints are achievable and whether the degree of mucosal healing (MH) affects long-term outcomes. Design/method: We performed a retrospective observational study between 2015 and 2022. Patients with CD who had baseline and follow-up SES-CD scores after biological therapy initiation were included. The primary outcome was treatment failure, defined as the need for: (1) change of biological therapy for active disease (2) corticosteroid use (3) CD-related hospitalisation or (4) surgery. We compared rates of treatment failure with the degree of MH achieved. Patients were followed up until treatment failure or study end (August 2022). Results: 50 patients were included and followed up for median 39.9 (34.6-48.6) months. Baseline characteristics: 62% male, median age 36.4 (27.8-43.9) years, disease distribution (L1: 4, L2: 11, L3: 35, perianal: 18). The proportion of patients achieving STRIDE-II end-points were: SES-CD≤2-25 (50%) and >50% reduction in SES-CD-35 (70%). Failure to achieve SES-CD≤2 (HR 11.62; 95% CI 3.33 to 40.56, p=0.003) or >50% improvement in SES-CD (HR 30.30; 95% CI 6.93 to 132.40, p<0.0001) predicted treatment failure. Conclusion: Use of SES-CD is feasible in real-world clinical practice. Achieving an SES-CD≤2 or a greater than 50% reduction, as set out by STRIDE-II, is associated with reduced rates of overall treatment failure including CD-related surgery.

Transnasal endoscopy: moving from endoscopy to the clinical outpatient-blue sky thinking in oesophageal testing.

Background: COVID-19 has severely affected UK endoscopy services with an estimate 86% loss of activity during the first wave. Subsequent delays in diagnostic and surveillance procedures highlight the need for novel solutions to tackle the resultant backlog. Transnasal endoscopy (TNE) provides an attractive option compared with conventional upper gastrointestinal endoscopy given its limited use of space, no sedation and reduced nursing resources. Our experience: We describe piloting and then establishing an outpatient model TNE service in the pandemic era and the implications on resource allocation, training and workforce. We also discuss our experiences and outline ways in which services can evolve to undertake more complex endoscopic diagnostic and therapeutic work. Over 90% of patients describe no discomfort and those who have previously experienced conventional transoral endoscopy preferred the transnasal approach. We describe a low complication rate (0.8%) comprising two episodes of mild epistaxis. The average procedure duration was reasonable (9.9±5.0 min) with full adherence to Joint Advisory Group quality standards. All biopsies assessed were deemed sufficient for diagnosis including those for surveillance procedures. Discussion: TNE can offer a safe, tolerable, high-quality service outside of a conventional endoscopy setting. Expanding procedural capacity without impacting on the current endoscopy footprint has great potential in recovering endoscopy services following the COVID-19 pandemic. Looking forward, TNE has potential to be used both within the endoscopy suite as part of therapeutic procedures, or outside of the endoscopy unit in outpatient clinics, community hospitals, or mobile units and to achieve this in a more sustainable and environmentally friendly way.

A retrospective cohort study: pre-operative oral enteral nutritional optimisation for Crohn's disease in a UK tertiary IBD centre.

BACKGROUND: Low-quality evidence suggests that pre-operative exclusive enteral nutrition (E/EN) can improve postoperative outcomes in patients with Crohn's disease (CD). It is not standard practice in most centres. AIMS: To test the hypothesis that pre-operative EN in patients undergoing ileal/ileocolonic surgery for CD is associated with improved postoperative outcome. METHODS: We performed a single centre retrospective observational study comparing surgical outcomes in patients receiving pre-operative EN (≥600 kcal/day for ≥2 weeks) with those who received no nutritional optimisation. Consecutive adult patients undergoing ileal/ileocolonic resection from 2008 to 2020 were included. The primary outcome was postoperative complications <30 days. Secondary outcomes included EN tolerance, specific surgical complications, unplanned stoma formation, length of stay, length of bowel resected, readmission and biochemical/anthropometric changes. RESULTS: 300 surgeries were included comprising 96 without nutritional optimisation and 204 optimised cases: oral EN n = 173, additional PN n = 31 (4 of whom had received nasogastric/nasojejunal EN). 142/204 (69.6%) tolerated EN. 125/204 (61.3%) initiated EN in clinic. Patients in the optimised cohort were younger at operation and diagnosis, with an increased frequency of penetrating disease and exposure to antibiotics or biologics, and were more likely to undergo laparoscopic surgery. The optimised cohort had favourable outcomes on multivariate analysis: all complications [OR 0.29; 0.15-0.57, p < 0.001], surgical complications [OR 0.41; 95% CI 0.20-0.87, p = 0.02], non-surgical complications [OR 0.24 95% CI 0.11-0.52, p < 0.001], infective complications [OR 0.32; 95% CI 0.16-0.66, p = 0.001]. CONCLUSIONS: Oral EN was reasonably well tolerated and associated with a reduction in 30-day postoperative complications. Randomised controlled trials are required to confirm these findings.

Depression, anxiety, and stress among inflammatory bowel disease patients during COVID-19: A UK cohort study.

BACKGROUND AND AIM: Patients with chronic diseases are believed to be at increased risk of mental health conditions during the COVID-19 pandemic. We aimed to assess the incidence of psychological morbidity in inflammatory bowel disease (IBD) patients during the COVID-19 pandemic, explore for association with risk of severe COVID-19 and other factors, and establish patients' interest in psychological support. METHODS: A survey including the Patient Health Questionnaire-9, General Anxiety Disorder-7, and Perceived Stress Scale tools for depression, anxiety, and stress was administered to IBD patients from a tertiary center in London, United Kingdom, in June 2020. RESULTS: Two hundred seventy-four patients responded to the survey (57% response rate), with 271 (99%) completing it. Moderate-severe depression was observed in 61 (22.5%), while 49 (18%) had moderate-severe anxiety; 39 (14%) had both diagnoses. Mean (SD) stress score was 16.2 (7.4). There was no association between degree of severe COVID-19 risk and psychological morbidity. Flare symptoms and fatigue were associated with worse psychological morbidity, while accessibility of information regarding COVID-19 risk and reducing that risk was protective for depression (odds ratio [OR] 0.56 [0.33-0.94], P = 0.03), anxiety (OR 0.62 [0.4-0.96], P = 0.03), and stress (standardized ß-coefficient -0.15 [-0.28 to -0.03], P = 0.02). Seventy-nine (30%) respondents were interested in receiving psychological support during the pandemic, while 200 (76%) expressed interest beyond the pandemic. CONCLUSIONS: Although depression, anxiety, and stress among IBD patients during the pandemic were common, their frequency was similar to pre-pandemic rates and recent general population levels. Ensuring easy access to personalized risk information with targeted psychological support may mitigate psychological burden as patients reintegrate into society and deal with future COVID-19 waves.

Azathioprine with Allopurinol Is a Promising First-Line Therapy for Inflammatory Bowel Diseases.

BACKGROUND: Beneficial response to first-line immunosuppressive azathioprine in patients with inflammatory bowel disease (IBD) is low due to high rates of adverse events. Co-administrating allopurinol has been shown to improve tolerability. However, data on this co-therapy as first-line treatment are scarce. AIM: Retrospective comparison of long-term effectiveness and safety of first-line low-dose azathioprine-allopurinol co-therapy (LDAA) with first-line azathioprine monotherapy (AZAm) in patients with IBD without metabolite monitoring. METHODS: Clinical benefit was defined as ongoing therapy without initiation of steroids, biologics or surgery. Secondary outcomes included CRP, HBI/SCCAI, steroid withdrawal and adverse events. RESULTS: In total, 166 LDAA and 118 AZAm patients (median follow-up 25 and 27 months) were evaluated. Clinical benefit was more frequently observed in LDAA patients at 6 months (74% vs. 53%, p = 0.0003), 12 months (54% vs. 37%, p = 0.01) and in the long-term (median 36 months; 37% vs. 24%, p = 0.04). Throughout follow-up, AZAm patients were 60% more likely to fail therapy, due to a higher intolerance rate (45% vs. 26%, p = 0.001). Only 73% of the effective AZA dose was tolerated in AZAm patients, while LDAA could be initiated and maintained at its target dose. Incidence of myelotoxicity and elevated liver enzymes was similar in both cohorts, and both conditions led to LDAA withdrawal in only 2%. Increasing allopurinol from 100 to 200-300 mg/day significantly lowered liver enzymes in 5/6 LDAA patients with hepatotoxicity. CONCLUSIONS: Our poor AZAm outcomes emphasize that optimization of azathioprine is needed. We demonstrated a long-term safe and more effective profile of first-line LDAA. This co-therapy may therefore be considered standard first-line immunosuppressive.

An observational study of switching infliximab biosimilar: no adverse impact on inflammatory bowel disease control or drug levels with first or second switch.

BACKGROUND: Biologics account for a significant cost in inflammatory bowel disease (IBD) management; however, switching from infliximab originator to its biosimilars has enabled cost saving without compromising disease control. The effects on IBD activity and infliximab trough levels of a second switch to another biosimilar are, however, uncertain. AIMS: To assess the effects on disease activity and infliximab trough levels associated with switching from infliximab biosimilar CT-P13 to another biosimilar SB2 and compare outcomes in those switching for the first and second time. METHODS: IBD patients on CT-P13, including some previously switched from originator, were prospectively followed during a switch to SB2. C-reactive protein (CRP), trough infliximab level and clinical disease activity indices were collected at baseline, Infusion 3 or 4 ('early' after switch), and 1 year. RESULTS: One hundred eighty-six patients (n = 99 second switch) on stable infliximab dosing underwent switching. Compared with baseline, there was no significant change in CRP, clinical disease activity scores or median trough infliximab level at the early time point among first-switch (baseline vs early: 5.7 vs 6.6 µg/mL, P = 0.05) and second-switch (4.3 vs 4.9 µg/mL, P = 0.07) patients nor at 1 year (median infliximab trough levels, baseline vs 1 year, in first-switch [5.7 vs 5.7 µg/mL, P = 0.37] and second-switch [4.3 vs 4.7 µg/mL, P = 0.06] patients). The proportion of patients in clinical remission did not significantly change at the early (92% vs 91% at baseline, P = 0.75) or 1 year (95% vs 91% at baseline, P = 0.16) time points. There was no significant difference in time to loss of response between patients switching for the first or second time (P = 0.69). CONCLUSIONS: Switching from one infliximab biosimilar to another had no adverse impact on infliximab trough levels, and clinical and biochemical disease activity, regardless of whether switching for the first or second time.

Therapeutic thresholds for golimumab serum concentrations during induction and maintenance therapy in ulcerative colitis: results from the GO-LEVEL study.

BACKGROUND: Significant associations between serum golimumab concentrations and favourable outcomes have been observed during both induction and maintenance therapy in ulcerative colitis (UC). However, data regarding optimal therapeutic serum golimumab concentration thresholds are limited. AIMS: To identify optimal serum golimumab concentration thresholds during induction and maintenance treatment with golimumab. METHODS: GO-LEVEL was an open label, phase IV study that included a prospective cohort of UC patients commencing golimumab, as well as a cross-sectional cohort receiving maintenance treatment. Patients commencing induction for active UC (defined as a simple clinical colitis activity index [SCCAI] >5 in addition to a raised faecal calprotectin [FC] >59µg/g or, raised C-reactive protein [CRP] [>5mg/L] or, Mayo endoscopic disease activity 2 or 3) were evaluated at weeks 6, 10 and 14. Patients receiving maintenance therapy were recruited either at the point of flare or during remission. Combined clinical-biochemical remission was defined as SCCAI ≤2 and FC <250µg/g. Serum golimumab concentrations were measured using a commercially available ELISA (LISATRACKER, Theradiag). RESULTS: Thirty-nine patients were included in the induction cohort, of whom 15 (38%) achieved combined clinical-biochemical remission at week 6. The median serum golimumab concentration of those in combined clinical-biochemical remission was significantly higher than those who were not (5.0 vs 3.1 µg/mL, respectively, P = 0.03). Receiver operating characteristic (ROC) curve analysis demonstrated 3.8 µg/mL as the optimal threshold (sensitivity 0.71, specificity 0.65, area under curve [AUC] 0.72, positive predictive value [PPV] 0.59 and negative predictive value [NPV] 0.79). Sixty-three patients were included in the maintenance cohort; 31 (49%) were in combined remission, 32 (51%) were not. The median serum golimumab concentration of those in combined remission was significantly higher (2.9 vs 2.1 µg/mL, respectively, P = 0.01). ROC curve analysis demonstrated 2.4 µg/mL as the optimal threshold (sensitivity 0.68, specificity 0.66, AUC 0.68, PPV 0.65 and NPV 0.66). CONCLUSIONS: GO-LEVEL (NCT03124121) offers further evidence regarding golimumab's exposure-response relationship. Clinicians may consider using therapeutic drug monitoring to optimise golimumab dosing aiming to achieve our suggested therapeutic thresholds of 3.8 µg/mL at week 6 and 2.4 µg/mL during maintenance.

Effectiveness of vedolizumab dose intensification to achieve inflammatory bowel disease control in cases of suboptimal response.

BACKGROUND: Despite the proven efficacy of vedolizumab (VDZ) for ulcerative colitis (UC) and Crohn's disease (CD), suboptimal response is commonly encountered. However, data regarding the effectiveness of dose intensification (by interval shortening) to achieve response are limited. OBJECTIVES: We evaluated the effectiveness of dose intensification at achieving response in patients with a previously suboptimal response to VDZ. Additionally, we aimed to identify predictors of response to this strategy. METHODS: We performed a retrospective cohort study of patients who underwent VDZ dose intensification for suboptimal response. Clinical disease activity was evaluated at the point of dose intensification (baseline) and at weeks 12 and 24. Response was defined as Harvey-Bradshaw Index (HBI) or Simple Clinical Colitis Activity Index (SCCAI) reduction of ≥3, and remission as HBI <5 or SCCAI <3. RESULTS: A total of 36 patients received dose intensification to 4-weekly infusions: 18 CD, 14 UC and 4 inflammatory bowel disease-unclassified (analysed in the UC group). Median SCCAI scores fell from 6 (range 0-11) at baseline to 4 (0-6, p=0.008) at week 24, while HBI scores did not change significantly (4 (0-27) and 3 (0-8), p=0.092). Overall median C reactive protein (CRP) fell from 6 mg/L (1-23) to 2 mg/L (1-17, p=0.011). Of 20 patients with clinically active disease at baseline, 10 (50%) responded, of whom 4 (20%) achieved remission at week 24. Univariate analysis demonstrated low baseline CRP (p=0.045) and response at week 12 (0.020) were associated with week 24 response. CONCLUSIONS: Our findings demonstrate VDZ dose intensification to be effective at achieving clinical response in half of patients. Low baseline CRP and response at week 12 are potential predictors of week 24 response.

Genetic and Inflammatory Biomarkers Classify Small Intestine Inflammation in Asymptomatic First-degree Relatives of Patients With Crohn's Disease.

BACKGROUND & AIMS: Relatives of individuals with Crohn's disease (CD) carry CD-associated genetic variants and are often exposed to environmental factors that increase their risk for this disease. We aimed to estimate the utility of genotype, smoking status, family history, and biomarkers can calculate risk in asymptomatic first-degree relatives of patients with CD. METHODS: We recruited 480 healthy first-degree relatives (full siblings, offspring or parents) of patients with CD through the Guy's and St Thomas' NHS Foundation Trust and from members of Crohn's and Colitis, United Kingdom. DNA samples were genotyped using the Immunochip. We calculated a risk score for 454 participants, based on 72 genetic variants associated with CD, family history, and smoking history. Participants were assigned to highest and lowest risk score quartiles. We assessed pre-symptomatic inflammation by capsule endoscopy and measured 22 markers of inflammation in stool and serum samples (reference standard). Two machine-learning classifiers (elastic net and random forest) were used to assess the ability of the risk factors and biomarkers to identify participants with small intestinal inflammation in the same dataset. RESULTS: The machine-learning classifiers identified participants with pre-symptomatic intestinal inflammation: elastic net (area under the curve, 0.80; 95% CI, 0.62-0.98) and random forest (area under the curve, 0.87; 95% CI, 0.75-1.00). The elastic net method identified 3 variables that can be used to calculate odds for intestinal inflammation: combined family history of CD (odds ratio, 1.31), genetic risk score (odds ratio, 1.14), and fecal calprotectin (odds ratio, 1.04). These same 3 variables were among the 5 factors associated with intestinal inflammation in the random forest model. CONCLUSION: Using machine learning classifiers, we found that genetic variants associated with CD, family history, and fecal calprotectin together identify individuals with pre-symptomatic intestinal inflammation who are therefore at risk for CD. A tool for detecting people at risk for CD before they develop symptoms would help identify the individuals most likely to benefit from early intervention.

Golimumab: early experience and medium-term outcomes from two UK tertiary IBD centres.

OBJECTIVE: To gain an understanding of the effectiveness of golimumab in a 'real-world' setting. DESIGN: Retrospective cohort study using prospectively maintained clinical records. SETTING: Two UK tertiary IBD centres. PATIENTS: Patients with ulcerative colitis (UC) were given golimumab at Guy's & St Thomas and King's College Hospitals between September 2014 and December 2016. INTERVENTION: Golimumab, a subcutaneously administered antitumour necrosis factor agent. MAIN OUTCOME MEASURES: Clinical disease activity was assessed at baseline and at the first clinical review following induction therapy using the Simple Clinical Colitis Activity Index (SCCAI). Response was defined as an SCCAI reduction of 3 points or more. Remission was defined as an SCCAI of less than 3. RESULTS: Fifty-seven patients with UC completed golimumab induction therapy. Paired preinduction and postinduction SCCAI values were available for 31 patients and fell significantly from 7 (2-19) to 3 (0-11) (p<0.001). To these 31, an additional 13 patients who did not have paired SCCAI data but stopped treatment due to documented 'non-response' in the opinion of their supervising clinician, were added. Among this combined cohort, 23/44 (52%) had a clinical response, 15/44 (34%) achieved remission and 13/44 (30%) achieved corticosteroid-free remission.Faecal calprotectin and CRP fell (FC: pre-induction: 1096 (15-4800) µg/g, post-induction: 114 (11-4800) µg/g, p = 0.011; n = 20; CRP: pre-induction: 4 (1-59) mg/L, post-induction: 2 (1-34) mg/L, p = 0.01 for n = 43). Post-induction endoscopy was carried out in 23 patients and a mucosal healing (Mayo 0 or 1) rate of 35% was observed. CONCLUSIONS: Our experience mirrors previously reported real-world cohorts and demonstrates similar outcomes to those observed in randomised controlled trials. These data demonstrate a meaningful reduction in clinical, biochemical and endoscopic disease activity as well as a steroid-sparing effect in patients with previously refractory disease.

Prevalence and Risk Factors for Functional Vitamin B12 Deficiency in Patients with Crohn's Disease.

BACKGROUND: Crohn's disease (CD) is a risk factor for vitamin B12 deficiency due to frequent involvement of the terminal ileum. Conventional screening for B12 deficiency with serum B12 is relatively insensitive and measures total B12 concentration, of which a minority is present in a biologically active form. Holotranscobalamin (holoTC) combined with methylmalonic acid (MMA) is believed to be more accurate in identifying impaired B12 status. We evaluated the prevalence and risk factors for B12 deficiency using holoTC supported by MMA among patients with CD. METHODS: We performed a single-center service evaluation of 381 patients with CD who underwent B12 assessment (holoTC/MMA) and compared them with 141 patients with ulcerative colitis. Eighty-nine patients with CD underwent paired serum B12 and holoTC. Among patients with CD, risk factors including terminal ileal resection length, ileal inflammation on endoscopy, and disease characteristics on magnetic resonance imaging were recorded. RESULTS: Prevalence of B12 deficiency among patients with CD was 33% compared with 16% in ulcerative colitis (P < 0.0001). In 89 patients who underwent paired tests, conventional testing identified B12 deficiency in 5% of patients with CD, which increased to 32% using holoTC/MMA. Independent risk factors for B12 deficiency were ileal resection length ≤20 cm (odds ratio: 3.0, 95% confidence interval, 1.5-6.0, P = 0.002) and >20 cm (odds ratio: 6.7, 95% confidence interval, 3.0-14.7, P < 0.0001) and ileal inflammation (odds ratio: 3.9, 95% confidence interval, 2.2-6.9, P < 0.0001). On magnetic resonance imaging, active terminal ileal inflammation (P = 0.02) and an increased disease burden (≥1 skip lesion, P = 0.01 and prestenotic dilatation >3 cm, P = 0.01) were associated with B12 deficiency. CONCLUSIONS: Vitamin B12 deficiency is common in patients with CD. holoTC supported by MMA identifies patients with B12 deficiency considered replete on conventional testing.

Serum silicon concentrations in pregnant women and newborn babies.

Earlier studies in animals have suggested an essential role for Si in connective tissues, but such works have not been replicated per se. Nonetheless, a study conducted in 2000 has reported that Si may be essential during pregnancy for the growing fetus, since serum Si concentrations in infants were approximately 300 % higher than those in older children and adults and serum Si concentrations in pregnant women were approximately 300 % lower than those in age-matched non-pregnant controls. To reproduce these potentially important findings, in the present study, serum Si concentrations were measured in fourteen pregnant women (15-24 weeks of gestation) and compared with those of seventeen non-pregnant, non-lactating female controls. Serum Si concentrations were also measured in fourteen full-term mothers at the time of delivery and in the umbilical cord (UC) vein and artery where possible. Fasting serum Si concentrations in pregnant women were not significantly different from those of the female controls and showed little change with advancing gestation (r 0·2). Mean serum Si concentrations in the UC vein samples were 52 % higher, while those in the UC artery samples were 235 % higher than those in the maternal forearm vein samples, although data were widely spread and differences were not significant. Mean maternal forearm vein Si concentrations at delivery were 50 % lower than those of pregnant women and female controls, but, again, these were not significant. Overall, we note that there are significant analytical challenges in comparing baseline Si levels between different groups; notwithstanding, our findings cannot confirm a reduction in fasting serum Si levels during pregnancy, but, equally, we cannot rule out higher serum Si levels in newborns than in their mothers, and further work is required.

The relevance of transient lower oesophageal sphincter relaxations in the pathophysiology and treatment of GORD.

Gastro-oesophageal reflux disease (GORD) is associated with the passage of gastric contents into the oesophagus resulting in potential oesophageal damage and impaired quality of life. GORD is a frequently encountered problem in today's population, with 25% of people in western populations reporting such symptoms at least once a month. Proton pump inhibitors (PPI) are the drug of choice, with surgery being employed in refractory cases. Although acid suppression is often effective, some patients remain symptomatic despite maximal PPI therapy. By delving into the mechanisms of the disease, it is clear that transient lower oesophageal sphincter relaxations are a key component of its pathophysiology. Research has demonstrated various therapeutic targets for reducing the frequency of such relaxations through GABA and glutamate modulation, for instance. This review highlights such modulations and hopes to explore these mechanisms and therapeutic targets in an area that will no doubt see a change in its pharmacological management in the near future.

Optimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol.

BACKGROUND AND AIMS: Azathioprine and mercaptopurine remain first line immunomodulatory treatments for inflammatory bowel disease. Toxicity and non-response are significant issues. Co-prescription of allopurinol with reduced-dose (25-33%) azathioprine or mercaptopurine may overcome these problems. We present the outcome of co-prescription in a large single-centre cohort. METHOD: Patients on thiopurine/allopurinol co-prescription were identified. Indication for and outcome on combination treatment were established. Blood parameters and metabolite results were compared on single agent and combination treatment. Toxicity associated with combination treatment was sought. RESULTS: 110 patients on combination treatment were identified. Clinical remission was achieved in 60/79 (76%) of patients in whom the effect of thiopurine could be studied in isolation. 20/25 patients with hepatotoxicity tolerated combination treatment and normalised their liver function tests. 24/28 patients with atypical side effects tolerated co-therapy. 13/20 non-responders responded to combination treatment. In patients started on combination treatment as first line therapy, 15/23 achieved clinical remission. Thioguanine nucleotides were significantly higher and methylated metabolites significantly lower on combination therapy. Mean cell volume was higher and total white cell and neutrophil counts lower on combination treatment. 13 adverse events occurred, including 6 specific to co-therapy (3 rash, 2 abnormal liver function tests, 1 dosing error). All were minor and self-limiting. CONCLUSION: This is the largest published experience of the use of allopurinol to optimise outcomes on thiopurine treatment. Combination therapy permitted successful treatment of a significant number of patients who would otherwise have been labelled as thiopurine failures. A few self-limiting side effects were encountered.

The comparative absorption of silicon from different foods and food supplements.

Dietary Si (orthosilicic acid; OSA) appears important in connective tissue health, and although the sources and intakes of Si are well established, its absorption is not. Si absorption was measured from eight high-Si-containing sources: alcohol-free beer; OSA solution (positive control); bananas; green beans; supplemental choline-stabilised OSA (ChOSA); supplemental monomethyl silanetriol (MMST); supplemental colloidal silica (CS); magnesium trisilicate British Pharmacopoeia antacid (MTBP). Two of the supplements and the antacid were pre-selected following an in vitro dissolution assay. Fasting, healthy subjects (CS, n 3; others, n > or = 5) each ingested two of the sources separated by a 1-week wash-out period. Blood and urine were collected and measured for total Si concentrations by inductively coupled plasma optical emission spectrometry. Absorption, based on urinary Si excretion, was highest for MMST and alcohol-free beer (64% of dose), followed by green beans (44%), OSA (43%), ChOSA (17%), bananas and MTBP (4%) and CS (1%). Peak serum concentrations occurred by 0.5 h for MMST and green beans, 1.5 h for OSA and alcohol-free beer, 2 h for ChOSA and CS, and 4 h for MTBP. Area under the serum curves correlated positively with urinary Si output (r 0.82; P < 0.0001). Absorption of Si from supplements and antacids was consistent with their known chemical speciation and kinetics of dissolution under simulated gastrointestinal conditions. Monomeric silicates were readily absorbed, while particulate silicates were decreasingly well absorbed with increasing polymerisation. The present results highlight the need to allow for relative absorption of Si from different foods or supplements in subsequent epidemiological and intervention studies.

Choline-stabilized orthosilicic acid supplementation as an adjunct to calcium/vitamin D3 stimulates markers of bone formation in osteopenic females: a randomized, placebo-controlled trial.

BACKGROUND: Mounting evidence supports a physiological role for silicon (Si) as orthosilicic acid (OSA, Si(OH)4) in bone formation. The effect of oral choline-stabilized orthosilicic acid (ch-OSA) on markers of bone turnover and bone mineral density (BMD) was investigated in a double-blind placebo-controlled trial. METHODS: Over 12-months, 136 women out of 184 randomized (T-score spine < -1.5) completed the study and received, daily, 1000 mg Ca and 20 microg cholecalciferol (Vit D3) and three different ch-OSA doses (3, 6 and 12 mg Si) or placebo. Bone formation markers in serum and urinary resorption markers were measured at baseline, and after 6 and 12 months. Femoral and lumbar BMD were measured at baseline and after 12 months by DEXA. RESULTS: Overall, there was a trend for ch-OSA to confer some additional benefit to Ca and Vit D3 treatment, especially for markers of bone formation, but only the marker for type I collagen formation (PINP) was significant at 12 months for the 6 and 12 mg Si dose (vs. placebo) without a clear dose response effect. A trend for a dose-corresponding increase was observed in the bone resorption marker, collagen type I C-terminal telopeptide (CTX-I). Lumbar spine BMD did not change significantly. Post-hoc subgroup analysis (baseline T-score femur < -1) however was significant for the 6 mg dose at the femoral neck (T-test). There were no ch-OSA related adverse events observed and biochemical safety parameters remained within the normal range. CONCLUSION: Combined therapy of ch-OSA and Ca/Vit D3 had a potential beneficial effect on bone collagen compared to Ca/Vit D3 alone which suggests that this treatment is of potential use in osteoporosis. NTR 1029.

Increased longitudinal growth in rats on a silicon-depleted diet.

Silicon-deficiency studies in growing animals in the early 1970s reported stunted growth and profound defects in bone and other connective tissues. However, more recent attempts to replicate these findings have found mild alterations in bone metabolism without any adverse health effects. Thus the biological role of silicon remains unknown. Using a specifically formulated silicon-depleted diet and modern methods for silicon analysis and assessment of skeletal development, we undertook, through international collaboration between silicon researchers, an extensive study of long-term silicon depletion on skeletal development in an animal. 21-day old female Sprague-Dawley rats (n=20) were fed a silicon-depleted diet (3.2 microg Si/g feed) for 26 weeks and their growth and skeletal development were compared with identical rats (n=10) on the same diet but with silicon added as Si(OH)(4) to their drinking water (53.2 microg Si/g water); total silicon intakes were 24 times different. A third group of rats, receiving a standard rodent stock feed (322 microg Si/g feed) and tap water (5 microg Si/g water), served as a reference group for optimal growth. A series of anthropometric and bone quality measures were undertaken during and following the study. Fasting serum silicon concentrations and especially urinary silicon excretion were significantly lower in the silicon-deprived group compared to the supplemented group (P=0.03 and 0.004, respectively). Tibia and soft-tissue silicon contents did not differ between the two groups, but tibia silicon levels were significantly lower compared to the reference group (P<0.0001). Outward adverse health effects were not observed in the silicon-deprived group. However, body lengths from week 18 onwards (P<0.05) and bone lengths at necropsy (P

The relationship between gastro-oesophageal reflux symptoms and achalasia.

BACKGROUND AND AIMS: Patients with achalasia can experience heartburn, which may be misinterpreted as gastro-oesophageal reflux disease (GORD), leading to a delay in diagnosis and subsequent treatment. We investigated the relationship between gastro-oesophageal reflux (GOR) and reflux symptoms in a large cohort of patients with achalasia. METHODS: The symptoms of all patients with a manometric diagnosis of achalasia made over the past 15 years were studied. The types of treatment, onset and pattern of heartburn, lower oesophageal sphincter pressure (LOSP) and 24-h oesophageal pH studies were compared. RESULTS: A total of 110 out of 225 untreated (48.9%) and 57 out of 99 treated (57.6%) patients experienced heartburn. An oesophageal pH study was performed on 80 patients and GOR was found in only six out of 57 untreated (10.5%) and 10 out of 23 treated (43.5%) patients. A low LOSP (<10 mmHg) was associated with an increased risk of GOR [odds ratio (OR) 14.2; 95% confidence interval (CI) 1.6-128.7; P<0.02). Treated patients were also more likely to develop GOR (OR 7.9; 95% CI 2.0-32.1; P<0.005). Neither the LOSP nor previous treatment was, however, a predictor of heartburn. The timing of the onset of dysphagia and heartburn was categorized in 111 patients. There was no significant difference in mean (or median) LOSP between these three groups, indicating that the LOSP is unlikely to predict the occurrence of symptoms. CONCLUSIONS: Heartburn is common in patients with untreated and treated achalasia, but is a poor predictor of GORD. Such patients should always be investigated with a 24-h oesophageal pH study to clarify the presence of GORD.