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Aim: The aim was to determine whether specialist‐led habit training using Habit Training with Biofeedback (HTBF) is more effective than specialist‐led habit training alone (HT) for chronic constipation and whether outcomes of interventions are improved by stratification to HTBF or HT based on diagnosis (functional defaecation disorder vs. no functional defaecation disorder) by radio‐physiological investigations (INVEST). Method: This was a parallel three‐arm randomized single‐blinded controlled trial, permitting two randomized comparisons: HTBF versus HT alone; INVEST‐ versus no‐INVEST‐guided intervention. The inclusion criteria were age 18–70 years; attending specialist hospitals in England; self‐reported constipation for >6 months; refractory to basic treatment. The main exclusions were secondary constipation and previous experience of the trial interventions. The primary outcome was the mean change in Patient Assessment of Constipation Quality of Life score at 6 months on intention to treat. The secondary outcomes were validated disease‐specific and psychological questionnaires and cost‐effectiveness (based on EQ‐5D‐5L). Results: In all, 182 patients were randomized 3:3:2 (target 384): HT n = 68; HTBF n = 68; INVEST‐guided treatment n = 46. All interventions had similar reductions (improvement) in the primary outcome at 6 months (approximately −0.8 points of a 4‐point scale) with no statistically significant difference between HT and HTBF (−0.03 points; 95% CI −0.33 to 0.27; P = 0.85) or INVEST versus no‐INVEST (0.22; −0.11 to 0.55; P = 0.19). Secondary outcomes showed a benefit for all interventions with no evidence of greater cost‐effectiveness of HTBF or INVEST compared with HT. Conclusion: The results of the study at 6 months were inconclusive. However, with the caveat of under‐recruitment and further attrition at 6 months, a simple, cheaper approach to intervention may be as clinically effective and more cost‐effective than more complex and invasive approaches. [ABSTRACT FROM AUTHOR]

Background: Constipation affects up to 20% of adults. Chronic constipation (CC) affects 1-2% of adults. Patient dissatisfaction is high; nearly 80% feel that laxative therapy is unsatisfactory and symptoms have significant impact on quality of life. There is uncertainty about the value of specialist investigations and whether equipment-intensive therapies using biofeedback confer additional benefit when compared with specialist conservative advice.Methods/design: A three-arm, parallel-group, multicentre randomised controlled trial.Objectives: to determine whether standardised specialist-led habit training plus pelvic floor retraining using computerised biofeedback is more clinically effective than standardised specialist-led habit training alone; to determine whether outcomes are improved by stratification based on prior investigation of anorectal and colonic pathophysiology. Primary outcome measure is response to treatment, defined as a 0.4-point (10% of scale) or greater reduction in Patient Assessment of Constipation-Quality of Life (PAC-QOL) score 6 months after the end of treatment. Other outcomes up to 12 months include symptoms, quality of life, health economics, psychological health and qualitative experience.Hypotheses: (1) habit training (HT) with computer-assisted direct visual biofeedback (HTBF) results in an average reduction in PAC-QOL score of 0.4 points at 6 months compared to HT alone in unselected adults with CC, (2) stratification to either HT or HTBF informed by pathophysiological investigation (INVEST) results in an average 0.4-point reduction in PAC-QOL score at 6 months compared with treatment not directed by investigations (No-INVEST). Inclusion: chronic constipation in adults (aged 18-70 years) defined by self-reported symptom duration of more than 6 months; failure of previous laxatives or prokinetics and diet and lifestyle modifications. Consenting participants (n = 394) will be randomised to one of three arms in an allocation ratio of 3:3:2: [1] habit training, [2] habit training and biofeedback or [3] investigation-led allocation to one of these arms. Analysis will be on an intention-to-treat basis.Discussion: This trial has the potential to answer some of the major outstanding questions in the management of chronic constipation, including whether costly invasive tests are warranted and whether computer-assisted direct visual biofeedback confers additional benefit to well-managed specialist advice alone.Trial Registration: International Standard Randomised Controlled Trial Number: ISRCTN11791740. Registered on 16 July 2015. [ABSTRACT FROM AUTHOR]

Free circulating DNA is present in the plasma of healthy subjects, and is elevated in conditions characterized by increased cell death, such as cancer and physical trauma. Analysis of circulating DNA in plasma could provide a useful biomarker in sickle cell disease (SCD) in view of the increased cell turnover through chronic ongoing haemolysis, recurrent vaso-occlusion and inflammation. Plasma DNA was determined by real-time quantitative polymerase chain reaction (PCR) amplification of the β-globin gene ( HBB) in 154 patients with SCD [105 haemoglobin (Hb)SS, 46 HbSC and three HbS/ β0 thalassaemia] and 53 ethnically matched controls. Blood samples were obtained from all patients in steady state; 21 of the 154 patients were also sampled during admission to hospital for acute pain. Median concentration of circulating plasma DNA in acute pain was more than 10-fold that in steady state and in controls – 10070 vs. 841 and 10070 vs. 933 genome equivalents/ml respectively ( P < 0·0001, in both cases). During steady state, patients had plasma DNA levels similar to controls. Plasma DNA levels in SCD correlated with C-reactive protein levels ( P < 0·005) and total white cell counts ( P < 0·05) in steady state. The study shows that plasma DNA concentration may have potential as a biomarker in sickle cell patients. [ABSTRACT FROM AUTHOR]

Serum bilirubin levels and predisposition to gallstones in sickle cell disease (SCD) are influenced by genetic variation in the hepatic uridine diphosphate (UDP)-glucuronosyltransferase ( UGT1A1) gene, but the association is not consistent. This study investigated whether variation in the gene encoding haem oxygenase ( HMOX1), a rate-limiting enzyme upstream of UGT1A in the haem catabolic pathway, and α-thalassaemia could explain some of the inconsistent effects. The UGT1A1 [TA]n and HMOX1 [GT]n promoter polymorphisms and α globin genotypes were determined in 263 SCD patients (199 HbSS, 5 HbS/ β0, 59 HbSC). Detection of gallstones was based on ultrasound of the liver/biliary tree. Regression analysis showed that serum bilirubin levels and the incidence of gallstones were strongly associated with the number of UGT1A1 [TA] repeats in all subjects ( P < 0·0001 and P < 0·01, respectively). While HMOX1 genotype had no effect, co-inheritance of α-thalassaemia reduced serum bilirubin levels in all SCD patients independently of the number of UGT1A1 [TA] repeats. Each additional [TA] repeat is associated with an increase in mean serum bilirubin levels of 21% and cholelithiasis risk of 87% in SCD. [ABSTRACT FROM AUTHOR]