Cure of Helicobacter pylori infection in patients with reflux oesophagitis treated with long term omeprazole reverses gastritis without exacerbation of reflux disease: results of a randomised controlled trial

BACKGROUND: Helicobacter pylori gastritis may progress to glandular atrophy and intestinal metaplasia, conditions that predispose to gastric cancer. Profound suppression of gastric acid is associated with increased severity of H pylori gastritis. This prospective randomised study aimed to investigate whether H pylori eradication can influence gastritis and its sequelae during long term omeprazole therapy for gastro-oesophageal reflux disease (GORD). METHODS: A total of 231 H pylori positive GORD patients who had been treated for > or =12 months with omeprazole maintenance therapy (OM) were randomised to either continuation of OM (OM only; n = 120) or OM plus a one week course of omeprazole, amoxycillin, and clarithromycin (OM triple; n = 111). Endoscopy with standardised biopsy sampling as well as symptom evaluation were performed at baseline and after one and two years. Gastritis was assessed according to the Sydney classification system for activity, inflammation, atrophy, intestinal metaplasia, and H pylori density. RESULTS: Corpus gastritis activity at entry was moderate or severe in 50% and 55% of the OM only and OM triple groups, respectively. In the OM triple group, H pylori was eradicated in 90 (88%) patients, and activity and inflammation decreased substantially in both the antrum and corpus (p<0.001, baseline v two years). Atrophic gastritis also improved in the corpus (p<0.001) but not in the antrum. In the 83 OM only patients with continuing infection, there was no change in antral and corpus gastritis activity or atrophy, but inflammation increased (p<0.01). H pylori eradication did not alter the dose of omeprazole required, or reflux symptoms. CONCLUSIONS: Most H pylori positive GORD patients have a corpus predominant pangastritis during omeprazole maintenance therapy. Eradication of H pylori eliminates gastric mucosal inflammation and induces regression of corpus glandular atrophy. H pylori eradication did not worsen reflux disease or lead to a need for increased omeprazole maintenance dose. We therefore recommend eradication of H pylori in GORD patients receiving long term acid suppression

Geriatric assessment of patients treated for cutaneous head and neck malignancies in a tertiary referral center:Predictors of postoperative complications

Introduction: As cutaneous head and neck malignancies are highly prevalent especially in older patients, the risk of surgical complications is substantial in this potentially vulnerable population. The objective of this study was to evaluate the value of geriatric assessment of this population with respect to postoperative complications. Methods: Patients were prospectively included in OncoLifeS, a databiobank. Before surgery, patients underwent a geriatric assessment including multiple validated screening tools for frailty, comorbidity, polypharmacy, nutrition, functional status, social support, cognition and psychological status. Postoperatively, complications (Clavien-Dindo ≥ grade II) were registered. Uni- and multivariable logistic regression analyses were performed yielding odds ratios (ORs) and 95% confidence intervals (95%CIs). Results: 151 patients undergoing surgery for cutaneous head and neck malignancies were included in this study (mean age 78.9 years, 73.5% male). In a multivariable analysis, frailty measured by the Geriatric 8 (G8) (OR = 6.34; 95%CI:1.73–23.25) was the strongest independent predictor of postoperative complications, among other predictors such as major treatment intensity (OR = 2.73; 95%CI:1.19–6.26) and general anesthesia (OR = 4.74; 95%CI:1.02–22.17), adjusted for age and sex. Conclusion: Frailty, measured by G8, is the strongest predictor of postoperative complications in patients undergoing surgery for cutaneous head and neck malignancies in addition to treatment intensity and type of anesthesia. Geriatric screening on multiple domains is recommended for patients with cutaneous malignancies undergoing head and neck surgery is recommended, as this population includes old patients and frequently suffers postoperative complications

Proteomic analyses do not reveal subclinical inflammation in fatigued patients with quiescent Inflammatory Bowel Disease

BackgroundFatigue is a common and clinically challenging symptom in patients with inflammatory bowel diseases (IBD). While fatigue occurs most often in patients with active disease, up to 50% of patients with quiescent disease still report significant fatigue of unknown aetiology. Here, we aimed to investigate whether fatigue in patients with quiescent IBD is reflected by circulating inflammatory proteins, that in turn might reflect ongoing subclinical inflammation.MethodsNinety-two (92) different inflammation-related proteins were measured in plasma of 350 patients with quiescent IBD (188 Crohn’s disease [CD]; 162 ulcerative colitis [UC]). Quiescent IBD was defined as clinical (Harvey-Bradshaw Index [HBI] &lt;5 or Simple Clinical Colitis Activity Index [SCCAI] &lt;2.5) and biochemical remission (C-reactive protein [CRP] &lt;5 mg/L) at time of sampling. Fatigue severity was assessed on a visual analogue scale (VAS).ResultsNone of the analysed plasma proteins were differentially abundant between mildly (1st quartile, Q1) or severely (4th quartile, Q4) fatigued patients under a false discovery rate of 10%. Considering nominal significance (P&lt;0.05), however, leukemia inhibitory factor receptor (LIF-R) concentrations were inversely associated with severe fatigue, also after adjustment for confounding factors (P &lt;0.05) (Figure 1). Although solely LIF-R showed weak ability to discriminate between mild (Q1) and severe (Q4) fatigue (area under the curve [AUC]=0.61, 95% CI: 0.53–0.69, P&lt;0.05), a combined set of the top seven (7) fatigue-associated proteins (LIF-R, vascular endothelial growth factor-A [VEGF-A], glial-derived neurotrophic factor [GDNF], interleukin-20 receptor subunit alpha [IL-20RA], Delta and Notch-like epidermal growth factor-related receptor [DNER], T-cell surface glycoprotein CD5 [CD5], and extracellular newly identified receptor for advanced glycation end-products binding protein [EN-RAGE], also known as protein S100-A12, all P&lt;0.10) was observed to have reasonable discriminative performance (AUC=0.82 [95% CI: 0.74–0.91], P&lt;0.01).ConclusionFatigue in patients with IBD is not clearly reflected by distinct circulating inflammatory protein signatures, which suggests that subclinical immune activation as defined by the studied panel of inflammatory proteins could not be detected. Reduced shedding of the LIF-R protein could be related to fatigue in IBD through modification of the oncostatin-M (OSM) signaling pathway, or through induction of pro-inflammatory phenotypes of T-cells, macrophages, or neural cells. Future studies are warranted to investigate other proteomic or metabolic markers that may accurately reflect fatigue in quiescent IBD, which might represent alternative pathophysiological pathways

Long-Term Dietary Patterns Are Reflected in the Plasma Inflammatory Proteome of Patients with Inflammatory Bowel Disease

Diet plays an important role in the development and progression of inflammatory bowel disease (IBD, comprising Crohn's disease (CD) and ulcerative colitis (UC)). However, little is known about the extent to which different diets reflect inflammation in IBD beyond measures such as faecal calprotectin or C-reactive protein. In this study, we aimed to unravel associations between dietary patterns and circulating inflammatory proteins in patients with IBD. Plasma concentrations of 73 different inflammation-related proteins were measured in 454 patients with IBD by proximity extension assay (PEA) technology. Food frequency questionnaires (FFQ) were used to assess habitual diet. Principal component analysis (PCA) was performed to extract data-driven dietary patterns. To identify associations between dietary patterns and plasma proteins, we used general linear models adjusting for age, sex, BMI, plasma storage time, smoking, surgical history and medication use. Stratified analyses were performed for IBD type, disease activity and protein intake. A high-sugar diet was strongly inversely associated with fibroblast growth factor-19 (FGF-19) independent of IBD type, disease activity, surgical history and deviance from recommended protein intake (false discovery rate (FDR) &lt; 0.05). Conversely, a Mediterranean-style pattern was associated with higher FGF-19 levels (FDR &lt; 0.05). A pattern characterised by high alcohol and coffee intake was positively associated with CCL11 (eotaxin-1) levels and with lower levels of IL-12B (FDR &lt; 0.05). All results were replicated in CD, whereas only the association with FGF-19 was significant in UC. Our study suggests that dietary habits influence distinct circulating inflammatory proteins implicated in IBD and supports the pro- and anti-inflammatory role of diet. Longitudinal measurements of inflammatory markers, also postprandial, are needed to further elucidate the diet-inflammation relationship

Variations in the slope of the psychometric functions for speech intelligibility: a systematic survey

Although many studies have looked at the effects of different listening conditions on the intelligibility of speech, their analyses have often concentrated on changes to a single value on the psychometric function, namely, the threshold. Far less commonly has the slope of the psychometric function, that is, the rate at which intelligibility changes with level, been considered. The slope of the function is crucial because it is the slope, rather than the threshold, that determines the improvement in intelligibility caused by any given improvement in signal-to-noise ratio by, for instance, a hearing aid. The aim of the current study was to systematically survey and reanalyze the psychometric function data available in the literature in an attempt to quantify the range of slope changes across studies and to identify listening conditions that affect the slope of the psychometric function. The data for 885 individual psychometric functions, taken from 139 different studies, were fitted with a common logistic equation from which the slope was calculated. Large variations in slope across studies were found, with slope values ranging from as shallow as 1% per dB to as steep as 44% per dB (median = 6.6% per dB), suggesting that the perceptual benefit offered by an improvement in signal-to-noise ratio depends greatly on listening environment. The type and number of maskers used were found to be major factors on the value of the slope of the psychometric function while other minor effects of target predictability, target corpus, and target/masker similarity were also found

Quantitative comparison of the neutralizing capacity, immunogenicity and cross-reactivity of anti-TNF-alpha biologicals and an Infliximab-biosimilar

Introduction TNF-alpha-neutralizing antibodies, such as infliximab (IFX) and adalimumab (ADA), are effective in the treatment of inflammatory bowel diseases (IBD), but they are expensive and become ineffective when patients develop anti-IFX or anti-ADA antibodies (ATI and ATA, respectively). Second-generation anti-TNF-alpha antibodies, such as Golimumab, Etanercept, Certolizumab-pegol and IFX biosimilars, may solve these issues. Aim To determine the neutralizing capacity of first- and second generation anti-TNF-alpha antibodies and to determine whether ATI show cross-reactivity with the IFX biosimilar CT-P13 (Inflectra). Methods TNF-alpha neutralization was measured using a quantitative TNF-alpha sensor assay consisting of HeLa 8D8 cells that express the Green Fluorescence Protein (GFP) under control of a NF kappa B response element. All available anti-TNF-alpha drugs and the IFX biosimilar CT-P13 (Inflectra) were tested for their TNF-alpha-neutralizing capacity. In addition, patient sera with ATI were tested for their potential to block the activity of IFX, IFX (F)ab(2)-fragment, biosimilar CT-P13 (Inflectra) and ADA. Results TNF-alpha strongly induced GFP expression in Hela 8D8 cells. Higher concentrations of firstgeneration anti-TNF-alpha drugs were required to neutralize TNF-alpha compared to the secondgeneration anti-TNF-alpha drugs. Serum of IBD patients with proven ATI blocked TNF-alpha-neutralizing properties of IFX biosimilar CT-P13 (Inflectra), whereas such sera did not block the effect of ADA. Conclusion The second-generation anti-TNF-alpha drugs show increased TNF-alpha-neutralizing potential compared to first-generation variants. ATI show cross-reactivity toward IFX biosimilar CT-P13 (Inflectra), consequently patients with ATI are unlikely to benefit from treatment with this IFX biosimilar

Synchronization modulation increases transepithelial potentials in MDCK monolayers through Na/K pumps

Peer reviewedPublisher PD

Phage-display immunoprecipitation sequencing of the antibody epitope repertoire in inflammatory bowel disease reveals distinct antibody signatures

Inflammatory bowel diseases (IBDs), e.g., Crohn's disease (CD) and ulcerative colitis (UC), are chronic immune-mediated inflammatory diseases. A comprehensive overview of an IBD-specific antibody epitope repertoire is, however, lacking. Using high-throughput phage-display immunoprecipitation sequencing (PhIP-Seq), we identified antibodies against 344,000 antimicrobial, immune, and food antigens in 497 individuals with IBD compared with 1,326 controls. IBD was characterized by 373 differentially abundant antibody responses (202 overrepresented and 171 underrepresented), with 17% shared by both IBDs, 55% unique to CD, and 28% unique to UC. Antibody reactivities against bacterial flagellins dominated in CD and were associated with ileal involvement, fibrostenotic disease, and anti-Saccharomyces cerevisiae antibody positivity, but not with fecal microbiome composition. Antibody epitope repertoires accurately discriminated CD from controls (area under the curve [AUC] = 0.89), and similar discrimination was achieved when using only ten antibodies (AUC = 0.87). Individuals with IBD thus show a distinct antibody repertoire against selected peptides, allowing clinical stratification and discovery of immunological targets.</p

In-depth characterisation of the serum antibody epitope repertoire in Inflammatory Bowel Disease by high-throughput phage-displayed immunoprecipitation sequencing

BackgroundPatients with IBD show distinct antibody responses, particularly against microbiota. However, a comprehensive overview of the antibody epitope repertoire in IBD is lacking. Here, we characterized serum antibody responses in patients with IBD and population controls using a high-throughput phage-displayed immunoprecipitation sequencing (PhIP-seq) workflow and associated these to disease phenotypes and the faecal microbiome.MethodsPhIP-seq was leveraged to characterise antibody responses against 344,000 rationally selected peptide antigens in 497 patients with IBD which were compared with 1,326 individuals from a population-based cohort (Fig. 1A-B). Antibody profiles were linked to 23 IBD-specific clinical features such as disease location and surgical history and to faecal microbiota composition (Fig. 1C).ResultsPatients with IBD demonstrated distinct antibody epitope repertoires compared with individuals from the general population, with 373 differentially abundant antibody-bound peptides (202 overrepresented, 171 underrepresented) belonging to bacterial flagellins (69), virulence factors (102), other antigens of both commensal and pathogenic bacteria (90) as well as viruses (67) and food proteins (24) (Figure 2). In particular, antibody responses against bacterial flagellins, many of which belong to Lachnospiraceae bacteria (e.g. Roseburia spp.), but also Eubacterium spp. and pathogens (e.g. Legionella, Clostridium, Burkholderia) dominated in patients with Crohn’s disease (CD), and were associated with ileal disease involvement and more complicated disease behaviour (e.g. fibrostenotic disease, surgical history) as well as anti-Saccharomyces cerevisiae antibody positivity. Furthermore, many other antigens were newly identified, e.g. decreased responses to E. coli virulence factors and genome polyproteins of enteroviruses, and increased responses to food antigens (wheat, barley) and autoantigens (particularly collagen type I and VI). Antibody epitope repertoires were able to accurately discriminate CD from population controls (area under the curve [AUC]=0.88, test set evaluation), showing very high discriminative performance (positive and negative predictive value of 72% and 93%, respectively, representing predicted classes in test set) (Fig. 3A-C), which was less accurate for ulcerative colitis (UC) (Fig. 3D-F).ConclusionThis study demonstrates the size, diversity and complexity of systemic antibody epitope repertoires in patients with IBD compared to controls, showing that distinct clinical phenotypes of IBD are characterized by unique antibody signatures. PhIP-seq is a powerful tool for identifying systemic immune-based biomarkers and exposing novel immunological targets in immune-mediated inflammatory diseases like IBD

PIN71 QUALITY OF LIFE (QOL) AND OTHER ENDPOINTS COMPARISON IN THE TREATMENT OF FACIAL LIPOATROPHY WITH INJECTION OF POLY-L-LACTIC ACID

Context: Longitudinal data on bone mineral density(BMD) in children and adolescents with Prader-Willi Syndrome (PWS) during long-term GH treatment are not available. Objective: This study aimed to determine effects of long-term GH treatment and puberty on BMD of total body (BMDTB), lumbar spine (BMDLS), and bone mineral apparent density of the lumbar spine (BMAD(LS)) in children with PWS. Design and Setting: This was a prospective longitudinal study of a Dutch PWS cohort. Participants: Seventy-seven children with PWS who remained prepubertal during GH treatment for 4 years and 64 children with PWS who received GH treatment for 9 years participated in the study. Intervention: The children received GH treatment, 1 mg/m(2)/day (congruent to 0.035 mg/kg/d). Main Outcome Measures: BMDTB, BMDLS, and BMAD(LS) was measured by using the same dual-energy x-ray absorptiometry machine for all annual measurements. Results: In the prepubertal group, BMDTB standard deviation score (SDS) and BMDLSSDS significantly increased during 4 years of GH treatment whereas BMAD(LS)SDS remained stable. During adolescence, BMDTBSDS and BMAD(LS)SDS decreased significantly, in girls from the age of 11 years and in boys from the ages of 14 and 16 years, respectively, but all BMD parameters remained within the normal range. Higher Tanner stages tended to be associated with lower BMDTBSDS (P = .083) and a significantly lowerBMAD(LS)SDS (P = .016). After 9 years of GH treatment, lean body mass SDS was the most powerful predictor of BMDTBSDS and BMDLSSDS in adolescents with PWS. Conclusions: This long-term GH study demonstrates that BMDTB, BMDLS, and BMAD(LS) remain stable in prepubertal children with PWS but decreases during adolescence, parallel to incomplete pubertal development. Based on our findings, clinicians should start sex hormone therapy from the age of 11 years in girls and 14 years in boys unless there is a normal progression of puberty