The Effect of Anti-rheumatic Drugs on the Skeleton.

The therapeutic armamentarium for rheumatoid arthritis has increased substantially over the last 20 years. Historically antirheumatic treatment was started late in the disease course and frequently included prolonged high-dose glucocorticoid treatment which was associated with accelerated generalised bone loss and increased vertebral and non-vertebral fracture risk. Newer biologic and targeted synthetic treatments and a combination of conventional synthetic DMARDs prevent accelerated systemic bone loss and may even allow repair of cortical bone erosions. Emerging data also gives new insight on the impact of long-term conventional synthetic DMARDs on bone health and fracture risk and highlights the need for ongoing studies for better understanding of "established therapeutics". An interesting new antirheumatic treatment effect is the potential of erosion repair with the use of biologic DMARDs and janus kinase inhibitors. Although several newer anti-rheumatic drugs seem to have favorable effects on bone mineral density in RA patients, these effects are modest and do not seem to influence the fracture risk thus far. We summarize recent developments and findings of the impact of anti-rheumatic treatments on localized and systemic bone integrity and health.

First-in-Human Clinical Trial to Assess the Safety, Tolerability and Pharmacokinetics of Single Doses of NTM-1633, a Novel Mixture of Monoclonal Antibodies against Botulinum Toxin E.

Botulism is a rare, life-threatening paralytic disease caused by botulinum neurotoxin (BoNT). Available treatments including an equine antitoxin and human immune globulin are given postexposure and challenging to produce and administer. NTM-1633 is an equimolar mixture of 3 human IgG monoclonal antibodies, E1, E2, and E3, targeting BoNT serotype E (BoNT/E). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1633. This double-blind, single-center, placebo-controlled dose escalation study randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1633 (0.033, 0.165, or 0.330 mg/kg) or saline placebo. Safety monitoring included physical examinations, clinical laboratory studies, and vital signs. Blood sampling was performed at prespecified time points for PK and immunogenicity analyses. Twenty-four subjects received study product (18 NTM-1633; 6 placebo), and no deaths were reported. An unrelated serious adverse event was reported in a placebo subject. Adverse events in the NTM-1633 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1633 has a favorable PK profile with a half-life >10 days for the 0.330 mg/kg dose and an approximately linear relationship with respect to maximum concentration and area under the concentration-time curve (AUC0→t). NTM-1633 also demonstrated low immunogenicity. NTM-1633 is well tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile supports further development as a treatment for BoNT/E intoxication and postexposure prophylaxis.

Everything in excess is opposed to nature, even vitamin D: a case report.

SUMMARY: Vitamin D intoxication in children is rare but its incidence is increasing as vitamin D is supplemented more often and in higher doses. Children with cystic fibrosis (CF) are at risk for vitamin D intoxication due to incorrect compounded preparations of liposoluble vitamins. Here, we report a severe vitamin D intoxication in a 4-year-old girl with CF, due to an error in the compounded vitamin A, D, E, and K preparation, presenting clinically with weight loss, constipation, polydipsia, polyuria, and nycturia. The administered compounded preparation contained 10 000-fold the prescribed vitamin D dose. The patient was treated with hyperhydration, loop diuretics, and bisphosphonates. Serum calcium levels normalized after 4 days but serum 25-hydroxyvitamin D levels remained elevated even up to 2 months after treatment. LEARNING POINTS: Vitamin D intoxication should be ruled out when patients with cystic fibrosis (CF) present with acute polyuria, constipation, and weight loss. Prompt treatment is necessary to avert life-threatening complications. Regularly measuring serum calcium and 25-hydroxyvitamin D concentrations in children with CF receiving vitamin A, D, E, and K supplements is important during their follow-up.

Safety, Tolerability, and Pharmacokinetics of NTM-1632, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin B.

Botulism is a rare, life-threatening paralytic disease caused by Clostridium botulinum neurotoxin (BoNT). Available treatments, including an equine antitoxin and human immune globulin, are given postexposure and challenging to produce and administer. NTM-1632 is an equimolar mixture of 3 human IgG monoclonal antibodies, B1, B2, and B3, targeting BoNT serotype B (BoNT/B). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1632. This double-blind, single-center, placebo-controlled dose escalation study randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1632 (0.033, 0.165, or 0.330 mg/kg) or saline placebo. Safety monitoring included physical examinations, clinical laboratory studies, and vital signs. Blood sampling was performed at prespecified time points for PK and immunogenicity analyses. Twenty-four subjects received study product (18 NTM-1632; 6 placebo), and no deaths or serious adverse events were reported. Adverse events in the NTM-1632 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1632 has a favorable PK profile with a half-life of >20 days for the 0.330-mg/kg dose and an approximately linear relationship with respect to maximum concentration and area under the concentration-time curve (AUC0→t). NTM-1632 demonstrated low immunogenicity with only a few treatment-emergent antidrug antibody responses in the low and middle dosing groups and none at the highest dose. NTM-1632 is well tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile of NTM-1632 supports further clinical development as a treatment for BoNT/B intoxication and postexposure prophylaxis. (This study has been registered at ClinicalTrials.gov under identifier NCT02779140.).

[Comparative economic analysis of the new concept for veal calf fattening «outdoor veal calf¼ and the conventional IP-SUISSE label]. / Vergleichende Wirtschaftlichkeitsanalyse des Kälbermastsystems «Freiluftkalb¼ und der konventionellen IP-SUISSE-Labelmast.

INTRODUCTION: The evaluation of new animal husbandry concepts includes, beyond the exploration of chosen parameters, that the question is addressed whether economic benefits for producers and ethical benefits for society result of the new system when compared to traditional systems. In a previous study, a novel management and housing concept for veal production («outdoor veal calf¼, OVC) was tested from October 2016 to July 2018. The OVC concept was associated with distinctly lower antimicrobial use while average daily weight gain was similar and calf welfare better; furthermore mortality was lower compared to conventional label fattening. The aim of the present study was to compare economics between the OVC concept on intervention farms (IF) and the IP-SUISSE label concept on control farms (CF) by calculating contribution margins (CM). The CM indicates the difference between the performance of a production branch (e. g. slaughter return) and the allocable costs for this production branch (e. g. feed costs). In the present study, two different approaches were used for CM calculation to analyze the available data in detail. No substantial differences in CM between the OVC concept and the IP-SUISSE concept were found in either approach. However, the specific CM varied between the approaches as different calculation criteria for quantities and prices were applied (approach «real¼ with accurate costs and returns from the OVC study and approach «standardized¼ with costs and returns based on the CM catalogue). The CM varied slightly for the CM per man-hour (IF «real¼: 6.96 CHF/man-hour, «standardized¼: 4.49 CHF/man-hour; CF: 7.90 CHF/man-hour and 8.08 CHF/man-hour, respectively) and considerably for the CM per fattening space and year (IF «real¼: -380.36 CHF, «standardized¼: -559.50 CHF; CF: -244.70 CHF and -318.80 CHF, -respectively). Producing veal with the OVC concept -allowed for achieving comparable CM/man-hour as in conventional label production. Thus, the farmers' economic interests should be warranted when implementing the OVC concept.

INTRODUCTION: Lors du développement de nouveaux systèmes d'élevage, on s'efforce de les tester par rapport à des paramètres sélectionnés pour évaluer si un changement apporterait une valeur ajoutée économique ou sociétale par rapport aux systèmes déjà établis. Dans une étude précédente, un nouveau type de système d'engraissement des veaux (système «veau en plein air¼, VPA) a été testé d'octobre 2016 à juillet 2018. Par rapport à l'engraissement conventionnel labellisé, considérablement moins d'antibiotiques ont été utilisés avec ce système tout en conservant les mêmes performances de croissance quotidienne et en améliorant le bien-être des animaux; de plus, la mortalité des veaux d'engraissement était plus faible. Le but de la présente étude était de procéder à une analyse économique comparative des deux systèmes de détention, VPA et label IP-SUISSE (IPS), à l'aide du calcul des marges brutes (MB). La MB indique la différence entre les performances d'une branche de production (par exemple les revenus d'abattage) et les coûts imputables à cette branche de production (par exemple les coûts d'alimentation). Dans cette étude, deux variantes des marges brutes ont été calculées afin d'évaluer en détail les données disponibles. Les deux variantes sont arrivées à la conclusion qu'il n'y avait pas de différences majeures dans la MB entre le nouveau système VPA et le système du label IP-SUISSE. Cependant, la MB spécifique différait entre les variantes, en raison des bases de calcul différentes utilisées pour chaque variante pour les quantités et les prix (variante «réelle¼ aves des revenus et coûts concrets dérivés de l'étude VPA et variante «standardisée¼ avec des revenus et des prix basés sur le catalogue des MB). Les MB variaient légèrement en ce qui concerne la MB par heure de travail productive (VPA: variante «réelle¼: 6.96 CHF/heure, «standardisée¼: 4.49 CHF/heure; IPS: variante «réelle¼ 7.90 CHF/heure, «standardisée¼ 8.08 CHF/heure) et considérablement pour la MB par place d'engraissement et par année (VPA: variante «réelle¼: ­380.36 CHF, «standardisée¼: ­559.50 CHF; IPS: variante «réelle¼: ­244.70 CHF, «standardisée¼: ­318.80 CHF). La production de viande de veau selon le système VPA permet de générer une MB/heure de travail positive similaire à celle de l'engraissement conventionnel labellisé IP-SUISSE. En conséquence, les intérêts économiques des producteurs ne paraissent pas être prétérités dans ce nouveau système d'élevage.

Long-term use of tube feeding in children with cystic fibrosis: results from two Belgian CF centers.

BACKGROUND: Enteral tube feeding (ETF) is often used in an attempt to optimize the nutritional status. The aim of this study was to observe the long term effect of ETF and to compare the start of ETF with the current European guidelines on nutrition care in CF. METHOD: From all patients who received ETF (ETFp) between February 2000 and September 2016 in the Ghent University Hospital (GUH) or Brussels University Hospital (BUH), z-scores for body weight (W), height (H), growth velocity (GV) and BMI, FEV1%, and FVC% were retrospectively collected from the patients' medical record, 3 years before and 5 years after the year of ETF initiation. Gender, age, and pancreatic status matched controls were selected from the GUH database. RESULTS: All baseline (T0) measurements in ETFp were worse compared to controls. Only 11% of the controls had a Hz < -1.6 compared 58% of the ETFp. After the initiation of ETF a rapid weight gain was noted until the second year (T + 2:-1.9 (-2.8; -1.0) vs. T0:-2.7 (-3.2; -2.1) (p = 0.01) with a stabilization afterwards. A rapid GVz increase was noted at T + 1:1.0 (-0.8; 1.9) vs. T0:-1.5 (-2.0;-0.3). After the start of ETF until T + 3, a stabilization of FEV1% was noted. However, compared to controls, it remained significantly lower (p < 0.05). CONCLUSION: ETF as a nutritional intervention has its effect on weight, height, GV, and BMI. To our knowledge this is the first study that describes the evolution of growth in ETFp. The effect on GV argues for a faster introduction of ETF in malnourished children with CF.

The role of age in post-cardiac arrest therapy in an elderly patient population.

AIM: We investigated the effect of age on post-cardiac arrest treatment outcomes in an elderly population, based on a local database and a systemic review of the literature. METHODS: Data were collected retrospectively from medical charts and reports. Sixty-one comatose patients, cooled to 32-34 °C for 24 h, were categorized into three groups: younger group (≤65 years), older group (66-75 years), and very old group (>75 years). Circumstances of cardiopulmonary resuscitation (CPR), patients' characteristics, post-resuscitation treatment, hemodynamic monitoring, neurologic outcome and survival were compared across age groups. Kruskal-Wallis test, Chi-square test and binary logistic regression (BLR) were applied. In addition, a literature search of PubMed/Medline database was performed to provide a background. RESULTS: Age was significantly associated with having a cardiac arrest on a monitor and a history of hypertension. No association was found between age and survival or neurologic outcome. Age did not affect hemodynamic parameter changes during target temperature management (TTM), except mean arterial pressure (MAP). Need of catecholamine administration was the highest among very old patients. During the literature review, seven papers were identified. Most studies had a retrospective design and investigated interventions and outcome, but lacked unified age categorization. All studies reported worse survival in the elderly, although old survivors showed a favorable neurologic outcome in most of the cases. CONCLUSION: There is no evidence to support the limitation of post-cardiac arrest therapy in the aging population. Furthermore, additional prospective studies are needed to investigate the characteristics and outcome of post-cardiac arrest therapy in this patient group.

Gastric emptying of solids in children: reference values for the (13) C-octanoic acid breath test.

BACKGROUND: (99m) Technetium scintigraphy ((99m) TS) is the 'gold standard' for measuring gastric emptying (GE), but it is associated with a radiation exposure. For this reason, the (13) C-octanoic acid breath test ((13) C-OBT) was developed for measuring GE of solids. The objective of this study was to determine normal values for gastric half-emptying time (t1/2 GE) of solids in healthy children. METHODS: Gastric emptying of a standardized solid test meal consisting of a pancake evaluated with (99m) TS and (13) C-OBT was compared in 22 children aged between 1 and 15 years with upper gastrointestinal symptoms. Subsequently, the (13) C-OBT was used to determine normal values for GE of the same solid test meal in 120 healthy children aged between 1 and 17 years. KEY RESULTS: The results showed a significant correlation (r = 0.748, p = 0.0001) between t1/2 GE measured with both techniques in the group of children with upper gastrointestinal symptoms. In the group of healthy children, mean t1/2 GE was 157.7 ± 54.0 min (range 71-415 min), but t1/2 GE decreased with age between 1 and 10 years and remained stable afterward. There was no influence of gender, weight, height, body mass index, and body surface area on t1/2 GE. CONCLUSIONS & INFERENCES: Normal values for GE of solids measured with the (13) C-OBT using a standardized methodology were determined in healthy children. We propose to use this method and corresponding reference ranges to study GE of solids in children with gastrointestinal problems.

Algorithms for managing infant constipation, colic, regurgitation and cow's milk allergy in formula-fed infants.

UNLABELLED: Gastrointestinal symptoms, such as constipation, regurgitation and infant colic, occur in about half of infants. These symptoms are often functional, but they may also be caused by cow's milk protein allergy. We developed three algorithms for formula-fed infants, which are consensus rather than evidence-based due to the limited research available in the existing literature. CONCLUSION: We believe that these algorithms will help primary healthcare practitioners to recognise and manage these frequent gastrointestinal manifestations in infants.

The use of probiotics in IBD and IBS.

While the role of microflora is well established in the development of inflammatory bowel disease (IBS); data is still emerging regarding IBS as the knowledge on brain-gut interaction grows. For both patient groups multiple efficacious treatments exist, but there are still unmet needs as long term disease control remains an issue. Given the importance of the microbiome on the development of the immune system and the interaction between the microbiome and the host organism, this "route" is being examined increasingly as a therapeutic possibility in both pathologies with variable results. We here provide a short overview on the existing data, meta-analysis and single studies, on probiotic treatment in both diseases.

Behind the (impedance) baseline in children.

Impedance baseline is a new parameter recently related to esophageal integrity. The aim of this study was to assess the effect of different factors on impedance baseline in pediatric patients. We analyzed the impedance baseline of 800 children with symptoms of gastroesophageal reflux. Mean impedance baseline was automatically calculated throughout 24-hour tracings. The presence of different age groups and of esophagitis was evaluated. Unpaired t-test, Spearman rank correlation, polynomial, and regression plot were used for statistical analysis. Age-related percentile curves were created. We considered a P-value<0.05 as statistically significant. Impedance baseline was significantly (P<0.001) lower in younger compared to older children up to 48 months. The mean increase of baseline per month was much higher in the first 36 months of life (47.5 vs. 2.9 Ohm in Channel 1 and 29.9 vs. 2.3 Ohm in Channel 6, respectively) than in older ages. Patients with esophagitis showed significantly decreased impedance baseline (P<0.05). Infants (especially in the first months of life) and young children present a significantly lower impedance baseline compared to older children both in proximal and distal esophagus. The presence of esophagitis may also determine a decreased impedance baseline regardless of the age of the patients.

Emerging technologies for non-invasive quantification of physiological oxygen transport in plants.

Oxygen plays a critical role in plant metabolism, stress response/signaling, and adaptation to environmental changes (Lambers and Colmer, Plant Soil 274:7-15, 2005; Pitzschke et al., Antioxid Redox Signal 8:1757-1764, 2006; Van Breusegem et al., Plant Sci 161:405-414, 2001). Reactive oxygen species (ROS), by-products of various metabolic pathways in which oxygen is a key molecule, are produced during adaptation responses to environmental stress. While much is known about plant adaptation to stress (e.g., detoxifying enzymes, antioxidant production), the link between ROS metabolism, O2 transport, and stress response mechanisms is unknown. Thus, non-invasive technologies for measuring O2 are critical for understanding the link between physiological O2 transport and ROS signaling. New non-invasive technologies allow real-time measurement of O2 at the single cell and even organelle levels. This review briefly summarizes currently available (i.e., mainstream) technologies for measuring O2 and then introduces emerging technologies for measuring O2. Advanced techniques that provide the ability to non-invasively (i.e., non-destructively) measure O2 are highlighted. In the near future, these non-invasive sensors will facilitate novel experimentation that will allow plant physiologists to ask new hypothesis-driven research questions aimed at improving our understanding of physiological O2 transport.

Profile of pediatric Crohn's disease in Belgium.

AIM: A Belgian registry for pediatric Crohn's disease, BELCRO, was created. This first report aims at describing disease presentation and phenotype and determining associations between variables at diagnosis and registration in the database. METHODS: Through a collaborative network, children with previously established Crohn's disease and newly diagnosed children and adolescents (under 18 y of age) were recruited over a 2 year period. Data were collected by 23 centers and entered in a database. Statistical association tests analyzed relationships between variables of interest at diagnosis. RESULTS: Two hundred fifty-five patients were included. Median age at diagnosis was 12.5 y (range: 1.6-18 y); median duration of symptoms prior to diagnosis was 3 m (range: 1-12 m). Neonatal history and previous medical history did not influence disease onset nor disease behavior. Fifty three % of these patients presented with a BMI z-score < -1. CRP was an independent predictor of disease severity. Steroids were widely used as initial treatment in moderate to severe and extensive disease. Over time, immunomodulators and biological were prescribed more frequently, reflecting a lower prescription rate for steroids and 5-ASA. A positive family history was the sole significant determinant for earlier use of immunosuppression. CONCLUSION: In Belgium, the median age of children presenting with Crohn's disease is 12.5 y. Faltering growth, extensive disease and upper GI involvement are frequent. CRP is an independent predictive factor of disease activity. A positive family history appears to be the main determinant for initial treatment choice.

MR enterography in children with Crohn disease: results from the Belgian pediatric Crohn registry (Belcro).

INTRODUCTION: Magnetic Resonance enterography (MRE) is an imaging modality avoiding ionizing radiation and the discomfort associated with enteroclysis. The results of MRE at diagnosis in the patients of the Belgian pediatric Crohn registry (Belcro) are compared to endoscopical and histological results. METHODS: Results of MRE, endoscopy and histology were obtained from the medical charts and assigned to one of the following segments: jejunum, ileum, ascending colon, transverse colon, descending colon or rectosigmoid. MRE images were reviewed in a blinded way by 4 radiologists with specific interest in pediatric MRE. RESULTS: From the Belcro registry, twenty-two patients underwent a MRE during their work-up for Crohn disease. The results of endoscopy, histology and MRE were concordant (either all negative or positive) in the ileum in 16/18 patients and in the rectosigmoid, descending colon, transverse colon and ascending colon in resp 9, 8, 8 and 8/22 patients. In the non-concordant cases (MRE colon negative but endoscopy and/or histology positive), MRE could not reflect the subtle endoscopic or histologic lesions such as erosions that were described.In 4 cases where ileocaecal valve intubation was impossible ileal MRE findings were abnormal. MRE detected ileal stenosis, jejunal lesions and fistula in resp 4/22, 3/22 en 2/22 patients. The 100% and 75% interobserver agreement was resp 50-82% and 773-100% according to the different intestinal segments. CONCLUSIONS: MRE is a promising imaging modality avoiding radiation in Crohn disease. It should probably become the technique of first choice for the evaluation of extensive small bowel disease in children with Crohn disease.

Probiotics and prebiotics in infants and children.

Probiotics and prebiotics have a major influence on gastrointestinal flora composition. This review analyses the relationship between this change in flora composition and health benefits in children. Literature databases were searched for relevant articles. Despite exhaustive research on the subject in different indications, such as prevention and treatment of acute gastroenteritis, antibiotic associated diarrhea (AAD), traveler's diarrhea, inflammatory bowel disease, irritable bowel syndrome, Helicobacter pylori, necrotizing enterocolitis, constipation, allergy and atopic dermatitis, colic and extraintestinal infections, reports of clear benefits for the use of prebiotics and probiotics in pediatric disorders remain scarce. The best evidence has been provided for the use of probiotics in acute gastroenteritis and in prevention of AAD. However, AAD in children is in general mild, and only seldom necessitates additional interventions. Overall, the duration of acute infectious diarrhea is reduced by approximately 24 hours. Evidence for clinically relevant benefit in all other indications (inflammatory bowel disease, irritable bowel syndrome, constipation, allergy) is weak to nonexistent. Selected probiotic strains given during late pregnancy and early infancy decrease atopic dermatitis. Adverse effects have very seldom been reported. Since the risk seems minimal to nonexistent, prebiotics and probiotics may be helpful in the prevention and treatment of some disorders in children, although the evidence for benefit is limited. The best evidence has been accumulated for some lactobacilli strains and for Saccharomyces boulardii in the reduction of the duration of acute diarrhea due to gastroenteritis and prevention of AAD.

Baseline esophageal impedance according to different time intervals.

Baseline impedance (BImp) reflects esophageal integrity. The study aims to identify the optimal method to calculate BImp. Mean BImp was calculated in 20 consecutive multichannel intraluminal impedance recordings including and excluding impedance events (IEs) (reflux, swallows, and gas episodes) in all channels during the full recording and during the first period of 1 minute without an IE every hour (method 1), every 2 hours (method 2), or 4 hours (method 3). BImp obtained during the total recording was set at 100%, and the variation (difference in BImp for the different methods) and variability (difference in BImp during one analysis period) were assessed. All children underwent endoscopy. No child had esophagitis. The mean difference over the six channels, in percentage, between BImp over the total recording with and without IE was ≈ 1.2% and comparable for each channel (range -5.87-6.99%). A mean of 980 IE were excluded in each tracing, and it took between 4 and 24 hours to delete all events in one tracing. The difference of BImp obtained with and without IE was mainly caused by the gas episodes at the upper and swallows in the lower channel. The mean BImp according to the three 1-minute analysis methods was comparable with the mean BImp according to the 24-hour analysis. The automatic determination of the mean BImp over the total tracing including the IE is an adequate method. In isolated tracings with numerous IE, the calculation of the mean BImp over 1 minute every 4 hours is an alternative option. Companies should develop software to calculate the mean BImp during the whole registration deleting all IE for the analysis.

Safety and cost of infliximab for the treatment of Belgian pediatric patients with Crohn's disease.

Biologicals have become an important component in the treatment of Crohn's disease in children. Their increased and long term use raises safety concerns. We describe safety and cost of infliximab in Belgian pediatric Crohn's disease patients. All patients on infliximab as part of the present or past treatment for Crohn's Disease until January 1st 2011 were selected from an existing database. Information on disease phenotype, medication and adverse events were extracted. Adverse events occurred in 25.9% of patients exposed to infliximab of which 29.6% were severe. In total 31.7% of patients stopped infliximab therapy. The main reasons for discontinuation were adverse events in 45.4% and loss of response in 30.3%. No malignancies or lethal complications occurred over this 241 patient year observation period. Immunomodulators were concomitant medication in 75% of patients and were discontinued subsequently in 38.4% of them. The cost of infliximab infusions per treated patient per year in the Belgian health care setting is approximately 9 474 euro, including only medication and hospital related costs. Even though infliximab is relatively safe in pediatric CD on the short term, close follow-up and an increased awareness of the possible adverse reactions is highly recommended. Adverse reactions appeared in 25.9% of all patients and were the main reason for discontinuation. Treatment cost has to be balanced against efficacy and modifications in disease course. In the Belgian health care system, the medication is available to all patients with moderate to severe CD.

The relationship between gastroesophageal reflux and cough in children with chronic unexplained cough using combined impedance-pH-manometry recordings.

INTRODUCTION: Assessment of the reflux-cough association in children is challenging. Esophageal (impedance) pH recording is sensitive to recognize reflux. However, cough recorded by an event marker, possibly lacks accuracy. We aimed to study the exact time relationship between reflux and cough in children with chronic cough. METHODS: Twenty-six children (12 boys; 1-10.5 years) with chronic unexplained cough underwent ambulatory impedance-pH-manometry recordings. Manometry was used for precise cough recognition. Reflux was assessed with impedance-pH monitoring and defined as acid (pH <4), weakly acidic (WA) (pH 4-7), weakly alkaline (WALK) (pH ≥7), or acid only (pH <4 for ≥4 sec without impedance pattern). Cough was considered "induced by" reflux, if it started ≤2 min after reflux. The Symptom Association Probability (SAP) was calculated and considered positive if >95%. Cough-induced reflux if it occurred 30 sec before the reflux event. RESULTS: Impedance-pH detected 30 (21-52) reflux episodes/patient (55.2% acid, 41.5% WA, and 3.3% WALK). Additionally 59 acid only events were identified [1 (0-21)/patient]. Manometry detected 47 (5-203) cough bursts/patient. Reflux-cough was found in 22/26 patients. Ten patients had a +SAP for reflux-cough (one acid, six WA, and three acid + WA gastroesophageal reflux [GER]), of which nine had a normal acid exposure. Six out of 10 patients with +SAP using manometry had a +SAP using the event marker. Cough-reflux was detected in 19 patients [3 (0-7)/patient]. Only a small fraction of the esophageal acid exposure [9.6 (0.4-31.8%)] was secondary to cough. CONCLUSION: Both acid and WA GER may precede cough in children with unexplained cough, but cough does not induce GER. Objective cough recording improves symptom association analysis.

Characteristics of gastroesophageal reflux and potential risk of gastric content aspiration in children with cystic fibrosis.

OBJECTIVES: Increased gastroesophageal reflux (GER) is common in children with cystic fibrosis (CF). We studied the occurrence of acid, weakly acidic (WA), and weakly alkaline (WALK) reflux in children with CF and evaluated a possible surrogate marker for risk of gastric content aspiration. PATIENTS AND METHODS: Twenty-four children with CF underwent impedance-pH monitoring for detection of acid (pH < 4), WA (pH 4-7), and WALK-GER (pH > or = 7). In 11 children, cough was objectively recorded with esophageal manometry and the symptom association probability was calculated to determine the reflux-cough relation. Presence of bile acids (BA) was measured in the saliva of 65 patients with CF and 23 healthy children, respectively. RESULTS: Sixteen of the 24 children had increased GER (esophageal acid exposure). The majority of reflux events were acidic in nature. WA reflux was less common and WALK reflux was rare. The sequence reflux-cough was found in 8 of the 11 children and 1 of 11 children had a positive symptom association probability for reflux-cough. The sequence cough-reflux was found in only 3 of the 11 children. Only a small fraction of the total esophageal acid and volume exposure was secondary to cough. Twenty-three of the 65 children with CF had BA in saliva compared with none of the healthy controls. CONCLUSIONS: Although WA-GER is uncommon, acid GER is prevalent in children with CF. It is a primary phenomenon and is not secondary to cough. One third of the children with CF have BA in saliva, which may indicate an increased risk for aspiration. However, the impact of salivary BA and potential aspiration on CF pulmonary disease needs further investigation.