An overview on chemical structures as ΔF508-CFTR correctors.

Eur J Med Chem. 2019 Jul 15;180:430-448

Authors: Spanò V, Montalbano A, Carbone A, Scudieri P, Galietta LJV, Barraja P

Abstract
Deletion of phenylalanine at position 508 (F508del) in the CFTR protein, is the most common mutation causing cystic fibrosis (CF). F508del causes misfolding and rapid degradation of CFTR protein a defect that can be targeted with pharmacological agents termed "correctors". Correctors belong to various chemical classes but are generally small molecules based on nitrogen sulfur or oxygen heterocycles. The mechanism of action of correctors is generally unknown but there is experimental evidence that some of them can directly act on mutant CFTR improving folding and stability. Here we overview the characteristics of the various F508del correctors described so far to obtain indications on key chemical structures and modifications that are required for mutant protein rescue.

PMID: 31326599 [PubMed - as supplied by publisher]

Positive Newborn Screening for Cystic Fibrosis, What to Do Next?

Indian J Pediatr. 2019 Jul 19;:

Authors: Kumar P, Goyal JP

PMID: 31325101 [PubMed - as supplied by publisher]

Inhibition of calpain 1 restores plasma membrane stability to pharmacologically rescued Phe508del-CFTR variant.

J Biol Chem. 2019 Jul 19;:

Authors: Matos AM, Pinto FR, Barros P, Amaral MD, Pepperkok R, Matos P

Abstract
Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding CF transmembrane conductance regulator (CFTR), a chloride channel normally expressed at the surface of epithelial cells. The most frequent mutation, resulting in Phe-508 deletion, causes CFTR misfolding and its premature degradation. Low temperature or pharmacological correctors can partly rescue the Phe508del-CFTR processing defect and enhance trafficking of this channel variant to the plasma membrane (PM). Nevertheless, the rescued channels have an increased endocytosis rate, being quickly removed from the PM by the peripheral protein quality-control pathway. We previously reported that rescued Phe508del-CFTR (rPhe508del) can be retained at the cell surface by stimulating signaling pathways that coax the adaptor molecule ezrin (EZR) to tether rPhe508del-Na+/H+-exchange regulatory factor-1 (NHERF1) complexes to the actin cytoskeleton, thereby averting the rapid internalization of this channel variant. However, the molecular basis for why rPhe508del fails to recruit active EZR to the PM remains elusive. Here, using a proteomics approach, we characterized and compared the core components of wt-CFTR- or rPhe508del-containing macromolecular complexes at the surface of human bronchial epithelial cells. We identified calpain 1 (CAPN1) as an exclusive rPhe508del interactor that prevents active EZR recruitment, impairs rPhe508del anchoring to actin, and reduces its stability in the PM. We show that either CAPN1 down-regulation or its chemical inhibition dramatically improves the functional rescue of Phe508del-CFTR in airway cells. These observations suggest that CAPN1 constitutes an appealing target for pharmacological intervention, as part of CF combination therapies restoring Phe508del-CFTR function.

PMID: 31324722 [PubMed - as supplied by publisher]

Pouchitis in pediatric ulcerative colitis: A multicenter study on behalf of Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition.

Dig Liver Dis. 2019 Jul 16;:

Authors: Dipasquale V, Mattioli G, Arrigo S, Bramuzzo M, Strisciuglio C, Faraci S, Romeo EF, Contini AC, Ventimiglia M, Zuin G, Felici E, Alvisi P, Romano C

Abstract
BACKGROUND: Data on the epidemiology and risk factors for pouchitis following restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA) in pediatric patients with ulcerative colitis (UC) are scarce.
AIMS: To determine incidence, risk factors and clinical outcome of pouchitis following IPAA in children.
METHODS: This multicenter, retrospective cohort study, included all pediatric UC patients who underwent colectomy and IPAA from January 2010 to December 2016.
RESULTS: Eighty-five patients were enrolled. During a median post-surgical period of 24.8 (range: 1.0-72.0) months following IPAA, 38 (44.7%) patients developed pouchitis, including 6 (15.8%) who developed chronic pouchitis. Kaplan-Meier survival estimates of the cumulative probability for pouchitis were 14.6% at 1 year and 27.3% and 51.5% at 2 and 5 years, respectively. Multiple Cox regression model showed that older age at colectomy (hazard ratio, HR: 0.89, p = 0.008) was a protective factor, whereas chronic active colitis as indication for surgery (HR: 4.45, p < 0.001), and a 3-stage IPAA (HR: 2.86, p = 0.028) increased the risk for pouchitis.
CONCLUSIONS: Long-term risk for pouchitis is significantly high in pediatric-onset UC after IPAA. Younger age at colectomy, chronic active colitis as indication for surgery and 3-stage IPAA may increase the risk for pouchitis.

PMID: 31324473 [PubMed - as supplied by publisher]

Furanoic Lipid F-6, A Novel Anti-Cancer Compound that Kills Cancer Cells by Suppressing Proliferation and Inducing Apoptosis.

Cancers (Basel). 2019 Jul 09;11(7):

Authors: Al-Hassan JM, Fang Liu Y, Khan MA, Yang P, Guan R, Wen XY, Afzal M, Oommen S, Paul BM, Nair D, Palaniyar N, Pace-Asciak C

Abstract
Identifying novel anti-cancer drugs is important for devising better cancer treatment options. In a series of studies designed to identify novel therapeutic compounds, we recently showed that a C-20 fatty acid (12,15-epoxy-13,14-dimethyleicosa-12,14-dienoic acid, a furanoic acid or F-6) present in the lipid fraction of the secretions of the Arabian Gulf catfish skin (Arius bilineatus Val.; AGCS) robustly induces neutrophil extracellular trap formation. Here, we demonstrate that a lipid mix (Ft-3) extracted from AGCS and F-6, a component of Ft-3, dose dependently kill two cancer cell lines (leukemic K-562 and breast MDA MB-231). Pure F-6 is approximately 3.5 to 16 times more effective than Ft-3 in killing these cancer cells, respectively. Multiplex assays and network analyses show that F-6 promotes the activation of MAPKs such as Erk, JNK, and p38, and specifically suppresses JNK-mediated c-Jun activation necessary for AP-1-mediated cell survival pathways. In both cell lines, F-6 suppresses PI3K-Akt-mTOR pathway specific proteins, indicating that cell proliferation and Akt-mediated protection of mitochondrial stability are compromised by this treatment. Western blot analyses of cleaved caspase 3 (cCasp3) and poly ADP ribose polymerase (PARP) confirmed that F-6 dose-dependently induced apoptosis in both of these cell lines. In 14-day cell recovery experiments, cells treated with increasing doses of F-6 and Ft-3 fail to recover after subsequent drug washout. In summary, this study demonstrates that C-20 furanoic acid F-6, suppresses cancer cell proliferation and promotes apoptotic cell death in leukemic and breast cancer cells, and prevents cell recovery. Therefore, F-6 is a potential anti-cancer drug candidate.

PMID: 31323958 [PubMed]

Microgallbladder: Self-Remitting Acute Cholecystitis-Like Condition Unique to Patients with Cystic Fibrosis.

Case Rep Radiol. 2019;2019:6737428

Authors: Mousa MS, Feldman JC, Mahajan P

Abstract
Microgallbladder is a nonsurgical medical condition characterized by chronic inflammation and atrophy of the gallbladder, which is considered a highly specific imaging finding unique to patients with cystic fibrosis (CF), and has been incidentally reported on abdominal imaging in up to 45% of cases with CF. The impairment of exocrine water efflux in CF leads to the production of hyperviscous biliary secretions, cholestasis, and transient cystic duct obstruction of the microgallbladder causing microcholecystitis-interestingly a self-remitting acute cholecystitis-like condition without surgical intervention. We present a case report of a 22-year-old male patient with history of CF with multiple hospital admissions for unexplained chronic abdominal pain found to be caused by microgallbladder, which was managed conservatively.

PMID: 31321111 [PubMed]

Cystic fibrosis transmembrane conductance regulator (CFTR) and autophagy: hereditary defects in cystic fibrosis versus gluten-mediated inhibition in celiac disease.

Oncotarget. 2019 Jul 08;10(43):4492-4500

Authors: Maiuri L, Raia V, Piacentini M, Tosco A, Villella VR, Kroemer G

Abstract
Cystic Fibrosis (CF) is the most frequent lethal monogenetic disease affecting humans. CF is characterized by mutations in cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel whose malfunction triggers the activation of transglutaminase-2 (TGM2), as well as the inactivation of the Beclin-1 (BECN1) complex resulting in disabled autophagy. CFTR inhibition, TGM2 activation and BECN1 sequestration engage in an 'infernal trio' that locks the cell in a pro-inflammatory state through anti-homeostatic feedforward loops. Thus, stimulation of CFTR function, TGM2 inhibition and autophagy stimulation can be used to treat CF patients. Several studies indicate that patients with CF have a higher incidence of celiac disease (CD) and that mice bearing genetically determined CFTR defects are particularly sensitive to the enteropathogenic effects of the orally supplied gliadin (a gluten-derived protein). A gluten/gliadin-derived peptide (P31-43) inhibits CFTR in mouse intestinal epithelial cells, causing a local stress response that contributes to the immunopathology of CD. In particular, P31-43-induced CFTR inhibition elicits an epithelial stress response perturbing proteostasis. This event triggers TGM2 activation, BECN1 sequestration and results in molecular crosslinking of CFTR and P31-43 by TGM2. Importantly, stimulation of CFTR function with a pharmacological potentiator (Ivacaftor), which is approved for the treatment of CF, could attenuate the autophagy-inhibition and pro-inflammatory effects of gliadin in preclinical models of CD. Thus, CD shares with CF a common molecular mechanism involving CFTR inhibition that might respond to drugs that intercept the "infernal trio". Here, we highlight how drugs available for CF treatment could be repurposed for the therapy of CD.

PMID: 31321000 [PubMed]

Polish Society of Allergology statement on the diagnosis and treatment of severe, difficult-to-control bronchial asthma.

Postepy Dermatol Alergol. 2019 Apr;36(2):147-157

Authors: Kupczyk M, Bartuzi Z, Bodzenta-Łukaszyk A, Kulus M, Kuna P, Kupryś-Lipińska I, Mazurek H

Abstract
Severe asthma requires at least high doses of inhaled corticosteroids (ICS) in combination with a long-acting β-agonist (LABA) or systemic corticosteroids (SCS) for more than 50% of days/year to avoid loss of control, or remains uncontrolled despite the treatment described above. The diagnosis of severe asthma should be confirmed in a reference centre as it requires careful differential diagnosis and the exclusion of factors hindering the achievement of optimal control. Severe asthma represents a significant burden for the patient, their family and the healthcare system. This is due to the severity of the symptoms, drug costs, significant impairment of everyday functioning and life quality, and limitation in the professional work. In the case of ineffectiveness of the step 4 GINA treatment, the patient should be referred to a specialist centre to consider additional treatment, including anti-IgE receptor (omalizumab), anti-IL-5 receptor (mepolizumab), or an antibody directed against the α-subunit of receptor for IL-5 (benralizumab). In the case of severe asthma, intensification of therapy should first of all include biological therapy and not the use of SCS. Biological drugs are available in Poland as a part of the therapeutic programme for the treatment of severe asthma. In practice, the therapeutic programme may change with subsequent notices of the Ministry of Health and does not have to be consistent with the Summary of Product Characteristics for individual preparations. The current review presents the basic principles of differential diagnosis of severe asthma and the selection of the optimal biological therapy in Polish conditions.

PMID: 31320846 [PubMed]

Random plasma glucose predicts the diagnosis of diabetes.

PLoS One. 2019;14(7):e0219964

Authors: Rhee MK, Ho YL, Raghavan S, Vassy JL, Cho K, Gagnon D, Staimez LR, Ford CN, Wilson PWF, Phillips LS

Abstract
AIMS/HYPOTHESIS: Early recognition of those at high risk for diabetes as well as diabetes itself can permit preventive management, but many Americans with diabetes are undiagnosed. We sought to determine whether routinely available outpatient random plasma glucose (RPG) would be useful to facilitate the diagnosis of diabetes.
METHODS: Retrospective cohort study of 942,446 U.S. Veterans without diagnosed diabetes, ≥3 RPG in a baseline year, and ≥1 primary care visit/year during 5-year follow-up. The primary outcome was incident diabetes (defined by diagnostic codes and outpatient prescription of a diabetes drug).
RESULTS: Over 5 years, 94,599 were diagnosed with diabetes [DIAB] while 847,847 were not [NONDIAB]. Baseline demographics of DIAB and NONDIAB were clinically similar, except DIAB had higher BMI (32 vs. 28 kg/m2) and RPG (150 vs. 107 mg/dl), and were more likely to have Black race (18% vs. 15%), all p<0.001. ROC area for prediction of DIAB diagnosis within 1 year by demographic factors was 0.701, and 0.708 with addition of SBP, non-HDL cholesterol, and smoking. These were significantly less than that for prediction by baseline RPG alone (≥2 RPGs at/above a given level, ROC 0.878, p<0.001), which improved slightly when other factors were added (ROC 0.900, p<0.001). Having ≥2 RPGs ≥115 mg/dl had specificity 77% and sensitivity 87%, and ≥2 RPGs ≥130 mg/dl had specificity 93% and sensitivity 59%. For predicting diagnosis within 3 and 5 years by RPG alone, ROC was reduced but remained substantial (ROC 0.839 and 0.803, respectively).
CONCLUSIONS: RPG levels below the diabetes "diagnostic" range (≥200 mg/dl) provide good discrimination for follow-up diagnosis. Use of such levels-obtained opportunistically, during outpatient visits-could signal the need for further testing, allow preventive intervention in high risk individuals before onset of disease, and lead to earlier identification of diabetes.

PMID: 31323063 [PubMed - in process]

Pharmacokinetic/pharmacodynamic analysis of weight- and height-scaled tobramycin dosage regimens for patients with cystic fibrosis.

J Antimicrob Chemother. 2019 Aug 01;74(8):2311-2317

Authors: Alghanem SS, Touw DJ, Thomson AH

Abstract
OBJECTIVES: To determine the outcomes of weight- and height-based tobramycin dosing regimens for patients with cystic fibrosis (CF).
METHODS: A simulated dataset of 5000 patients based on 331 patients with CF was created using NONMEM. Pharmacokinetic (PK) parameters were derived for each patient from a published model using Monte Carlo simulation. The abilities of 10 and 12 mg/kg/day and 3 and 4 mg/cm/day to achieve standard and extended Cmax (20-30 and 20-40 mg/L) and AUC0-24 (80-120 and 80-150 mg·h/L) targets were evaluated. PK/pharmacodynamic (PK/PD) indices were a Cmax/MIC ratio ≥10 and an AUC0-24/MIC ratio ≥110. For these indices and a range of MICs, cumulative fractions of response (CFRs) for Pseudomonas aeruginosa were also determined.
RESULTS: More patients achieved standard Cmax and AUC0-24 targets with 3 mg/cm/day (64% and 62%, respectively) than with 10 mg/kg/day (43% and 48%, respectively). AUC0-24 estimates >120 mg·h/L were more common with weight-based dosing. With higher doses, 72% achieved high target peaks with 4 mg/cm/day and 65% with 12 mg/kg/day. For the Cmax/MIC index, the maximal MIC for the target microorganism was 2 mg/L with lower doses, 2.5 mg/L with higher doses and 0.5 mg/L for AUC0-24/MIC-based regimens. The CFR for all regimens was >90% for Cmax targets and 66% to 79% for AUC0-24 targets.
CONCLUSIONS: A tobramycin dose of 3 mg/cm/day rather than 10 mg/kg/day achieved similar PK/PD outcomes but dose and AUC0-24 ranges were narrower and the incidence of high AUC0-24 values was lower. Height-based doses should therefore be considered for patients with CF.

PMID: 31322695 [PubMed - in process]

Endothelial Dysfunction in Cystic Fibrosis: Role of Oxidative Stress.

Oxid Med Cell Longev. 2019;2019:1629638

Authors: Tucker MA, Fox BM, Seigler N, Rodriguez-Miguelez P, Looney J, Thomas J, McKie KT, Forseen C, Davison GW, Harris RA

Abstract
Oxidative stress and vascular endothelial dysfunction are established characteristics of cystic fibrosis (CF). Oxidative stress may contribute to vascular dysfunction via inhibition of nitric oxide (NO) bioavailability. Purpose. To determine if ingestion of a single antioxidant cocktail (AOC) improves vascular endothelial function in patients with CF. Methods. In 18 patients with CF (age 8-39 y), brachial artery flow-mediated dilation (FMD) was assessed using a Doppler ultrasound prior to and two hours following either an AOC (n = 18; 1,000 mg vitamin C, 600 IU vitamin E, and 600 mg α-lipoic acid) or a placebo (n = 9). In a subgroup of patients (n = 9), changes in serum concentrations of α-tocopherol and lipid hydroperoxide (LOOH) were assessed following AOC and placebo. Results. A significant (p = 0.032) increase in FMD was observed following AOC (Δ1.9 ± 3.3%), compared to no change following placebo (Δ - 0.8 ± 1.9%). Moreover, compared with placebo, AOC prevented the decrease in α-tocopherol (Δ0.48 ± 2.91 vs. -1.98 ± 2.32 μM, p = 0.024) and tended to decrease LOOH (Δ - 0.2 ± 0.1 vs. 0.1 ± 0.1 μM, p = 0.063). Conclusions. These data demonstrate that ingestion of an antioxidant cocktail can improve vascular endothelial function and improve oxidative stress in patients with CF, providing evidence that oxidative stress is a key contributor to vascular endothelial dysfunction in CF.

PMID: 31320980 [PubMed - in process]

Making precision medicine personal for cystic fibrosis.

Science. 2019 07 19;365(6450):220-221

Authors: Manfredi C, Tindall JM, Hong JS, Sorscher EJ

PMID: 31320522 [PubMed - in process]

Prospective comparison of a nonmodified and a modified mite extract for immunotherapy in children and adolescents.

Immunotherapy. 2019 Jul 19;:

Authors: Hartmann D, Fischl A, Herrmann E, Schulze J, Schubert R, Zielen S

Abstract
Aim: This prospective study compares nonmodified and modified house dust mite extracts for allergen immunotherapy (AIT) in pediatric patients with allergic asthma. Materials & methods: Total 95 patients underwent bronchial allergen provocation (BAP). AIT was recommended to 62 patients. Complete datasets of 54 subjects were obtained. Primary aim was the comparison of treatment success defined by BAP between two extracts after 1 year. Secondary parameters were laboratory parameters and clinical symptoms. Results: Significant improvement (p < 0.001) was measured by BAP in both treatment groups. No change was seen in the controls. Both extracts exerted comparable effects on all parameters. Conclusion: After 1 year of AIT, the extracts were equally efficient, with significant improvements in 70.0% (nonmodified) and 72.2% (modified) of patients.

PMID: 31319714 [PubMed - as supplied by publisher]

Ivacaftor Is Associated with Reduced Lung Infection by Key Cystic Fibrosis Pathogens: A Cohort Study Using National Registry Data.

Ann Am Thorac Soc. 2019 Jul 19;:

Authors: Frost FJ, Nazareth DS, Charman SC, Winstanley C, Walshaw MJ

Abstract
RATIONALE: Ivacaftor can greatly improve clinical outcomes in people with cystic fibrosis (CF) and has been shown to have in-vitro antibacterial properties, yet the long-term microbiological outcomes of treatment are unknown.
OBJECTIVES: To investigate changes in respiratory microbiology associated with long-term ivacaftor use.
METHODS: Retrospective cohort study utilising data from the United Kingdom CF Registry 2011-2016. Primary outcome was the annual prevalence ratios for key CF pathogens between ivacaftor users and their contemporaneous comparators. Multivariate log-binomial regression models were designed to adjust for confounders. Changes in Pseudomonas aeruginosa status were compared between groups using non-parametric maximum likelihood estimate for the purposes of Kaplan-Meier approximation.
RESULTS: Ivacaftor use was associated with early and sustained reduction in P. aeruginosa rates (2016 Adjusted Prevalence Ratio [95% CI] 0.68 [0.58, 0.79], p<0.001) via a combination of increased clearance in those with infection (Ivacaftor: 33/87 [37.9%] vs. Non ivacaftor: 432/1872 [22.8%], p<0.001) and reduced acquisition in those without infection (33/134 [24.6%] vs. 1157/2382 [48.6%], p=0.01). The improved prevalence of P. aeruginosa infection was independent of reduced sampling in the ivacaftor cohort. Ivacaftor was also associated with reduced prevalence of Staphylococcus aureus and Aspergillus spp. but not Burkholderia cepacia complex. Conclusion In this study, long-term ivacaftor use was associated with reduced infection with important CF pathogens including P. aeruginosa. These findings have implications for antibiotic stewardship and the need for on-going chronic antimicrobial therapy in this cohort.

PMID: 31319678 [PubMed - as supplied by publisher]

Furocoumarins as multi-target agents in the treatment of cystic fibrosis.

Eur J Med Chem. 2019 Jul 10;180:283-290

Authors: Carbone A, Montalbano A, Spanò V, Musante I, Galietta LJV, Barraja P

Abstract
Multi-target molecular entities, offer a path to progress both in understanding causes of disease and in defining effective small molecule treatments. Coumarin and its derivatives belong to an important group of natural compounds with diverse biological properties. They are found in vegetables and plants for which literature reports thousands of publications for the great variety of biological applications among which the photoprotective effects, thus being considered multi-targeting agents. Their furan condensed analogues constitute the family of furocoumarins, less represented in the literature, endowed with photosensitizing properties and often used for the treatment of skin diseases such as vitiligo and psoriasis. Despite the study of biological properties of linear and angular furocumarins dates back to ancient times, mainly as photosensitizers, these small molecules still represent an attractive scaffold for further development and applications in several therapeutic fields. The aim of the present review is to summarize the most promising chemical entities belonging to the class of furocumarins and coumarins, emerged in the last decades, and the methods used for their synthesis with a particular focus on main targets involved in the cystic fibrosis treatment.

PMID: 31319264 [PubMed - as supplied by publisher]

Hepatic enzyme ALT as a marker of glucose abnormality in men with cystic fibrosis.

PLoS One. 2019;14(7):e0219855

Authors: Colomba J, Netedu SR, Lehoux-Dubois C, Coriati A, Boudreau V, Tremblay F, Cusi K, Rabasa-Lhoret R, Leey JA

Abstract
AIM: Cystic fibrosis (CF) patients are at high risk of developing CF-related diabetes (CFRD). In non-CF patients, liver disease, specifically steatosis and non-alcoholic fatty liver disease (NAFLD), is strongly associated with type 2 diabetes. We compared glycemic status and metabolic profiles in CF patients according to a biomarker of hepatic injury, alanine aminotransferase (ALT).
METHODS: We conducted a cross-sectional study among 273 adult CF patients recruited from the Montreal CF Cohort. A 2-hour oral glucose tolerance test (OGTT) was performed to collect glucose and insulin measures every 30 minutes. Fasting ALT levels and anthropometric measures were also obtained. Patients were categorized into 2 groups based on ALT cut-off of 25 U/L.
RESULTS: Patients in the high ALT group were mostly men (83%), had higher mean weight and BMI (p<0.001) and showed elevated glucose levels throughout OGTT (p≤0.01). When stratified by sex, only men with high ALT showed significantly higher weight (p<0.001), higher glycemic values at 60, 90 and 120 minutes of OGTT (p≤0.01), higher frequency of de novo CFRD (20.5% vs 8.2%, p = 0.04) as well as lower insulin sensitivity than men with normal ALT (p = 0.03). ALT levels were strongly associated with HOMA-IR in CFRD patients (p = 0.001, r2 = 0.28).
CONCLUSIONS: Adult CF men with higher ALT show an increased frequency of dysglycemia and de novo CFRD, lower insulin sensitivity and higher eight. Our data suggests that ALT levels could be an interesting tool to guide targeted diabetes screening, particularly among CF men. Prospective studies are needed to confirm these observations.

PMID: 31318914 [PubMed - in process]

Efficacy and safety of infliximab in very early onset inflammatory bowel disease: a national comparative retrospective study.

United European Gastroenterol J. 2019 Jul;7(6):759-766

Authors: Bramuzzo M, Arrigo S, Romano C, Filardi MC, Lionetti P, Agrusti A, Dipasquale V, Paci M, Zuin G, Aloi M, Strisciuglio C, Miele E, Pastore M, Martelossi S, Alvisi P, SIGENP IBD Working Group

Abstract
Background: Very few data regarding the use of infliximab in children with very early-onset inflammatory bowel disease (VEO-IBD) have been reported.
Objective: We aimed to assess the efficacy and the safety of infliximab in children with VEO-IBD compared with older children.
Methods: Children treated with infliximab were identified within the Italian IBD registry. The primary outcome was the rate of clinical remission at weeks 14 and 54. Secondary outcomes included the proportion of partial clinical response, treatment duration, and incidence of adverse events.
Results: Forty-two children with VEO-IBD were compared with 130 children with IBD. Despite significantly higher infliximab withdrawals in VEO-IBD patients during induction (42.9% vs 7.7% p < 0.01), remission rates at week 14 were similar (28.6% vs 43.8%, p = 0.10). At week 54 fewer VEO-IBD children were in remission (15.8% vs 54.3%, p < 0.01). The treatment duration was shorter in VEO-IBD (median 12.0 vs 18.4 months, p < 0.01). During the induction phase, adverse events were more common in the VEO-IBD group (p < 0.01).
Conclusion: Compared with older children, VEO-IBD patients have higher rates of infliximab failures, lower remission rates at one year, and more often experience adverse events during induction.

PMID: 31316780 [PubMed]

Establishment and equilibrium levels of deleterious mutations in large populations.

Sci Rep. 2019 Jul 17;9(1):10384

Authors: Viljoen JW, de Villiers JP, van Zyl AJ, Mezzavilla M, Pepper MS

Abstract
Analytical and statistical stochastic approaches are used to model the dispersion of monogenic variants through large populations. These approaches are used to quantify the magnitude of the selective advantage of a monogenic heterozygous variant in the presence of a homozygous disadvantage. Dunbar's results regarding the cognitive upper limit of the number of stable social relationships that humans can maintain are used to determine a realistic effective community size from which an individual can select mates. By envisaging human community structure as a network where social proximity rather than physical geography predominates, a significant simplification is achieved, implicitly accounting for the effects of migration and consanguinity, and with population structure and genetic drift becoming emergent features of the model. Effective community size has a dramatic effect on the probability of establishing beneficial alleles. It also affects the eventual equilibrium values that are reached in the case of variants conferring a heterozygous selective advantage, but a homozygous disadvantage, as in the case of cystic fibrosis and sickle cell disease. The magnitude of this selective advantage can then be estimated based on observed occurrence levels of a specific allele in a population, without requiring prior information regarding its phenotypic manifestation.

PMID: 31316137 [PubMed - in process]

Comparing clinical characteristics of pediatric patients with pancreatic diabetes to patients with type 1 diabetes - a matched case-control study.

Pediatr Diabetes. 2019 Jul 17;:

Authors: Lanzinger S, Welters A, Thon A, Konrad K, Kapellen T, Grulich-Henn J, Raddatz D, Holl RW

Abstract
BACKGROUND: Only few studies have been conducted on pancreatic diabetes and data from large epidemiological studies are missing. Our main objective was to study the most important differences and similarities between pediatric individuals with pancreatic diabetes and type 1 diabetes.
METHODS: Patients <20 years of age were identified from the diabetes patient follow-up registry (DPV). Data of the most recent treatment year between January 2000 and March 2018 was aggregated. Propensity score was used to match individuals with pancreatic diabetes to individuals with type 1 diabetes. Matching was conducted one to one by sex, age, diabetes duration, BMI-SDS and migration background.
RESULTS: We studied 731 individuals with pancreatic diabetes and 74,460 with type 1 diabetes. In the matched cohort of 631 pairs, HbA1c was significantly lower in pancreatic diabetes (7.4% [95%-confidence interval: 7.2; 7.5%]) compared to type 1 diabetes patients (8.7% [8.5; 8.8%]). Daily insulin dose (0.80 IU/kg [0.77; 0.84] vs. 0.86 IU/kg [0.82; 0.90]) and insulin pump use (13.3% [10.7; 16.4] vs. 22.1% [19.0; 25.6%]) were lower in patients with pancreatic diabetes. However, event rates of severe hypoglycemia were similar between pancreatic and type 1 diabetes patients (8.8 [5.4; 14.2] vs. 9.6 [5.9; 15.6] events per 100 patient years).
CONCLUSIONS: With the use of robust epidemiological data our study improves the knowledge on clinical characteristics in pediatric individuals with pancreatic diabetes. Moreover, our results serve as a basis to reconsider treatment options and for discussing clinical practice guidelines for patients with this rare medical condition. This article is protected by copyright. All rights reserved.

PMID: 31314155 [PubMed - as supplied by publisher]

What is the recommended amikacin dosing for cystic fibrosis patients with acute pulmonary exacerbations?

Pediatr Pulmonol. 2019 Jul 16;:

Authors: Thirion DJG, Pasche V, Marsot A

PMID: 31313524 [PubMed - as supplied by publisher]