A brief version of the Pediatric Inventory for Parents (PIP) in Spanish population: Stress of main family carers of chronic paediatric patients.

PLoS One. 2018;13(7):e0201390

Authors: Casaña-Granell S, Lacomba-Trejo L, Valero-Moreno S, Prado-Gasco V, Montoya-Castilla I, Pérez-Marín M

Abstract
A chronic illness in childhood has a negative impact on the paediatric patient and on family functioning. Psychological stress in parents influences the level of adjustment to the illness of their children. The Pediatric Inventory for Parents (PIP) was designed to measure stress in parents whose child has a chronic illness or requires prolonged medical monitoring. The main objective of this study is to provide a brief version of the Spanish translation of the PIP, across a sample consisting of 465 main familial caregivers (85.2% female, n = 396) between 27 and 67 years old ([Formula: see text] = 44.13; SD = 5.35) of paediatric patients between 9 and 18 years old ([Formula: see text] = 12.10, SD = 2.20; 56.8% men, n = 264) diagnosed with diabetes mellitus type I (20.9% of the sample; n = 97), short stature (32.5% of the sample; n = 151), or a chronic respiratory disease (asthma, cystic fibrosis, bronchiolitis obliterans and bronchiectasis) (46.6% of the sample; n = 217). After performing several EFAs (Exploratory Factor Analyses) and CFAs (Confirmatory Factorial Analyses), it was decided that 30 items need to be removed. Reliability and validity results suggest that the new 12-item version possesses appropriate psychometric properties. Cronbach's alpha value ranging between α = .42 and α = .81 and fit values obtained indicate a good fit: χ2/df (88.393/48) = 1.84 (α < .01); S-B χ2(df) = 88.393 (48); CFI = .95; IFI = .95; RMSEA = .05 (.033 - .074) for the frequency scales and χ2/df (72.002/48) = 1.5 (α < .01); S-Bχ2(df) = 72.002 (48); CFI = .97; IFI = .97; RMSEA = .04 (.011 - .063) for the difficulty scales. The PIP also showed predictive ability in regards to anxiety and depression, a positive relationship between the instrument's own scales and a negative relationship with the caregiver's age. Finally, depending on the paediatric patient's diagnosis, differences in stress levels were found.

PMID: 30048532 [PubMed - in process]

Sonographic pancreas echogenicity in cystic fibrosis compared to exocrine pancreatic function and pancreas fat content at Dixon-MRI.

PLoS One. 2018;13(7):e0201019

Authors: Engjom T, Kavaliauskiene G, Tjora E, Erchinger F, Wathle G, Lærum BN, Njølstad PR, Frøkjær JB, Gilja OH, Dimcevski G, Haldorsen IS

Abstract
OBJECTIVE: Fatty infiltration of the pancreas is a dominating feature in cystic fibrosis (CF). We evaluate the association between pancreatic fat content assessed by Dixon magnetic resonance imaging (MRI), pancreatic echogenicity at ultrasonography (US) and exocrine function in CF patients and healthy controls (HC).
MATERIAL AND METHODS: Transabdominal US, pancreatic Dixon-MRI and diffusion-weighted imaging (DWI) were performed in 21 CF patients and 15 HCs. Exocrine function was assessed by endoscopic secretin test and fecal elastase.
RESULTS: CF patients were grouped according to exocrine pancreatic function as subjects with normal (CFS: n = 11) or reduced (CFI: n = 10) function. Among CFI 90% (9/10) had visual hyperechogenicity. CFI also had increased echo-level values (p<0.05 vs others). All CFI (10/10) had markedly increased pancreatic fat content estimated by MRI compared to sufficient groups, p<0.001). Among CFS patients and HC, 27% (3/11) and 33% (5/15), respectively, had hyperechoic pancreas. However, all these had low pancreatic fat-content at MRI compared to CFI. In CFI, pancreatic fat content was correlated to ADC (r = -0.93, p<0.001).
CONCLUSION: Pancreas insufficient CF patients exhibit severe pancreatic fatty-infiltration at MRI and hyperechoic pancreas at US. Pancreas hyperechogenicity in pancreatic sufficient subjects does not co-exist with fatty infiltration at MRI. MRI evaluates pancreatic fatty infiltration more accurately than US and fat infiltration estimated by MRI outperforms sonographic hyper-echogenicity as a marker for exocrine pancreatic failure in CF.

PMID: 30048483 [PubMed - in process]

Difference between SF6 and N2 Multiple Breath Washout kinetics is due to N2 back diffusion and error in N2 offset.

J Appl Physiol (1985). 2018 Jul 26;:

Authors: Guglani L, Kasi A, Starks M, Pedersen KE, Nielsen JG, Weiner DJ

Abstract
BACKGROUND: Measurement of Lung Clearance Index (LCI) by Multiple Breath Washout (MBW) is a sensitive method for monitoring of lung disease in Cystic Fibrosis (CF). To compare N2MBW and SF6MBW, we connected these two gas analysis systems in series to obtain truly simultaneous measurements, with no differences other than the gas used.
METHODS: Non-smoking healthy controls (HC) and subjects with CF were recruited at two institutions. The Exhalyzer-D (for N2MBW measurement) was connected in series with the Innocor (for SF6MBW measurement). Subjects washed in SF6 from a Douglas bag with tidal breathing, and washed out SF6 and nitrogen with 100% oxygen provided as bias flow. Washout of both gases was continued past the LCI point (1/40th of equilibration concentration) in triplicate.
RESULTS: N2MBW resulted in higher Cumulative Exhaled Volume (CEV), Functional Residual Capacity (FRC), and LCI when compared to SF6 derived parameters in HC subjects (p&lt;0.0001 for all comparisons). All N2MBW parameters were also significantly higher than SF6MBW parameters in CF subjects (p&lt;0.01 for all comparisons). After recalculation with a common FRC, N2MBW-LCI was higher than SF6MBW-LCI in CF subjects (19.73 vs. 11.39; p&lt;0.0001) and in HC (8.12 vs. 6.78; p&lt;0.0001). Adjusting for N2 back diffusion and an offset error in the nitrogen measurement resulted in near complete agreement between the two methodologies.
CONCLUSION: We found significant differences in LCI and FRC measurements using two different gases for MBW. This may have significant implications for the future use and interpretation of LCI data in clinical trials and routine clinical care.

PMID: 30048204 [PubMed - as supplied by publisher]

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SLC26A3 inhibitor identified in small molecule screen blocks colonic fluid absorption and reduces constipation.

JCI Insight. 2018 Jul 26;3(14):

Authors: Haggie PM, Cil O, Lee S, Tan JA, Rivera AA, Phuan PW, Verkman AS

Abstract
SLC26A3 (downregulated in adenoma; DRA) is a Cl-/anion exchanger expressed in the luminal membrane of intestinal epithelial cells, where it facilitates electroneutral NaCl absorption. SLC26A3 loss of function in humans or mice causes chloride-losing diarrhea. Here, we identified slc26a3 inhibitors in a screen of 50,000 synthetic small molecules done in Fischer rat thyroid (FRT) cells coexpressing slc26a3 and a genetically encoded halide sensor. Structure-activity relationship studies were done on the most potent inhibitor classes identified in the screen: 4,8-dimethylcoumarins and acetamide-thioimidazoles. The dimethylcoumarin DRAinh-A250 fully and reversibly inhibited slc26a3-mediated Cl- exchange with HCO3-, I-, and thiocyanate (SCN-), with an IC50 of ~0.2 μM. DRAinh-A250 did not inhibit the homologous anion exchangers slc26a4 (pendrin) or slc26a6 (PAT-1), nor did it alter activity of other related proteins or intestinal ion channels. In mice, intraluminal DRAinh-A250 blocked fluid absorption in closed colonic loops but not in jejunal loops, while the NHE3 (SLC9A3) inhibitor tenapanor blocked absorption only in the jejunum. Oral DRAinh-A250 and tenapanor comparably reduced signs of constipation in loperamide-treated mice, with additive effects found on coadministration. DRAinh-A250 was also effective in loperamide-treated cystic fibrosis mice. These studies support a major role of slc26a3 in colonic fluid absorption and suggest the therapeutic utility of SLC26A3 inhibition in constipation.

PMID: 30046015 [PubMed - as supplied by publisher]

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Residual function of cystic fibrosis mutants predicts response to small molecule CFTR modulators.

JCI Insight. 2018 Jul 25;3(14):

Authors: Han ST, Rab A, Pellicore MJ, Davis EF, McCague AF, Evans TA, Joynt AT, Lu Z, Cai Z, Raraigh KS, Hong JS, Sheppard DN, Sorscher EJ, Cutting GR

Abstract
Treatment of individuals with cystic fibrosis (CF) has been transformed by small molecule therapies that target select pathogenic variants in the CF transmembrane conductance regulator (CFTR). To expand treatment eligibility, we stably expressed 43 rare missense CFTR variants associated with moderate CF from a single site in the genome of human CF bronchial epithelial (CFBE41o-) cells. The magnitude of drug response was highly correlated with residual CFTR function for the potentiator ivacaftor, the corrector lumacaftor, and ivacaftor-lumacaftor combination therapy. Response of a second set of 16 variants expressed stably in Fischer rat thyroid (FRT) cells showed nearly identical correlations. Subsets of variants were identified that demonstrated statistically significantly higher responses to specific treatments. Furthermore, nearly all variants studied in CFBE cells (40 of 43) and FRT cells (13 of 16) demonstrated greater response to ivacaftor-lumacaftor combination therapy than either modulator alone. Together, these variants represent 87% of individuals in the CFTR2 database with at least 1 missense variant. Thus, our results indicate that most individuals with CF carrying missense variants are (a) likely to respond modestly to currently available modulator therapy, while a small fraction will have pronounced responses, and (b) likely to derive the greatest benefit from combination therapy.

PMID: 30046002 [PubMed - as supplied by publisher]

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Using exome sequencing to decipher family history in a healthy individual: Comparison of pathogenic and population MTM1 variants.

Mol Genet Genomic Med. 2018 Jul 25;:

Authors: Penon M, Zahed H, Berger V, Su I, Shieh JT

Abstract
BACKGROUND: When a family encounters the loss of a child early in life, extensive genetic testing of the affected neonate is sometimes not performed or not possible. However, the increasing availability of genomic sequencing may allow for direct application to families in cases where there is a condition inherited from parental gene(s). When neonatal testing is not possible, it is feasible to perform family testing as long as there is optimal interpretation of the genomic information. Here, we present an example of a healthy adult woman with a history of recurrent male neonatal losses due to severe respiratory distress who presented to Medical Genetics for evaluation. A family history of additional male neonatal loss was present, suggesting a potential inherited genetic etiology.
METHODS: Although there was no DNA available from the neonates, by performing exome sequencing on the healthy adult woman, we found a missense variant in MTM1 as a potential candidate, which was deemed pathogenic based on multiple criteria including past report.
RESULTS: By performing an analysis of all known MTM1-disease associated mutations and control population variation, we can also better infer the effects of missense variations on MTM1, as not all variants are truncating. MTM1-X-linked myotubular myopathy is a condition that leads to male perinatal respiratory failure and a high risk for early mortality.
CONCLUSIONS: The application of genetic testing in the healthy population here highlights the broader utility of genomic sequencing in evaluating unexplained recurrent neonatal loss, especially when genetic testing is not available on the affected neonates.

PMID: 30047259 [PubMed - as supplied by publisher]

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Novel and Recurring Disease-Causing NF1 Variants in Two Chinese Families with Neurofibromatosis Type 1.

J Mol Neurosci. 2018 Jul 25;:

Authors: Xiao H, Yuan L, Xu H, Yang Z, Huang F, Song Z, Yang Y, Zeng C, Deng H

Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder primarily characterized by multiple café-au-lait macules, peripheral neurofibromas, skinfold freckling, and Lisch nodules. The causative genetic factor is the neurofibromin 1 gene (NF1), which encodes a Ras GTPase-activating protein called neurofibromin. NF1 variants may lead to loss of neurofibromin function and activation of downstream cell growth. This study aims to discover the disease-causing variants responsible for NF1 in two Han Chinese families by using exome sequencing combined with Sanger sequencing. A recurrent missense variant c.269T>C (p.Leu90Pro) and a novel nonsense variant c.2993dupA (p.Tyr998*) in the NF1 gene were identified. These variants co-segregated with the disorder in the pedigrees and were absent in the normal controls. The results broaden the NF1 mutation spectrum responsible for NF1. This may be helpful in genetic counseling, clinical management, and gene-targeted therapies for NF1.

PMID: 30046999 [PubMed - as supplied by publisher]

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Identification of likely pathogenic and known variants in TSPEAR, LAMB3, BCOR, and WNT10A in four Turkish families with tooth agenesis.

Hum Genet. 2018 Jul 26;:

Authors: Du R, Dinckan N, Song X, Coban-Akdemir Z, Jhangiani SN, Guven Y, Aktoren O, Kayserili H, Petty LE, Muzny DM, Below JE, Boerwinkle E, Wu N, Gibbs RA, Posey JE, Lupski JR, Letra A, Uyguner ZO

Abstract
Tooth agenesis (TA), the failure of development of one or more permanent teeth, is a common craniofacial abnormality observed in different world populations. The genetic etiology of TA is heterogeneous; more than a dozen genes have been associated with isolated or nonsyndromic TA, and more than 80 genes with syndromic forms. In this study, we applied whole exome sequencing (WES) to identify candidate genes contributing to TA in four Turkish families. Likely pathogenic variants with a low allele frequency in the general population were identified in four disease-associated genes, including two distinct variants in TSPEAR, associated with syndromic and isolated TA in one family each; a variant in LAMB3 associated with syndromic TA in one family; and a variant in BCOR plus a disease-associated WNT10A variant in one family with syndromic TA. With the notable exception of WNT10A (Tooth agenesis, selective, 4, MIM #150400), the genotype-phenotype relationships described in the present cohort represent an expansion of the clinical spectrum associated with these genes: TSPEAR (Deafness, autosomal recessive 98, MIM #614861), LAMB3 (Amelogenesis imperfecta, type IA, MIM #104530; Epidermolysis bullosa, junctional, MIMs #226700 and #226650), and BCOR (Microphthalmia, syndromic 2, MIM #300166). We provide evidence supporting the candidacy of these genes with TA, and propose TSPEAR as a novel nonsyndromic TA gene. Our data also suggest potential multilocus genomic variation, or mutational burden, in a single family, involving the BCOR and WNT10A loci, underscoring the complexity of the genotype-phenotype relationship in the common complex trait of TA.

PMID: 30046887 [PubMed - as supplied by publisher]

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Subclonal evolution in disease progression from MGUS/SMM to multiple myeloma is characterised by clonal stability.

Leukemia. 2018 Jul 25;:

Authors: Dutta AK, Fink JL, Grady JP, Morgan GJ, Mullighan CG, To LB, Hewett DR, Zannettino ACW

Abstract
Multiple myeloma (MM) is a largely incurable haematological malignancy defined by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow. Clonal heterogeneity has recently been established as a feature in MM, however, the subclonal evolution associated with disease progression has not been described. Here, we performed whole-exome sequencing of serial samples from 10 patients, providing new insights into the progression from monoclonal gammopathy of undetermined significance (MGUS) and smouldering MM (SMM), to symptomatic MM. We confirm that intraclonal genetic heterogeneity is a common feature at diagnosis and that the driving events involved in disease progression are more subtle than previously reported. We reveal that MM evolution is mainly characterised by the phenomenon of clonal stability, where the transformed subclonal PC populations identified at MM are already present in the asymptomatic MGUS/SMM stages. Our findings highlight the possibility that PC extrinsic factors may play a role in subclonal evolution and MGUS/SMM to MM progression.

PMID: 30046162 [PubMed - as supplied by publisher]

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Novel ALPK3 mutation in a Tunisian patient with pediatric cardiomyopathy and facio-thoraco-skeletal features.

J Hum Genet. 2018 Jul 25;:

Authors: Jaouadi H, Kraoua L, Chaker L, Atkinson A, Delague V, Levy N, Benkhalifa R, Mrad R, Abdelhak S, Zaffran S

Abstract
Pediatric cardiomyopathy is a complex disease with clinical and genetic heterogeneity. Recently, the ALPK3 gene was described as a new hereditary cardiomyopathy gene underlying pediatric cardiomyopathies. Only eight patients carrying mutations in ALPK3 have been reported to date. Here, we report a 3-year-old male patient with both hypertrophic and dilated cardiomyopathy. The patient presented dysmorphic features and skeletal deformities of hands and feet, pectus excavatum, and cleft palate. The genetic investigation was performed by whole-exome sequencing in the patient and his parents. We identified a novel homozygous mutation in ALPK3 (c.1531_1532delAA; p.Lys511Argfs*12). Our work extends the phenotypic spectrum of the ALPK3-associated cardiomyopathy by reporting additional clinical features. This is the first study of a Tunisian patient with mutation in the ALPK3 gene. In conclusion, ALPK3 should be included in the list of genes to be considered in genetic studies for patients affected with pediatric syndromic cardiomyopathy.

PMID: 30046096 [PubMed - as supplied by publisher]

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The Experience of Management of High-Alert Medications.

Am J Med Qual. 2017 Sep/Oct;32(5):571

Authors: Peng TR, Wu TW

PMID: 28862027 [PubMed - indexed for MEDLINE]

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Gingival bleeding, a possible "serious" adverse drug reaction: An observational study in the French PharmacoVigilance Database.

J Clin Periodontol. 2017 Sep;44(9):898-904

Authors: Bondon-Guitton E, Mourgues T, Rousseau V, Cousty S, Cottin J, Drablier G, Micallef J, Montastruc JL

Abstract
INTRODUCTION: Antithrombotic drugs are known to increase the risk of gingival bleeding because they affect coagulation. However, other drugs could also be involved in gingival bleeding.
AIM: We performed a pharmacoepidemiological study to identify the drugs most frequently "suspected" in the occurrence of gingival bleeding.
MATERIAL AND METHODS: We selected reports of "gingival bleeding" from 1 January 1985 to 30 September 2014 in the French PharmacoVigilance Database.
RESULTS: Among 523,808 reports of adverse drug reactions, we identified 454 reports of gingival bleeding (0.09%). Most of them were "serious" (58.4%) and occurred in females (54.6%). The frequency of gingival bleeding increased with age. The most frequently "suspected" drugs were antithrombotics (67.8%), particularly fluindione. Other drugs frequently involved were furosemide followed by paracetamol, amiodarone, amoxicillin, paroxetine, ketoprofen, zolpidem, enalapril and ramipril. Thirty-nine reports involved a drug-drug interaction with antithrombotics, mainly with anti-infectives.
CONCLUSION: Gingival bleeding can be an adverse drug reaction, often "serious" and rarely fatal. Patients older than 50 years and women are particularly at risk. Among drugs known to increase the risk of gingival bleeding, the most frequently involved were fluindione, furosemide, paracetamol, amiodarone, amoxicillin, paroxetine or ketoprofen. We also identified signal for drugs not usually known to be involved in bleeding, like zolpidem, enalapril or ramipril.

PMID: 28667742 [PubMed - indexed for MEDLINE]

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Advances in hypersensitivity drug reactions.

Curr Opin Allergy Clin Immunol. 2016 08;16(4):297-9

Authors: Blanca M, Thong BY

PMID: 27327122 [PubMed - indexed for MEDLINE]

Funding Opportunity RFA-HD-19-008 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to invite applications to support a national program of mentored advanced career development and training in research for junior faculty in pediatric critical care medicine and pediatric trauma surgery. Such a program is necessary to fuel the pipeline of well trained young investigators and advance research in these two clinically demanding fields.

Notice NOT-HS-18-012 from the NIH Guide for Grants and Contracts

Notice NOT-HD-18-015 from the NIH Guide for Grants and Contracts

Notice NOT-OD-18-214 from the NIH Guide for Grants and Contracts

Notice NOT-CA-18-090 from the NIH Guide for Grants and Contracts

Notice NOT-OD-18-213 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-18-879 from the NIH Guide for Grants and Contracts. The purpose of this FOA is to support extramural investigator-initiated clinical research in collaboration and partnership with intramural investigators at the NIH Clinical Center in Bethesda, MD. This new FOA will leverage the resources (inpatient and outpatient) and assets of the NIH Clinical Center (e.g., scientific, clinical trial and expertise, nursing, beds, critical care services, ambulatory care services, laboratories, imaging, biostatistics, protocol development, regulatory guidance, clinical trials management and safety oversight) in accelerating the discovery and translation from lab to clinic of therapies for allergy, asthma, autoimmune disease and transplantation. Extramural scientists proposing research within NIAIDs priorities has the opportunity to utilize this unique resources of the Clinical Center (for a description of resources, see https://clinicalcenter.nih.gov/translational-research-resources/resources.html). This FOA will specifically support hypothesis-driven mechanistic studies alone or within clinical projects employing small Phase 0, 1, and/or 2a clinical trial designs.