Elementary, My Dear Watson! The Accumulating Evidence for the Lung Clearance Index in Monitoring Early Cystic Fibrosis Lung Disease.

Am J Respir Crit Care Med. 2017 May 01;195(9):1131-1132

Authors: Pittman J, Rosenfeld M

PMID: 28459345 [PubMed - in process]

AJRCCM: 100-Year Anniversary. Progress along the Pathway of Discovery Leading to Treatment and Cure of Cystic Fibrosis.

Am J Respir Crit Care Med. 2017 May 01;195(9):1092-1099

Authors: Ramsey BW, Welsh MJ

PMID: 28459323 [PubMed - in process]

Innate immunity and chronic rhinosinusitis: What we have learned from animal models.

Laryngoscope Investig Otolaryngol. 2016 Jun;1(3):49-56

Authors: London NR, Lane AP

Abstract
OBJECTIVE: Chronic rhinosinusitis (CRS) is a heterogeneous and multifactorial disease characterized by dysregulated inflammation. Abnormalities in innate immune function including sinonasal epithelial cell barrier function, mucociliary clearance, response to pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs), and the contribution of innate immune cells will be highlighted in this review.
DATA SOURCES: PubMed literature review.
REVIEW METHODS: A review of the literature was conducted to determine what we have learned from animal models in relation to innate immunity and chronic rhinosinusitis.
RESULTS: Dysregulation of innate immune mechanisms including sinonasal barrier function, mucociliary clearance, PAMPs, and innate immune cells such as eosinophils, mast cells, and innate lymphoid cells may contribute to CRS pathogenesis. Sinonasal inflammation has been studied using mouse, rat, rabbit, pig, and sheep explant or in vivo models. Study using these models has allowed for analysis of experimental therapeutics and furthered our understanding of the aforementioned aspects of the innate immune mechanism as it relates to sinonasal inflammation. These include augmenting mucociliary clearance through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) and study of drug toxicity on ciliary beat frequency. Knockout models of Toll-like receptors (TLR) have demonstrated the critical role these PRRs play in allergic inflammation as loss of TLR2 and TLR4 leads to decreased lower airway inflammation. Mast cell deficient mice are less susceptible to ovalbumin-induced sinonasal inflammation.
CONCLUSION: Animal models have shed light as to the potential contribution of dysregulated innate immunity in chronic sinonasal inflammation.

PMID: 28459101 [PubMed - in process]

In vitro Multi-Species Biofilms of Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa and Their Host Interaction during In vivo Colonization of an Otitis Media Rat Model.

Front Cell Infect Microbiol. 2017;7:125

Authors: Yadav MK, Chae SW, Go YY, Im GJ, Song JJ

Abstract
Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA) are known to cause biofilm-related infections. MRSA and PA have been frequently isolated from chronically infected wounds, cystic fibrosis, chronic suppurative otitis media (CSOM), and from indwelling medical devices, and these bacteria co-exist; however, their interaction with each-other or with the host is not well known. In this study, we investigated MRSA and PA multi-species biofilm communities in vitro and their interaction with the host during in vivo colonization using an OM rat-model. In-vitro biofilm formation and in-vivo colonization were studied using CV-microtiter plate assay and OM rat-model respectively. The biofilms were viewed under scanning electron microscope and bacteria were enumerated using cfu counts. The differential gene expressions of rat mucosa colonized with single or multi-species of MRSA or PA were studied using RNA-sequencing of total transcriptome. In multi-species in-vitro biofilms PA partially inhibited SA growth. However, no significant inhibition of MRSA was detected during in-vivo colonization of multi-species in rat bullae. A total of 1,797 genes were significantly (p < 0.05) differentially expressed in MRSA or PA or MRSA + PA colonized rat middle ear mucosa with respect to the control. The poly-microbial colonization of MRSA and PA induced the differential expression of a significant number of genes that are involved in immune response, inflammation, signaling, development, and defense; these were not expressed with single species colonization by either MRSA or PA. Genes involved in defense, immune response, inflammatory response, and developmental process were exclusively up-regulated, and genes that are involved in nervous system signaling, development and transmission, regulation of cell growth and development, anatomical and system development, and cell differentiation were down-regulated after multi-species inoculation. These results indicate that poly-microbial colonization induces a host response that is different from that induced by single species infection.

PMID: 28459043 [PubMed - in process]

Inflammatory Responses Regulating Alveolar Ion Transport during Pulmonary Infections.

Front Immunol. 2017;8:446

Authors: Peteranderl C, Sznajder JI, Herold S, Lecuona E

Abstract
The respiratory epithelium is lined by a tightly balanced fluid layer that allows normal O2 and CO2 exchange and maintains surface tension and host defense. To maintain alveolar fluid homeostasis, both the integrity of the alveolar-capillary barrier and the expression of epithelial ion channels and pumps are necessary to establish a vectorial ion gradient. However, during pulmonary infection, auto- and/or paracrine-acting mediators induce pathophysiological changes of the alveolar-capillary barrier, altered expression of epithelial Na,K-ATPase and of epithelial ion channels including epithelial sodium channel and cystic fibrosis membrane conductance regulator, leading to the accumulation of edema and impaired alveolar fluid clearance. These mediators include classical pro-inflammatory cytokines such as TGF-β, TNF-α, interferons, or IL-1β that are released upon bacterial challenge with Streptococcus pneumoniae, Klebsiella pneumoniae, or Mycoplasma pneumoniae as well as in viral infection with influenza A virus, pathogenic coronaviruses, or respiratory syncytial virus. Moreover, the pro-apoptotic mediator TNF-related apoptosis-inducing ligand, extracellular nucleotides, or reactive oxygen species impair epithelial ion channel expression and function. Interestingly, during bacterial infection, alterations of ion transport function may serve as an additional feedback loop on the respiratory inflammatory profile, further aggravating disease progression. These changes lead to edema formation and impair edema clearance which results in suboptimal gas exchange causing hypoxemia and hypercapnia. Recent preclinical studies suggest that modulation of the alveolar-capillary fluid homeostasis could represent novel therapeutic approaches to improve outcomes in infection-induced lung injury.

PMID: 28458673 [PubMed - in process]

Standardized Treatment of Pulmonary exacerbations (STOP) study: Physician treatment practices and outcomes for individuals with cystic fibrosis with pulmonary exacerbations.

J Cyst Fibros. 2017 Apr 27;:

Authors: West NE, Beckett VV, Jain R, Sanders DB, Nick JA, Heltshe SL, Dasenbrook EC, VanDevanter DR, Solomon GM, Goss CH, Flume PA, STOP investigators

Abstract
BACKGROUND: Pulmonary exacerbations (PEx) are associated with increased morbidity and mortality in individuals with CF. PEx management practices vary widely, and optimization through interventional trials could potentially improve outcomes. The object of this analysis was to evaluate current physician treatment practices and patient outcomes for PEx.
METHODS: The Standardized Treatment of Pulmonary exacerbations (STOP) observational study enrolled 220 participants ≥12years old admitted to the hospital for PEx at 11 U.S. CF centers. Spirometry and daily symptom scores were collected during the study. Physicians were surveyed on treatment goals and their management practices were observed. Treatment outcomes were compared to stated goals.
RESULTS: The mean (SD) duration of IV antibiotic treatment was 15.9 (6.0) days. Those individuals with more severe lung disease (<50% FEV1) were treated nearly two days longer than those with >50% FEV1. Physician-reported FEV1 improvement goals were 10% (95% CI: 5%, 14%) lower for patients with 6-month baseline FEV1 ≤50% predicted compared with those with 6-month baseline FEV1 >50% predicted. There were clinically and statistically significant improvements in symptoms from the start of IV antibiotic treatment to the end of IV antibiotic treatment and 28days after the start of treatment. The mean absolute increase in FEV1 from admission was 9% predicted at end of IV antibiotic treatment, and 7% predicted at day 28. Only 39% fully recovered lost lung function, and only 65% recovered at least 90% of lost lung function. Treatment was deemed successful by 84% of clinicians, although 6-month baseline FEV1 was only recovered in 39% of PEx.
CONCLUSIONS: In this prospective observational study of PEx, treatment regimens and durations showed substantial variation. A significant proportion of patients did not reach physician's treatment goals, yet treatment was deemed successful.

PMID: 28457954 [PubMed - as supplied by publisher]

In vitro activity of a novel compound, mul-1867, against clinically significant fungi candida spp. and aspergillus spp.

Int J Antimicrob Agents. 2017 Apr 27;:

Authors: Tetz G, Cynamon M, Hendricks G, Vikina D, Tetz V

Abstract
There is an urgent need for new antifungal compounds to treat various types of fungal infections, including pulmonary infections. This study was designed to investigate the potency of a novel compound (Mul-1867) against Candida spp. and Aspergillus spp. isolated from patients with fungal pneumonia, cystic fibrosis and chronic obstructive pulmonary disease. Mul-1867 was highly effective against susceptible control strains as well as resistant clinical isolates, with minimum fungicidal concentrations (MFCs) varying from 0.06 µg/mL to 0.5 µg/mL. It was also highly effective against pre-formed 48-h-old biofilms formed by yeasts and moulds. The half-minimal biofilm eradication concentration (MBEC50) was equal to the MFC. The minimum biofilm eradication concentration to eliminate 90% of biofilms (MBEC90) varied from 1× to 4× MFC. Scanning electron microscopy revealed morphological changes accompanied by the release of intracellular material from the fungal cells following exposure to Mul-1867. Furthermore, an increased concentration of nucleic acids was found in the medium after 5 min and 20 min of Mul-1867 treatment, indicating leakage of cytoplasmic contents. Overall, these data indicate that Mul-1867 may be a promising inhaled antifungal agent for the treatment and prevention of fungal respiratory infections.

PMID: 28457835 [PubMed - as supplied by publisher]

Lung Transplantation From Donors After Previous Cardiac Surgery: Ideal Graft in Marginal Donor?

Transplant Proc. 2017 May;49(4):686-691

Authors: Palleschi A, Mendogni P, Tosi D, Montoli M, Carrinola R, Mariolo AV, Briganti F, Nosotti M

Abstract
Lung transplantation is a limited by donor pool shortage. Despite the efforts to extend the graft acceptability with recurrent donor criteria reformulations, previous cardiothoracic surgery is still considered a contraindication. A donor who underwent cardiac surgery could potentially provide an ideal lung but high intraoperative risks and intrinsic technical challenges are expected during the graft harvesting. The purpose of this study is to present our dedicated protocol and four clinical cases of successful lung procurements from donors who had a previous major cardiac surgery. One donor had ascending aortic root (AAR) substitution, another had mitral valve substitution, and two had coronary artery bypass surgery. The others' eligibility criteria for organ allocation, such as ABO compatibility, PaO2/FiO2 ratio, absence of aspiration, or sepsis were respected. In one of the cases with previous coronary bypass grafting, the donor had a veno-arterial extracorporeal membrane oxygenation support. Consequently, the grafts required an ex vivo lung perfusion evaluation. We report the technical details of procurement and postoperative courses of recipients. All procurements were uneventful, without lung damage or waste of abdominal organs related to catastrophic intraoperative events. All recipients had a successful clinical outcome. We believe that successful transplantation is achievable even in a complicated setting, such as cases involving donors with previous cardiac surgery frequently are. Facing lung donor shortage, we strongly support any effort to avoid the loss of possible acceptable lungs. In particular, previous major cardiac surgery does not strictly imply a poor quality of lungs as well as unsustainable graft procurement.

PMID: 28457372 [PubMed - in process]

Lobar Lung Transplantation From Deceased Donor: Monocentric Experience.

Transplant Proc. 2017 May;49(4):682-685

Authors: Mendogni P, Palleschi A, Tosi D, Righi I, Montoli M, Damarco F, Morlacchi LC, Santambrogio L, Nosotti M, Rosso L

Abstract
INTRODUCTION: Lung transplantation is considered a therapeutic option in selected patients affected by end-stage pulmonary disease. The mortality on the waiting list is mainly attributed to the shortage of the donor pool available for transplantation. There are various strategies to overcome this shortage; one of them is lobar transplantation.
METHODS: The aim of the current study was to analyze the outcome of lobar lung transplantation from deceased donors in our Lung Transplant Center. Overall survival, perioperative mortality and morbidity, problem on bronchial anastomosis, and chronic rejection were prospectively recorded in a 5-year time-frame.
RESULTS: From November 2010 to October 2015, we performed 100 lung transplantations; 6 of which (6%) were lobar transplantations from deceased donors. Three recipients were on an emergency list due to preoperative extracorporeal support. The causes of lobectomy leading to lobar transplantation were: size mismatch (3), iatrogenic vascular damage (2), and chronic atelectasis (1). One patient died 5 months after surgery for sepsis; and 5 patients were alive at the study end (median follow-up: 17.5 months). Prevalence of grade 3 primary graft dysfunction at 72 hours was 50%. One patient developed bronchial stenosis. No cases of chronic rejection were recorded.
CONCLUSIONS: Lobar transplantation can be considered a valid tool to overcome the donor pool shortage in selected cases; such a technique has proved particularly useful in critically ill patients who were scheduled in an emergency transplant program.

PMID: 28457371 [PubMed - in process]

IFT81 as a Candidate Gene for Nonsyndromic Retinal Degeneration.

Invest Ophthalmol Vis Sci. 2017 May 01;58(5):2483-2490

Authors: Dharmat R, Liu W, Ge Z, Sun Z, Yang L, Li Y, Wang K, Thomas K, Sui R, Chen R

Abstract
Purpose: IFT81, a core component of the IFT-B complex, involved in the bidirectional transport of ciliary proteins, has been recently implicated in syndromic ciliopathies. However, none of the IFT-B core complex proteins have been associated with nonsyndromic retinal dystrophies. Given the importance of ciliary transport in photoreceptor function and structural maintenance, we sought to investigate the impact of IFT (intraflagellar transport) mutations in nonsyndromic retinopathies.
Methods: Whole exome sequencing was performed on 50 cone-rod dystrophy (CRD) patients that were previously screened for mutations in known retinal disease genes. The impact of candidate mutation was studied using in vitro cell system and in vivo zebrafish assay to determine the pathogenicity of the variant.
Results: Compound heterozygous mutations in IFT81, including one nonsense (c.1213C>T, p.R405*) and one missense variant (c.1841T>C, p.L614P), were identified in a nonsyndromic CRD proband. Extensive functional analyses of the missense variant in cell culture and zebrafish strongly suggests its pathogenic nature. Loss of IFT81 impairs ciliogenesis and, interestingly, the missense variant displayed significantly reduced rescue of ciliogenesis in the IFT81 knockdown in vitro system. Consistently, dramatic reduction of rescue efficiency of the ift81 mutant zebrafish embryo by mRNA with the missense variant was observed, further supporting its pathogenicity.
Conclusions: Consistent with the function of the IFT-B complex in the maintenance of photoreceptor cilium, we report a case of mutations in a core IFT-B protein, IFT81. This represents the first report of mutations in IFT81 as a candidate gene for nonsyndromic retinal dystrophy, hence expanding the phenotype spectrum of IFT-B components.

PMID: 28460050 [PubMed - in process]

Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia.

Brain. 2017 Apr 27;:

Authors: Minnerop M, Kurzwelly D, Wagner H, Soehn AS, Reichbauer J, Tao F, Rattay TW, Peitz M, Rehbach K, Giorgetti A, Pyle A, Thiele H, Altmüller J, Timmann D, Karaca I, Lennarz M, Baets J, Hengel H, Synofzik M, Atasu B, Feely S, Kennerson M, Stendel C, Lindig T, Gonzalez MA, Stirnberg R, Sturm M, Roeske S, Jung J, Bauer P, Lohmann E, Herms S, Heilmann-Heimbach S, Nicholson G, Mahanjah M, Sharkia R, Carloni P, Brüstle O, Klopstock T, Mathews KD, Shy ME, de Jonghe P, Chinnery PF, Horvath R, Kohlhase J, Schmitt I, Wolf M, Greschus S, Amunts K, Maier W, Schöls L, Nürnberg P, Zuchner S, Klockgether T, Ramirez A, Schüle R

Abstract
Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10-4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.

PMID: 28459997 [PubMed - as supplied by publisher]

Novel candidate genes may be possible predisposing factors revealed by whole exome sequencing in familial esophageal squamous cell carcinoma.

Tumour Biol. 2017 May;39(5):1010428317699115

Authors: Forouzanfar N, Baranova A, Milanizadeh S, Heravi-Moussavi A, Jebelli A, Abbaszadegan MR

Abstract
Esophageal squamous cell carcinoma is one of the deadliest of all the cancers. Its metastatic properties portend poor prognosis and high rate of recurrence. A more advanced method to identify new molecular biomarkers predicting disease prognosis can be whole exome sequencing. Here, we report the most effective genetic variants of the Notch signaling pathway in esophageal squamous cell carcinoma susceptibility by whole exome sequencing. We analyzed nine probands in unrelated familial esophageal squamous cell carcinoma pedigrees to identify candidate genes. Genomic DNA was extracted and whole exome sequencing performed to generate information about genetic variants in the coding regions. Bioinformatics software applications were utilized to exploit statistical algorithms to demonstrate protein structure and variants conservation. Polymorphic regions were excluded by false-positive investigations. Gene-gene interactions were analyzed for Notch signaling pathway candidates. We identified novel and damaging variants of the Notch signaling pathway through extensive pathway-oriented filtering and functional predictions, which led to the study of 27 candidate novel mutations in all nine patients. Detection of the trinucleotide repeat containing 6B gene mutation (a slice site alteration) in five of the nine probands, but not in any of the healthy samples, suggested that it may be a susceptibility factor for familial esophageal squamous cell carcinoma. Noticeably, 8 of 27 novel candidate gene mutations (e.g. epidermal growth factor, signal transducer and activator of transcription 3, MET) act in a cascade leading to cell survival and proliferation. Our results suggest that the trinucleotide repeat containing 6B mutation may be a candidate predisposing gene in esophageal squamous cell carcinoma. In addition, some of the Notch signaling pathway genetic mutations may act as key contributors to esophageal squamous cell carcinoma.

PMID: 28459198 [PubMed - in process]

The end of a dogma: the safety of doxycycline use in young children for malaria treatment.

Malar J. 2017 Apr 13;16(1):148

Authors: Gaillard T, Briolant S, Madamet M, Pradines B

Abstract
Anti-malarial drug resistance to chloroquine and sulfadoxine-pyrimethamine has spread from Southeast Asia to Africa. Furthermore, the recent emergence of resistance to artemisinin-based combination therapy (ACT) in Southeast Asia highlights the need to identify new anti-malarial drugs. Doxycycline is recommended for malaria chemoprophylaxis for travel in endemic areas, or in combination with the use of quinine for malaria treatment when ACT is unavailable or when the treatment of severe malaria with artesunate fails. However, doxycycline is not used in young children under 8 years of age due to its contraindication due to the risk of yellow tooth discolouration and dental enamel hypoplasia. Doxycycline was developed after tetracycline and was labelled with the same side-effects as the earlier tetracyclines. However, recent studies report little or no effects of doxycycline on tooth staining or dental enamel hypoplasia in children under 8 years of age. In the United States, the Centers for Disease Control and Prevention have recommended the use of doxycycline for the treatment of acute and chronic Q fever and tick-borne rickettsial diseases in young children. It is time to rehabilitate doxycycline and to recommend it for malaria treatment in children under 8 years of age.

PMID: 28407772 [PubMed - indexed for MEDLINE]

Association Between Readmission After Liver Transplant and Adverse Immunosuppressant Reactions: A Prospective Cohort With a 1-Year Follow-up.

Transplant Proc. 2017 Mar;49(2):330-337

Authors: Haddad L, Andrade K, Mendes L, Ducatti L, D'Albuquerque LA, Andraus W

Abstract
OBJECTIVE: To measure the association between readmission after liver transplantation and corresponding adverse drug reactions.
METHODS: A total of 48 patients undergoing liver transplantation were prospectively followed for 1 year. Of these, 23 were readmitted and evaluated by a pharmacist for causes of adverse drug reaction. The detection of adverse drug reactions was based on a combination of clinical interviews and physical and laboratory exams. Adverse reactions were defined in accordance with the Naranjo algorithm.
RESULTS: A total of 67.6% of all readmissions were related to adverse drug reactions, with tacrolimus accounting for 80% of the drug reactions. The most common cause of readmission was infection (48.6%), followed by procedure-related reasons (29.7%). Of all patients requiring admission, 39.1% had Model for End-stage Liver Disease (MELD) scores below 21 at the time of transplantation, 17.4% had MELD scores between 21 and 29, and 43.5% had MELD scores above 29. Most (66.7%) of those readmitted more than twice had MELD scores above 29.
CONCLUSION: Adverse drug reactions related to immunosuppressants frequently lead to readmission among liver transplant patients, and in our series tacrolimus was the most frequently associated drug.

PMID: 28219594 [PubMed - indexed for MEDLINE]

Adverse drug reactions of botulinum neurotoxin type A in children with cerebral palsy: a pharmaco-epidemiological study in VigiBase.

Dev Med Child Neurol. 2017 Mar;59(3):329-334

Authors: Montastruc J, Marque P, Moulis F, Bourg V, Lambert V, Durrieu G, Montastruc JL, Montastruc F

Abstract
AIM: The aim of this study was to assess the risk of adverse drug reactions (ADRs) with botulinum neurotoxin type A (BoNT-A) in children with cerebral palsy (CP) using the World Health Organization global individual case safety report (ICSR) database, VigiBase.
METHOD: We extracted all children ICSRs for ADRs with BoNT-A used as anti-spastic drug in CP recorded between 1995 and 2015 in VigiBase. We also performed a case/non-case method (disproportionality analysis) to assess the link between exposure to BoNT-A and each ADR of interest in children and adults, calculating reporting odds ratios (RORs).
RESULTS: In VigiBase, 162 ICSRs were registered. They involved mainly males (n=95, 59%) and mean (SD) age was 7 years 11 months (4y 4mo). The most frequent ADR was dysphagia (27 ICSRs, 17%) followed by asthenia and muscular weakness (25 ICSRs each, 16%). Nineteen ICSRs (12%) were lethal. There was a significant association between BoNT-A and death in children (ROR=11.1 95%, confidence interval [CI] 7.0-17.7) but not in adults.
INTERPRETATION: In children with CP, most ADRs seem to be linked to a systemic spread of BoNT-A. Our study suggests a higher risk of ADRs with BoNT-A in children than in adults.

PMID: 27682175 [PubMed - indexed for MEDLINE]

mRECIST response combined with sorafenib-related adverse events is superior to either criterion alone in predicting survival in HCC patients treated with TACE plus sorafenib.

Int J Cancer. 2017 Jan 15;140(2):390-399

Authors: Wang W, Bai W, Wang E, Zhao Y, Liu L, Yang M, Cai H, Xia D, Zhang L, Niu J, Yin Z, Zhang Z, Fan D, Xia J, Han G

Abstract
The mRECIST and dermatologic adverse events (AEs) can be used to assess the patient response to transarterial chemoembolization (TACE) and/or sorafenib for hepatocellular carcinoma (HCC). Here, we aimed to combine the two criteria to stratify the prognosis in patients with unresectable HCC receiving TACE plus sorafenib (TACE-S). In total, 176 consecutive HCC patients treated with TACE-S were enrolled. CT scans and laboratory tests were conducted pretreatment (at baseline, 5-7 days before the TACE-S) and post-treatment (at 1, 2 and 3 months). The radiological response was assessed according to mRECIST. Sorafenib-related AEs were recorded every 2 weeks after oral administration, and patients with dermatologic AEs of Grade 2 or more were defined as dermatologic responders. The earliest time at which mRECIST and dermatologic responses correlated with survival was 2 months after therapy. The mRECIST-dermatologic AE combination assessment stratified patients into three different prognoses; responders on both assessments exhibited the longest median overall survival (OS), followed by responders on one assessment and non-responders on both assessments (30.5, 17.4 and 8.3 months, respectively; p < 0.001). Achieving the highest C-index, the mRECIST-dermatologic AE combination showed better performance in predicting survival than either mRECIST or dermatologic AEs alone. Furthermore, the mRECIST-dermatologic AE combination remained a significant predictor of OS, even when the patients were stratified according to the BCLC stage, ECOG score or alpha-fetoprotein (AFP) value. This study showed that the combination of mRECIST response and dermatologic AEs is superior to either criterion used alone for predicting the survival of HCC patients treated with TACE-S.

PMID: 27681592 [PubMed - indexed for MEDLINE]

Patterns of Prescription Drug Use Before and After Fragility Fracture.

JAMA Intern Med. 2016 Oct 01;176(10):1531-1538

Authors: Munson JC, Bynum JP, Bell JE, Cantu R, McDonough C, Wang Q, Tosteson TD, Tosteson AN

Abstract
Importance: Patients who have a fragility fracture are at high risk for subsequent fractures. Prescription drugs represent 1 factor that could be modified to reduce the risk of subsequent fracture.
Objective: To describe the use of prescription drugs associated with fracture risk before and after fragility fracture.
Design, Setting, and Participants: Retrospective cohort study conducted between February 2015 and March 2016 using a 40% random sample of Medicare beneficiaries from 2007 through 2011 in general communities throughout the United States. A total of 168 133 community-dwelling Medicare beneficiaries who survived a fracture of the hip, shoulder, or wrist were included. Cohort members were required to be enrolled in fee-for-service Medicare with drug coverage (Parts A, B, and D) and to be community dwelling for at least 30 days in the immediate 4-month postfracture period.
Exposures: Prescription drug use during the 4-month period before and after a fragility fracture.
Main Outcomes and Measures: Prescription fills for drug classes associated with increased fracture risk were measured using Part D retail pharmacy claims. These were divided into 3 categories: drugs that increase fall risk; drugs that decrease bone density; and drugs with unclear fracture risk mechanism. Drugs that increase bone density were also tracked.
Results: A total of 168 133 patients with a fragility fracture (141 569 women; 84.2%) met the inclusion criteria for this study; 91.8% were white. Across all fracture types, the mean (SD) age was 80.0 (7.7) years, and 53.2% of the fracture cohort was hospitalized at the time of the index fracture, although this varied significantly depending on fracture type (100% of hip fractures, 8.2% of wrist fractures, and 15.0% of shoulder fractures). The frequency of discharge to an institution for rehabilitation following hospitalization also varied by fracture type, but the mean (SD) duration of acute rehabilitation did not: 28.1 (19.8) days. Most patients were exposed to at least 1 nonopiate drug associated with increased fracture risk in the 4 months before fracture (77.1% of hip, 74.1% of wrist, and 75.9% of shoulder fractures). Approximately 7% of these patients discontinued this drug exposure after the fracture, but this was offset by new users after fracture. Consequently, the proportion of the cohort exposed following fracture was unchanged (80.5%, 74.3%, and 76.9% for hip, wrist, and shoulder, respectively). There was no change in the average number of fracture-associated drugs used. This same pattern of use before and after fracture was observed across all 3 drug mechanism categories. Use of drugs to strengthen bone density was uncommon (≤25%) both before and after fracture.
Conclusions and Relevance: Exposure to prescription drugs associated with fracture risk is infrequently reduced following fragility fracture occurrence. While some patients eliminate their exposure to drugs associated with fracture, an equal number initiate new high-risk drugs. This pattern suggests there is a missed opportunity to modify at least one factor contributing to secondary fractures.

PMID: 27548843 [PubMed - indexed for MEDLINE]

Primary Care Requirements for Pharmacists-Clinical Reasoning Education at Schools of Pharmaceutical Sciences.

Yakugaku Zasshi. 2016;136(7):939-44

Authors: Ashizawa T

Abstract
For appropriate primary care practice corresponding to the various symptoms of a patient, team medicine on that combines the expertise of physicians and other medical staff has been recommended in recent years. It results in (1) higher quality of medical care, (2) lower burden on the physician, (3) better medical safety, and (4) reduced medical expenses. In order to promote team medicine through inter-professional collaboration, the responsibilities of the medical staff need to be reviewed to expand their respective roles. The Ministry of Health, Labour and Welfare designated nine specific medical acts by pharmacists in 2010. Some acts require clinical reasoning (medical interview and physical assessment) in order to manage side effects in patients undergoing drug therapy. The new curriculum introduced in 2015 includes primary care education for pharmacists who see patients before they are seen by a physician. Because such patients are usually seen by the pharmacist on a walk-in basis, medical interview and inspection education is especially important in this situation. However, there is incongruity in the physical assessment education of prospective pharmacists among schools of pharmaceutical sciences in recent years, which tends to focus primarily on vital signs. Moreover, there is currently no consensus among physicians on the optimum range of procedures performed by a pharmacist before the patient is seen by a physician. In this presentation, the practice of primary care by pharmacists is discussed from the following perspectives: (1) target symptoms and patients, (2) clinical reasoning education at pharmaceutical schools, and (3) future issues.

PMID: 27374954 [PubMed - indexed for MEDLINE]

Influence of inhaled corticosteroids on pubertal growth and final height in asthmatic children.

Pediatr Allergy Immunol. 2016 08;27(5):499-506

Authors: De Leonibus C, Attanasi M, Roze Z, Martin B, Marcovecchio ML, Di Pillo S, Chiarelli F, Mohn A

Abstract
BACKGROUND: Controversial data exist on the possibility that inhaled corticosteroids (ICs) affect growth in children with mild-to-moderate asthma. We assessed whether ICs affect growth and final height (FH) in asthmatic children compared to controls.
METHODS: A retrospective study was conducted on 113 asthmatic children compared with 66 control children. Asthmatic children presented with mild-to-moderate asthma and had exclusive ICs. Anthropometric data of four specific time-points were collected for both groups (pre-puberty, onset and late puberty, and FH) and converted to standard deviation scores (SDS). Growth trajectories were assessed as follows: (i) in puberty, using peak height velocity (PHV) and pubertal height gain SDS (PHG-SDS); (ii) until FH achievement, using FH-SDS and FH gain SDS (FHG-SDS). Repeated measurement analysis was performed across longitudinal study visits. A general linear model (GLM) was performed in asthmatic group evaluating the effect of corticosteroid type, treatment duration, and cumulative dose on FH corrected for multiple variables.
RESULTS: At pre-puberty, height and weight SDS were similar between the groups (p > 0.05). Height SDS progressively declined over the study period in asthmatic patients from pre-puberty to FH (p-trend < 0.05), whereas it did not change over time in controls (p-trend > 0.05), in both boys and girls. Asthmatic children had exclusive ICs [budesonide (n = 36) vs. fluticasone (n = 43) vs. mometasone (n = 34)] for a mean period of 6.25 ± 1.20 years and a mean cumulative dose of 560.07 ± 76.02 mg. They showed decreased PHG-SDS and lower PHV compared to controls (all p < 0.05). FH-SDS and FHG-SDS were significantly reduced in asthmatic group compared to controls. FH in asthmatic patients was 2.5 ± 2.89 cm lower in boys and 2.0 ± 2.03 cm lower in girls than controls. The GLM showed that FH achievement was dependent on the type of ICs, duration of the treatment, and cumulative dose (p < 0.05).
CONCLUSIONS: ICs affect pubertal growth determining reduced final height in asthmatic children compared to controls, in a dose- and duration-dependent manner.

PMID: 26919136 [PubMed - indexed for MEDLINE]

The prospective IQ-CSRC trial: A prototype early clinical proarrhythmia assessment investigation for replacing the ICH E14 thorough QTc (TQT) study.

J Pharmacol Toxicol Methods. 2016 Jul-Aug;80:1-8

Authors: Cavero I, Holzgrefe H, Clements M

Abstract
INTRODUCTION: Early clinical Phase I ECG investigations designed to replace the currently applied thorough QT (TQT) study are reviewed to examine how they could complement and verify the conclusions of nonclinical investigations and, in particular, the Comprehensive in vitro Proarrhythmia Assay (CiPA).
TOPICS: The IQ-CSRC trial is a prospective ascending multiple-dose first in human (FIH) type investigation performed as a possible replacement for the thorough QT study (TQT). Designed in accordance with the results of a simulation study by the FDA QT Interdisciplinary Review Team (IRT), it succeeded in correctly categorizing 5/5 established QTc-prolonging agents free of notable heart rate effects (dofetilide, dolasetron, moxifloxacin, ondansetron, and quinine) and the QTc-negative drug, levocetirizine.
DISCUSSION: The positive results obtained with the IQ-CSRC study require additional confirmation with threshold QTc-positive and negative drugs and established QTc prolongers producing both increases and decreases in heart rate. In the future, similar studies should also adopt and validate innovative proarrhythmic metrics, in addition to, or instead of, the traditional proarrhythmic surrogate of QTc, to assess the proarrhythmic safety of candidate drugs.

PMID: 26903171 [PubMed - indexed for MEDLINE]