Allergic bronchopulmonary aspergillosis presenting as nephrotic syndrome due to secondary amyloidosis: Case report and systematic review of the literature.

Lung India. 2018 Jul-Aug;35(4):332-335

Authors: Muthu V, Sehgal IS, Dhooria S, Bal A, Agarwal R

Abstract
Allergic bronchopulmonary aspergillosis (ABPA) is a complex inflammatory lung disorder complicating bronchial asthma and cystic fibrosis. Although the condition responds to treatment with glucocorticoids and antifungal drugs, lack of timely recognition, and inadequate treatment of ABPA can lead to progressive lung damage. Uncommonly, long standing inflammation and bronchiectasis can also lead to the development of secondary amyloidosis. Herein, we report a case of ABPA, which presented as nephrotic syndrome and progressed rapidly to end-stage renal disease.

PMID: 29970774 [PubMed]

Specific autophagy and ESCRT components participate in the unconventional secretion of CFTR.

Autophagy. 2018 Jul 04;:

Authors: Noh SH, Gee HY, Kim Y, Piao H, Kim J, Kang CM, Lee G, Mook-Jung I, Lee Y, Cho JW, Lee MG

Abstract
The most common mutation in cystic fibrosis patients is a phenylalanine deletion at position 508 (ΔF508) in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. This mutation impairs cell-surface trafficking of CFTR. During cellular stress, core-glycosylated CFTRΔF508 is transported to the cell surface from the endoplasmic reticulum (ER) via an unconventional route that bypasses the Golgi. However, the mechanisms for this unconventional secretory pathway of CFTR are not well delineated. Here, we report that components of the macroautophagy/autophagy and ESCRT (endosomal sorting complex required for transport) pathways are involved in unconventional secretion of CFTR. In mammalian cells, we found that autophagic pathways were modulated by conditions that also stimulate unconventional secretion, namely ER stress and an ER-to-Golgi transport blockade. Additionally, we found that knockdown of early autophagy components, ATG5 and ATG7, and treatment with pharmacological autophagy inhibitors, wortmannin and 3-methyladenine, abolished the unconventional secretion of CFTR that had been stimulated by ER stress and an ER-to-Golgi blockade. Interestingly, immunoelectron microscopy revealed that GORASP2/GRASP55, which mediates unconventional CFTR trafficking, is present in multivesicular bodies (MVB) and autophagosomal structures under ER stress conditions. A custom small-interfering RNA screen of mammalian ESCRT proteins that mediate MVB biogenesis showed that silencing of some ESCRTs, including MVB12B, inhibited unconventional CFTRΔF508 secretion. Furthermore, MVB12B overexpression partially rescued cell-surface expression and Cl- channel function of CFTRΔF508. Taken together, these results suggest that components involved in early autophagosome formation and the ESCRT/MVB pathway play a key role in the stress-induced unconventional secretion of CFTR.

PMID: 29969945 [PubMed - as supplied by publisher]

Alzheimer's Disease and Frontotemporal Dementia: The Current State of Genetics and Genetic Testing Since the Advent of Next-Generation Sequencing.

Mol Diagn Ther. 2018 Jul 03;:

Authors: Goldman JS, Van Deerlin VM

Abstract
The advent of next-generation sequencing has changed genetic diagnostics, allowing clinicians to test concurrently for phenotypically overlapping conditions such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). However, to interpret genetic results, clinicians require an understanding of the benefits and limitations of different genetic technologies, such as the inability to detect large repeat expansions in such diseases as C9orf72-associated FTD and amyotrophic lateral sclerosis. Other types of mutations such as large deletions or duplications and triple repeat expansions may also go undetected. Additionally, the concurrent testing of multiple genes or the whole exome increases the likelihood of discovering variants of unknown significance. Our goal here is to review the current knowledge about the genetics of AD and FTD and suggest up-to-date guidelines for genetic testing for these dementias. Despite the improvements in diagnosis due to biomarkers testing, AD and FTD can have overlapping symptoms. When used appropriately, genetic testing can elucidate the diagnosis and specific etiology of the disease, as well as provide information for the family and determine eligibility for clinical trials. Prior to ordering genetic testing, clinicians must determine the appropriate genes to test, the types of mutations that occur in these genes, and the best type of genetic test to use. Without this analysis, interpretation of genetic results will be difficult. Patients should be counseled about the benefits and limitations of different types of genetic tests so they can make an informed decision about testing.

PMID: 29971646 [PubMed - as supplied by publisher]

Association of APOL1 With Heart Failure With Preserved Ejection Fraction in Postmenopausal African American Women.

JAMA Cardiol. 2018 Jul 03;:

Authors: Franceschini N, Kopp JB, Barac A, Martin LW, Li Y, Qian H, Reiner AP, Pollak M, Wallace RB, Rosamond WD, Winkler CA

Abstract
Importance: APOL1 genotypes are associated with kidney diseases in African American individuals and may influence cardiovascular disease and mortality risk, but findings have been inconsistent.
Objective: To discern whether high-risk APOL1 genotypes are associated with cardiovascular disease and stroke in postmenopausal African American women, who are at high risk for these outcomes.
Design, Setting, and Participants: The Women's Health Initiative is a prospective cohort that enrolled 161 838 postmenopausal women into clinical trials and an observational study between 1993 and 1998. This study includes 11 137 African American women participants who had a clinical event from enrollment to June 2014. Data analyses were completed from January 2017 to August 2017.
Exposures: The variants of APOL1 were genotyped or imputed from whole-exome sequencing.
Main Outcomes and Measures: Incident coronary heart disease, stroke and heart failure subtypes, and overall and cause-specific mortality were adjudicated from hospital records and death certificates. Estimated incidence rates were determined for each outcome and hazard ratios (HR) and 95% CIs for the associations of APOL1 groups with outcomes.
Results: The mean (SD) age of participants was 61.7 (7.1) years. Carriers of high-risk APOL1 variants (n = 1370; 12.3%) had higher prevalence of hypertension, use of cholesterol-lowering medications, and reduced estimated glomerular filtration rate (eGFR). After a mean (SD) of 11.0 (3.6) years, carriers of high-risk APOL1 variants had a higher incidence rate of hospitalized heart failure with preserved ejection fraction (HFpEF) than low-risk carriers did but showed no differences for other outcomes. In adjusted models, there was a significant 58% increased hazard of hospitalized HFpEF (HR, 1.58 [95% CI, 1.03-2.41]) among carriers of high-risk APOL1 variants compared with carriers of low-risk APOL1 variants. The association with HFpEF was attenuated (HR = 1.50 [95% CI, 0.98-2.30]) and no longer significant when adjusting for baseline eGFR.
Conclusions and Relevance: Status as a carrier of a high-risk APOL1 genotype was associated with HFpEF hospitalization among postmenopausal women, which is partly accounted for by baseline kidney function. These findings do not support an association of high-risk APOL1 genotypes with coronary heart disease, stroke, or mortality in postmenopausal African American women.

PMID: 29971324 [PubMed - as supplied by publisher]

Whole-exome sequencing identifies novel pathogenic mutations and putative phenotype-influencing variants in Polish limb-girdle muscular dystrophy patients.

Hum Genomics. 2018 Jul 03;12(1):34

Authors: Fichna JP, Macias A, Piechota M, Korostyński M, Potulska-Chromik A, Redowicz MJ, Zekanowski C

Abstract
BACKGROUND: Limb girdle muscular dystrophies (LGMD) are a group of heterogeneous hereditary myopathies with similar clinical symptoms. Disease onset and progression are highly variable, with an elusive genetic background, and around 50% cases lacking molecular diagnosis.
METHODS: Whole exome sequencing (WES) was performed in 73 patients with clinically diagnosed LGMD. A filtering strategy aimed at identification of variants related to the disease included integrative analysis of WES data and human phenotype ontology (HPO) terms, analysis of genes expressed in muscle, analysis of the disease-associated interactome and copy number variants analysis.
RESULTS: Genetic diagnosis was possible in 68.5% of cases. On average, 36.3 rare variants in genes associated with various muscle diseases per patient were found that could relate to the clinical phenotype. The putative causative mutations were mostly in LGMD-associated genes, but also in genes not included in the current LGMD classification (DMD, COL6A2, and COL6A3). In three patients, mutations in two genes were suggested as the joint cause of the disease (CAPN3+MYH7, COL6A3+CACNA1S, DYSF+MYH7). Moreover, a variety of phenotype-influencing variants were postulated, including in patients with an identified already known primary pathogenic mutation.
CONCLUSIONS: We hypothesize that LGMD could be better described as oligogenic disorders in which dominant clinical presentation can result from the combined effect of mutations in a set of genes. In this view, the inter- and intrafamilial variability could reflect a specific genetic background and the presence of sets of phenotype-influencing or co-causative mutations in genes that either interact with the known LGMD-associated genes or are a part of the same pathways or structures.

PMID: 29970176 [PubMed - in process]

Whole-exome sequencing identifies R1279X of MYH6 gene to be associated with congenital heart disease.

BMC Cardiovasc Disord. 2018 Jul 03;18(1):137

Authors: Razmara E, Garshasbi M

Abstract
BACKGROUND: Myosin VI, encoded by MYH6, is expressed dominantly in human cardiac atria and plays consequential roles in cardiac muscle contraction and comprising the cardiac muscle thick filament. It has been reported that the mutations in the MYH6 gene associated with sinus venosus atrial septal defect (ASD type III), hypertrophic (HCM) and dilated (DCM) cardiomyopathies.
METHODS: Two patients in an Iranian family have been identified who affected to Congenital Heart Disease (CHD). The male patient, besides CHD, shows that the thyroglossal sinus, refractive errors of the eye and mitral stenosis. The first symptoms emerged at the birth and diagnosis based on clinical features was made at about 5 years. The family had a history of ASD. For recognizing mutated gene (s), whole exome sequencing (WES) was performed for the male patient and variants were analyzed by autosomal dominant inheritance mode.
RESULTS: Eventually, by several filtering processes, a mutation in MYH6 gene (NM_002471.3), c.3835C > T; R1279X, was identified as the most likely disease-susceptibility variant and then confirmed by Sanger sequencing in the family. The mutation frequency was checked out in the local databases. This mutation results in the elimination of the 660 amino acids in the C-terminal of Myosin VI protein, including the vital parts of the coiled-coil structure of the tail domain.
CONCLUSIONS: Our study represents the first case of Sinus venosus defect caused directly by MYH6 stop codon mutation. Our data indicate that by increase haploinsufficiency of myosin VI, c.3835C > T mutation with reduced penetrance could be associated with CHD.

PMID: 29969989 [PubMed - in process]

Multiple inputs ensure yeast cell size homeostasis during cell cycle progression.

Elife. 2018 Jul 04;7:

Authors: Garmendia-Torres C, Tassy O, Matifas A, Molina N, Charvin G

Abstract
Coordination of cell growth with division is essential for proper cell function. In budding yeast, although some molecular mechanisms responsible for cell size control during G1 have been elucidated, the mechanism by which cell size homeostasis is established remains to be discovered. Here, we developed a new technique based on quantification of histone levels to monitor cell cycle progression in individual cells with unprecedented accuracy. Our analysis establishes the existence of a mechanism controlling bud size in G2/M that prevents premature onset of anaphase, and controls the overall size variability. While most G1 mutants do not display impaired size homeostasis, mutants in which Cyclin B-Cdk regulation is altered display large size variability. Our study thus demonstrates that size homeostasis is not controlled by a G1-specific mechanism alone but is likely to be an emergent property resulting from the integration of several mechanisms that coordinate cell and bud growth with division.

PMID: 29972352 [PubMed - as supplied by publisher]

Actionable Metabolic Pathways in Heart Failure and Cancer-Lessons From Cancer Cell Metabolism.

Front Cardiovasc Med. 2018;5:71

Authors: Karlstaedt A, Schiffer W, Taegtmeyer H

Abstract
Recent advances in cancer cell metabolism provide unprecedented opportunities for a new understanding of heart metabolism and may offer new approaches for the treatment of heart failure. Key questions driving the cancer field to understand how tumor cells reprogram metabolism and to benefit tumorigenesis are also applicable to the heart. Recent experimental and conceptual advances in cancer cell metabolism provide the cardiovascular field with the unique opportunity to target metabolism. This review compares cancer cell metabolism and cardiac metabolism with an emphasis on strategies of cellular adaptation, and how to exploit metabolic changes for therapeutic benefit.

PMID: 29971237 [PubMed]

Integrated Multi-Omic Analysis of Mycobacterium tuberculosis H37Ra Redefines Virulence Attributes.

Front Microbiol. 2018;9:1314

Authors: Pinto SM, Verma R, Advani J, Chatterjee O, Patil AH, Kapoor S, Subbannayya Y, Raja R, Gandotra S, Prasad TSK

Abstract
H37Ra is a virulence attenuated strain of Mycobacterium tuberculosis widely employed as a model to investigate virulence mechanisms. Comparative high-throughput studies have earlier correlated its avirulence to the presence of specific mutations or absence of certain proteins. However, a recent sequencing study of H37Ra, has disproved several genomic differences earlier reported to be associated with virulence. This warrants further investigations on the H37Ra proteome as well. In this study, we carried out an integrated analysis of the genome, transcriptome, and proteome of H37Ra. In addition to confirming single nucleotide variations (SNVs) and insertion-deletions that were reported earlier, our study provides novel insights into the mutation spectrum in the promoter regions of 7 genes. We also provide transcriptional and proteomic evidence for 3,900 genes representing ~80% of the total predicted gene count including 408 proteins that have not been identified previously. We identified 9 genes whose coding potential was hitherto reported to be absent in H37Ra. These include 2 putative virulence factors belonging to ESAT-6 like family of proteins. Furthermore, proteogenomic analysis enabled us to identify 63 novel proteins coding genes and correct 25 existing gene models in H37Ra genome. A majority of these were found to be conserved in the virulent strain H37Rv as well as in other mycobacterial species suggesting that the differences in the virulent and avirulent strains of M. tuberculosis are not entirely dependent on the expression of certain proteins or their absence but may possibly be ascertained to functional changes.

PMID: 29971057 [PubMed]

The CoLoMoTo Interactive Notebook: Accessible and Reproducible Computational Analyses for Qualitative Biological Networks.

Front Physiol. 2018;9:680

Authors: Naldi A, Hernandez C, Levy N, Stoll G, Monteiro PT, Chaouiya C, Helikar T, Zinovyev A, Calzone L, Cohen-Boulakia S, Thieffry D, Paulevé L

Abstract
Analysing models of biological networks typically relies on workflows in which different software tools with sensitive parameters are chained together, many times with additional manual steps. The accessibility and reproducibility of such workflows is challenging, as publications often overlook analysis details, and because some of these tools may be difficult to install, and/or have a steep learning curve. The CoLoMoTo Interactive Notebook provides a unified environment to edit, execute, share, and reproduce analyses of qualitative models of biological networks. This framework combines the power of different technologies to ensure repeatability and to reduce users' learning curve of these technologies. The framework is distributed as a Docker image with the tools ready to be run without any installation step besides Docker, and is available on Linux, macOS, and Microsoft Windows. The embedded computational workflows are edited with a Jupyter web interface, enabling the inclusion of textual annotations, along with the explicit code to execute, as well as the visualization of the results. The resulting notebook files can then be shared and re-executed in the same environment. To date, the CoLoMoTo Interactive Notebook provides access to the software tools GINsim, BioLQM, Pint, MaBoSS, and Cell Collective, for the modeling and analysis of Boolean and multi-valued networks. More tools will be included in the future. We developed a Python interface for each of these tools to offer a seamless integration in the Jupyter web interface and ease the chaining of complementary analyses.

PMID: 29971009 [PubMed]

Logical Modeling and Analysis of Cellular Regulatory Networks With GINsim 3.0.

Front Physiol. 2018;9:646

Authors: Naldi A, Hernandez C, Abou-Jaoudé W, Monteiro PT, Chaouiya C, Thieffry D

Abstract
The logical formalism is well adapted to model large cellular networks, in particular when detailed kinetic data are scarce. This tutorial focuses on this well-established qualitative framework. Relying on GINsim (release 3.0), a software implementing this formalism, we guide the reader step by step toward the definition, the analysis and the simulation of a four-node model of the mammalian p53-Mdm2 network.

PMID: 29971008 [PubMed]

A system-wide approach to monitor responses to synergistic BRAF and EGFR inhibition in colorectal cancer cells.

Mol Cell Proteomics. 2018 Jul 03;:

Authors: Ressa A, Bosdriesz E, de Ligt J, Mainardi S, Maddalo G, Prahallad A, Jager M, de la Fonteijne L, Fitzpatrick M, Groten S, Altelaar AFM, Bernards R, Cuppen E, Wessels L, Heck AJR

Abstract
Intrinsic and/or acquired resistance represents one of the great challenges in targeted cancer therapy. A deeper understanding of the molecular biology of cancer has resulted in more efficient strategies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has also been observed in colorectal cancer patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block intrinsic resistance to BRAF inhibitors. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant colorectal cancer cells as a model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both known and novel responses. We primarily observe widespread upregulation of receptor tyrosine kinases and metabolic pathways upon BRAF inhibition. These findings point to mechanisms by which the drug-treated cells switch energy sources and enter a quiescent-like state as a defensive response, while additionally compensating for the MAPK pathway inhibition.

PMID: 29970458 [PubMed - as supplied by publisher]

Short linear motifs in intrinsically disordered regions modulate HOG signaling capacity.

BMC Syst Biol. 2018 Jul 03;12(1):75

Authors: Strome B, Hsu IS, Li Cheong Man M, Zarin T, Nguyen Ba A, Moses AM

Abstract
BACKGROUND: The effort to characterize intrinsically disordered regions of signaling proteins is rapidly expanding. An important class of disordered interaction modules are ubiquitous and functionally diverse elements known as short linear motifs (SLiMs).
RESULTS: To further examine the role of SLiMs in signal transduction, we used a previously devised bioinformatics method to predict evolutionarily conserved SLiMs within a well-characterized pathway in S. cerevisiae. Using a single cell, reporter-based flow cytometry assay in conjunction with a fluorescent reporter driven by a pathway-specific promoter, we quantitatively assessed pathway output via systematic deletions of individual motifs. We found that, when deleted, 34% (10/29) of predicted SLiMs displayed a significant decrease in pathway output, providing evidence that these motifs play a role in signal transduction. Assuming that mutations in SLiMs have quantitative effects on mechanisms of signaling, we show that perturbations of parameters in a previously published stochastic model of HOG signaling could reproduce the quantitative effects of 4 out of 7 mutations in previously unknown SLiMs.
CONCLUSIONS: Our study suggests that, even in well-characterized pathways, large numbers of functional elements remain undiscovered, and that challenges remain for application of systems biology models to interpret the effects of mutations in signaling pathways.

PMID: 29970070 [PubMed - in process]

Specific autophagy and ESCRT components participate in the unconventional secretion of CFTR.

Autophagy. 2018 Jul 04;:

Authors: Noh SH, Gee HY, Kim Y, Piao H, Kim J, Kang CM, Lee G, Mook-Jung I, Lee Y, Cho JW, Lee MG

Abstract
The most common mutation in cystic fibrosis patients is a phenylalanine deletion at position 508 (ΔF508) in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. This mutation impairs cell-surface trafficking of CFTR. During cellular stress, core-glycosylated CFTRΔF508 is transported to the cell surface from the endoplasmic reticulum (ER) via an unconventional route that bypasses the Golgi. However, the mechanisms for this unconventional secretory pathway of CFTR are not well delineated. Here, we report that components of the macroautophagy/autophagy and ESCRT (endosomal sorting complex required for transport) pathways are involved in unconventional secretion of CFTR. In mammalian cells, we found that autophagic pathways were modulated by conditions that also stimulate unconventional secretion, namely ER stress and an ER-to-Golgi transport blockade. Additionally, we found that knockdown of early autophagy components, ATG5 and ATG7, and treatment with pharmacological autophagy inhibitors, wortmannin and 3-methyladenine, abolished the unconventional secretion of CFTR that had been stimulated by ER stress and an ER-to-Golgi blockade. Interestingly, immunoelectron microscopy revealed that GORASP2/GRASP55, which mediates unconventional CFTR trafficking, is present in multivesicular bodies (MVB) and autophagosomal structures under ER stress conditions. A custom small-interfering RNA screen of mammalian ESCRT proteins that mediate MVB biogenesis showed that silencing of some ESCRTs, including MVB12B, inhibited unconventional CFTRΔF508 secretion. Furthermore, MVB12B overexpression partially rescued cell-surface expression and Cl- channel function of CFTRΔF508. Taken together, these results suggest that components involved in early autophagosome formation and the ESCRT/MVB pathway play a key role in the stress-induced unconventional secretion of CFTR.

PMID: 29969945 [PubMed - as supplied by publisher]

PTENα Regulates Mitophagy and Maintains Mitochondrial Quality Control.

Autophagy. 2018 Jul 04;:

Authors: Yin Y, Li G, Yang J, Yang C, Zhu M, Jin Y, McNutt MA

Abstract
PTEN plays an important role in tumor suppression, and PTEN family members are involved in multiple biological processes in various subcellular locations. Here we report that PTENαααthe first identified PTEN isoform, αregulates mitophagy through promotion of PARK2 recruitment to damaged mitochondria. We show that PTENα-deficient mice exhibit accumulation of cardiac mitochondria with structural and functional abnormalities, and PTENα-deficient mouse hearts are more susceptible to injury induced by isoprenaline and ischemia-reperfusion. Mitochondrial clearance by mitophagy is also impaired in PTENα-deficient cardiomyocytes. In addition, we found PTENα physically interacts with the E3 ubiquitin ligase PRKN, which is an important mediator of mitophagy. PTENααbinds PRKN through the membrane binding helix in its N terminus, and promotes PRKN mitochondrial translocation through enhancing PRKN self-association in a phosphatase-independent manner. Loss of PTENααcompromises mitochondrial translocation of PRKN and resultant mitophagy following mitochondrial depolarization. We propose that PTENααfunctions as a mitochondrial quality controller that maintains mitochondrial function and cardiac homeostasis.

PMID: 29969932 [PubMed - as supplied by publisher]

Comparative genomic analysis of two emergent human adenovirus type 14 respiratory pathogen isolates in China reveals similar yet divergent genomes.

Emerg Microbes Infect. 2017 Nov 01;6(11):e92

Authors: Zhang Q, Jing S, Cheng Z, Yu Z, Dehghan S, Shamsaddini A, Yan Y, Li M, Seto D

Abstract
Human adenovirus type 14 (HAdV-B14p) was originally identified as an acute respiratory disease (ARD) pathogen in The Netherlands in 1955. For approximately fifty years, few sporadic infections were observed. In 2005, HAdV-B14p1, a genomic variant, re-emerged and was associated with several large ARD outbreaks across the U.S. and, subsequently, in Canada, the U.K., Ireland, and China. This strain was associated with an unusually higher fatality rate than previously reported for both this prototype and other HAdV types in general. In China, HAdV-B14 was first observed in 2010, when two unrelated HAdV-B14-associated ARD cases were reported in Southern China (GZ01) and Northern China (BJ430), followed by three subsequent outbreaks. While comparative genomic analysis, including indel analysis, shows that the three China isolates, with whole genome data available, are similar to the de Wit prototype, all are divergent from the U.S. strain (303600; 2007). Although the genomes of strains GZ01 and BJ430 are nearly identical, as per their genome type characterization and percent identities, they are subtly divergent in their genome mutation patterns. These genomes indicate possibly two lineages of HAdV-B14 and independent introductions into China from abroad, or subsequent divergence from one; CHN2012 likely represents a separate sub-lineage. Observations of these simultaneously reported emergent strains in China add to the understanding of the circulation, epidemiology, and evolution of these HAdV pathogens, as well as provide a foundation for developing effective vaccines and public health strategies, including nationwide surveillance in anticipation of larger outbreaks with potentially higher fatality rates associated with HAdV-B14p1.

PMID: 29089589 [PubMed - indexed for MEDLINE]

Autoimmune Hepatitis in the Elderly: Diagnosis and Pharmacologic Management.

Drugs Aging. 2018 Jul 04;:

Authors: Rizvi S, Gawrieh S

Abstract
Autoimmune hepatitis (AIH) may present as acute or chronic hepatitis in the elderly. Advanced hepatic fibrosis and cirrhosis are common on first presentation in this population. In this review, we discuss the presentation, approach to diagnosis and management of AIH in the elderly. As polypharmacy is common in the elderly, careful medication use history is essential for detecting drug-induced AIH-like hepatitis. Steroid-sparing or minimizing therapeutic regimens are preferred to treat AIH in the elderly. For the purpose of induction, budesonide or lower dose prednisone in combination with azathioprine (AZA) regimens are preferred over high-dose prednisone monotherapy due to the higher risk of side effects of the later in the elderly. The goal of maintenance therapy should be to achieve full biochemical and histologic remission. Bone density monitoring and interventions to prevent steroid-related bone disease should be implemented throughout the course of the disease. Liver transplantation should be considered in the elderly patient with liver failure or early hepatocellular carcinoma if there are no significant comorbidities or compromise in functional status.

PMID: 29971609 [PubMed - as supplied by publisher]

Safety and immune response after two-dose meningococcal C conjugate immunization in HIV-infected children and adolescents in Rio de Janeiro, Brazil.

Vaccine. 2017 12 15;35(50):7042-7048

Authors: Frota ACC, Ferreira B, Harrison LH, Pereira GS, Pereira-Manfro W, Machado ES, de Oliveira RH, Abreu TF, Milagres LG, Hofer CB

Abstract
We aimed to evaluate immunogenicity and adverse events (AEs) after a booster dose of Meningococcal C conjugated (MCC) vaccine in HIV-infected children and adolescents, who had a previous low seroconversion rate after priming with MCC, at a reference HIV-care center in Rio de Janeiro.
METHODS: 2-18 years old HIV-infected subjects with CD4+ T-lymphocyte cell (CD4) ≥15%, without active infection or antibiotic use, were enrolled to receive 2 doses of conjugated meningococcal C oligosaccharide-CRM197 12-18 months apart. All patients were evaluated before and 1-2 months after immunization for seroprotection [defined as human serum bactericidal activity (hSBA) titer ≥1:4]. AEs were assessed at 20 min, 3 and 7 days after each dose. Factors independently associated with seroprotection were studied.
RESULTS: 156 subjects were enrolled and 137 received a booster MCC dose. 55% were female, and median age was 12 years. Eight-nine percent were receiving combined antiretroviral therapy (cART) at the booster visit (median duration of 7.7 years), 59.9% had undetectable viral load (VL) at baseline, and 56.2% at the booster visit. Seroprotection was achieved in 78.8% (108/137) subjects, with a significantly higher GMT than after the priming dose (p < 0.01). Mild AEs were experienced after a second MCC dose (38%). In logistic regression, undetectable viral load at entry [odds ratio (OR) = 7.1, 95% confidence interval (95%CI): 2.14-23.37], and probably higher CD4 percent at the booster immunization visit (OR): 1.1, 95%CI: 1.01-1.17 were associated with seroprotection after a booster dose of MCC.
CONCLUSION: A booster dose of MCC was safe and induced high seroprotection rate even 12-18 months after priming. MCC should be administered after maximum virologic suppression has been achieved. These results support the recommendation of 2-dose of MCC for primary immunization in HIV-infected children and adolescents with restored immune function.

PMID: 29100708 [PubMed - indexed for MEDLINE]

A multi-site feasibility study to assess fever and wheezing in children after influenza vaccines using text messaging.

Vaccine. 2017 12 15;35(50):6941-6948

Authors: Stockwell MS, Marchant CD, Wodi AP, Barnett ED, Broder KR, Jakob K, Lewis P, Kattan M, Rezendes AM, Barrett A, Sharma D, Fernandez N, LaRussa P

Abstract
BACKGROUND: Using text messaging for vaccine safety monitoring, particularly for non-medically attended events, would be valuable for pandemic influenza and emergency vaccination program preparedness. We assessed the feasibility and acceptability of text messaging to evaluate fever and wheezing post-influenza vaccination in a prospective, observational, multi-site pediatric study.
METHODS: Children aged 2-11 years old, with an emphasis on children with asthma, were recruited during the 2014-2015 influenza season from three community-based clinics in New York City, and during the 2014-2015 and 2015-2016 seasons from a private practice in Fall River, Massachusetts. Parents of enrolled children receiving quadrivalent live attenuated (LAIV4) or inactivated influenza vaccine (IIV4) replied to text messages assessing respiratory symptoms (day 3 and 7, then weekly through day 42), and temperature on the night of vaccination and the next seven nights (day 0-7). Missing data were collected via diary (day 0-7 only) and phone. Phone confirmation was obtained for both presence and absence of respiratory symptoms. Reporting rates, fever (T≥100.4 °F) frequency, proportion of wheezing and/or chest tightness reports captured via text message versus all sources (text, phone, diary, electronic health record) and parental satisfaction were assessed.
RESULTS: Across both seasons, 266 children were analyzed; 49.2% with asthma. Parental text message response rates were high (>70%) across sites. Overall, fever frequency was low (day 0-2: 4.1% [95% confidence interval (CI) 2.3-7.4%]; d3-7: 6.7% [95% CI 4.1-10.8%]). A third (39.2%) of parents reported a respiratory problem in their child, primarily cough. Most (88.2%) of the 52 wheezing and/or chest tightness reports were by text message. Most (88.1%) participants preferred text messaging over paper reporting.
CONCLUSIONS: Text messaging can provide information about pediatric post-vaccination fever and wheezing and was viewed positively by parents. It could be a helpful tool for rapid vaccine safety monitoring during a pandemic or other emergency vaccination program.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02295007.

PMID: 29089191 [PubMed - indexed for MEDLINE]

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