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Phosphoryl Group Flow within the Pseudomonas aeruginosa Pil-Chp Chemosensory System: DIFFERENTIAL FUNCTION OF THE EIGHT PHOSPHOTRANSFERASE AND THREE RECEIVER DOMAINS.

J Biol Chem. 2016 Aug 19;291(34):17677-91

Authors: Silversmith RE, Wang B, Fulcher NB, Wolfgang MC, Bourret RB

Abstract
Bacterial chemosensory signal transduction systems that regulate motility by type IV pili (T4P) can be markedly more complex than related flagellum-based chemotaxis systems. In T4P-based systems, the CheA kinase often contains numerous potential sites of phosphorylation, but the signaling mechanisms of these systems are unknown. In Pseudomonas aeruginosa, the Pil-Chp system regulates T4P-mediated twitching motility and cAMP levels, both of which play roles in pathogenesis. The Pil-Chp histidine kinase (ChpA) has eight "Xpt" domains; six are canonical histidine-containing phosphotransfer (Hpt) domains and two have a threonine (Tpt) or serine (Spt) in place of the histidine. Additionally, there are two stand-alone receiver domains (PilG and PilH) and a ChpA C-terminal receiver domain (ChpArec). Here, we demonstrate that the ChpA Xpts are functionally divided into three categories as follows: (i) those phosphorylated with ATP (Hpt4-6); (ii) those reversibly phosphorylated by ChpArec (Hpt2-6), and (iii) those with no detectable phosphorylation (Hpt1, Spt, and Tpt). There was rapid phosphotransfer from Hpt2-6 to ChpArec and from Hpt3 to PilH, whereas transfer to PilG was slower. ChpArec also had a rapid rate of autodephosphorylation. The biochemical results together with in vivo cAMP and twitching phenotypes of key ChpA phosphorylation site point mutants supported a scheme whereby ChpArec functions both as a phosphate sink and a phosphotransfer element linking Hpt4-6 to Hpt2-3. Hpt2 and Hpt3 are likely the dominant sources of phosphoryl groups for PilG and PilH, respectively. The data are synthesized in a signaling circuit that contains fundamental features of two-component phosphorelays.

PMID: 27354279 [PubMed - indexed for MEDLINE]

The New Genomics: What Molecular Databases Can Tell us About Human Population Variation and Endocrine Disease.

Endocrinology. 2017 May 11;:

Authors: Rotwein P

Abstract
Major recent advances in genetics and genomics present unique opportunities for enhancing our understanding of human physiology and disease predisposition. Here I demonstrate how analysis of genomic information can provide new understanding of endocrine systems, using the human growth hormone (GH) signaling pathway as an illustrative example. GH is essential for normal postnatal growth in children, and plays important roles in other biological processes throughout life. GH actions are mediated by the GH receptor, primarily via the JAK2 protein tyrosine kinase and the STAT5B transcription factor, and inactivating mutations in this pathway all lead to impaired somatic growth. Variation in GH signaling genes has been evaluated using DNA sequence data from the Exome Aggregation Consortium, a compendium of information from over 60,000 individuals. Results reveal many potential missense and other alterations in the coding regions of GH1, GHR, JAK2, and STAT5B, with most changes being uncommon. The total number of different alleles per gene varied by ∼3-fold, from 101 for GH1 to 338 for JAK2. Several known disease-linked mutations in GH1, GHR, and JAK2 were present but infrequent in the population, although three amino acid changes in the GHR were sufficiently prevalent (∼4% to 44% of chromosomes) to suggest that they are not disease causing. Collectively these data provide new opportunities to understand how genetically driven variability in GH signaling and action may modify human physiology and disease.

PMID: 28498917 [PubMed - as supplied by publisher]

Identification of a missense HOXD13 mutation in a Chinese family with syndactyly type I-c using exome sequencing.

Mol Med Rep. 2017 May 11;:

Authors: Deng H, Tan T, He Q, Lin Q, Yang Z, Zhu A, Guan L, Xiao J, Song Z, Guo Y

Abstract
Syndactyly is one of the most common hereditary limb malformations, and is characterized by the fusion of specific fingers and/or toes. Syndactyly type I‑c is associated with bilateral cutaneous or bony webbing of the third and fourth fingers and occasionally of the third to fifth fingers, with normal feet. The aim of the present study was to identify the genetic basis of syndactyly type I‑c in four generations of a Chinese Han family by exome sequencing. Exome sequencing was conducted in the proband of the family, followed by direct sequencing of other family members of the same ancestry, as well as 100 ethnically‑matched, unrelated normal controls. A missense mutation, c.917G>A (p.R306Q), was identified in the homeobox D13 gene (HOXD13). Sanger sequencing verified the presence of this mutation in all of the affected family members. By contrast, this mutation was absent in the unaffected family members and the 100 ethnically‑matched normal controls. The results suggest that the c.917G>A (p.R306Q) mutation in the HOXD13 gene, may be responsible for syndactyly type I‑c in this family. Exome sequencing may therefore be a powerful tool for identifying mutations associated with syndactyly, which is a disorder with high genetic and clinical heterogeneity. The results provide novel insights into the etiology and diagnosis of syndactyly, and may influence genetic counseling and the clinical management of the disease.

PMID: 28498426 [PubMed - as supplied by publisher]

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Determination of disease phenotypes and pathogenic variants from exome sequence data in the CAGI 4 gene panel challenge.

Hum Mutat. 2017 May 12;:

Authors: Kundu K, Pal LR, Yin Y, Moult J

Abstract
The use of gene panel sequence for diagnostic and prognostic testing is now widespread, but there are so far few objective tests of methods to interpret these data. We describe the design and implementation of a gene panel sequencing data analysis pipeline (VarP) and its assessment in a CAGI4 community experiment. The method was applied to clinical gene panel sequencing data of 106 patients, with the goal of determining which of 14 disease classes each patient has and the corresponding causative variant(s). The disease class was correctly identified for 36 cases, including 10 where the original clinical pipeline did not find causative variants. For a further seven cases, we found strong evidence of an alternative disease to that tested. Many of the potentially causative variants are missense, with no previous association with disease, and these proved the hardest to correctly assign pathogenicity or otherwise. Post analysis showed that three-dimensional structure data could have helped for up to half of these cases. Over-reliance on HGMD annotation led to a number of incorrect disease assignments. We used a largely ad hoc method to assign probabilities of pathogenicity for each variant, and there is much work still to be done in this area. This article is protected by copyright. All rights reserved.

PMID: 28497567 [PubMed - as supplied by publisher]

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Leveraging multiple genomic data to prioritize disease-causing indels from exome sequencing data.

Sci Rep. 2017 May 11;7(1):1804

Authors: Wu M, Chen T, Jiang R

Abstract
The emergence of exome sequencing in recent years has enabled rapid and cost-effective detection of genetic variants in coding regions and offers a great opportunity to combine sequencing experiments with subsequent computational analysis for dissecting genetic basis of human inherited diseases. However, this strategy, though successful in practice, still faces such challenges as limited sample size and substantial number or diversity of candidate variants. To overcome these obstacles, researchers have been concentrated in the development of advanced computational methods and have recently achieved great progress for analysing single nucleotide variant. Nevertheless, it still remains unclear on how to analyse indels, another type of genetic variant that accounts for substantial proportion of known disease-causing variants. In this paper, we proposed an integrative method to effectively identify disease-causing indels from exome sequencing data. Specifically, we put forward a statistical method to combine five functional prediction scores, four genic association scores and a genic intolerance score to produce an integrated p-value, which could then be used for prioritizing candidate indels. We performed extensive simulation studies and demonstrated that our method achieved high accuracy in uncovering disease-causing indels. Our software is available at http://bioinfo.au.tsinghua.edu.cn/jianglab/IndelPrioritizer/.

PMID: 28496131 [PubMed - in process]

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Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis.

Eur Respir J. 2017 May;49(5):

Authors: Juge PA, Borie R, Kannengiesser C, Gazal S, Revy P, Wemeau-Stervinou L, Debray MP, Ottaviani S, Marchand-Adam S, Nathan N, Thabut G, Richez C, Nunes H, Callebaut I, Justet A, Leulliot N, Bonnefond A, Salgado D, Richette P, Desvignes JP, Lioté H, Froguel P, Allanore Y, Sand O, Dromer C, Flipo RM, Clément A, Béroud C, Sibilia J, Coustet B, Cottin V, Boissier MC, Wallaert B, Schaeverbeke T, Dastot le Moal F, Frazier A, Ménard C, Soubrier M, Saidenberg N, Valeyre D, Amselem S, FREX consortium, Boileau C, Crestani B, Dieudé P

Abstract
Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls.Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations in RA-ILD patients (OR 3.17, 95% CI 1.53-6.12; p=9.45×10(-4)). Telomeres were shorter in RA-ILD patients with a TERT, RTEL1 or PARN mutation than in controls (p=2.87×10(-2)).Our results support the contribution of FPF-linked genes to RA-ILD susceptibility.

PMID: 28495692 [PubMed - in process]

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Safety and Tolerability of Intravenous Valproic Acid in Healthy Subjects: A Phase I Dose-Escalation Trial.

Clin Pharmacokinet. 2017 May 11;:

Authors: Georgoff PE, Nikolian VC, Bonham T, Pai MP, Tafatia C, Halaweish I, To K, Watcharotone K, Parameswaran A, Luo R, Sun D, Alam HB

Abstract
BACKGROUND: Valproic acid, a histone deacetylase inhibitor, has beneficial effects in the setting of cancer, neurologic diseases, and traumatic injuries. In animal models of traumatic injury, a single dose of valproic acid has been shown to reduce mortality. The purpose of this trial was to determine the maximum tolerated single dose of intravenous valproic acid in healthy humans.
METHODS: A double-blinded, placebo-controlled, dose-escalation trial design was used to identify dose-limiting toxicities in healthy subjects who received a single dose of intravenous valproic acid. Patients were monitored for adverse events and data were collected for pharmacokinetic, pharmacodynamic, and safety profiling of valproic acid.
RESULTS: Fifty-nine healthy subjects (mean 30 ± 12 years) were enrolled. Forty-four subjects received valproic acid in doses from 15 to 150 mg/kg. The most common adverse events were hypoacusis (n = 19), chills (n = 18), and headache (n = 16). The maximum tolerated dose was 140 mg/kg. Dose-limiting toxicities included headache and nausea lasting longer than 12 h. No drug-related abnormalities were seen in other safety measures including laboratory tests, hemodynamic parameters, cardiac rhythm monitoring, and cognitive testing. A two-compartment model was predictive of valproic acid concentration-time profiles, with a strong correlation (R (2) = 0.56) observed between the number of reported adverse events and the dose level.
CONCLUSIONS: The maximum tolerated dose of intravenous valproic acid in healthy subjects is 140 mg/kg. This is significantly higher than the previously established maximum tolerated dose of 60-75 mg/kg. Next, the safety and tolerability of high-dose valproic acid will be tested in trauma patients in hemorrhagic shock. ClinicalTrials.gov Identifier: NCT01951560.

PMID: 28497259 [PubMed - as supplied by publisher]

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Unusual side effect from a luteinizing hormone-releasing hormone agonist, leuprorelin, in the treatment of prostate cancer: a case report.

J Med Case Rep. 2016 Nov 11;10(1):323

Authors: Chang JI, Bucci J

Abstract
BACKGROUND: The treatment options for high-risk prostate cancer are either radical prostatectomy or radiotherapy/brachytherapy depending on the patients' prognosis. In older men with multiple comorbidities, radiotherapy with androgen deprivation therapy is an attractive option. Common side effects of androgen deprivation therapy include hot flushes, tiredness, increased risk of fractures, increased risk of metabolic disorders, coronary heart disease, and psychological effects. This case highlights the potential side effect of lipodystrophy secondary to leuprolide acetate injections. To the best of our knowledge, this is the first reported case of such an instance.
CASE PRESENTATION: In this case report, we describe a 70-year-old white man with prostate-specific antigen of 1.8 ng/mL, clinical stage T2bN0M0, Gleason 4+5=9 prostate cancer who developed an unusual side effect from leuprolide acetate as part of his androgen deprivation therapy. Approximately 2 months after the initial 3-monthly injection of leuprolide acetate (Eligard 22.5 mg) our patient developed abnormal lipid deposition particularly in his deltoid and abdominal region. His upper limb mobility gradually became compromised due to the size of these abnormal fat depositions. He had liposuction to correct this lipodystrophy and had a good functional outcome and cosmesis from the procedure.
CONCLUSIONS: To the best of our knowledge, this is the first reported case of lipodystrophy secondary to leuprolide acetate injections. Leuprolide acetate in commonly used as one of the gonadotrophin-releasing hormone agonists and thus we should be mindful of the potential effect of producing lipodystrophy, especially in patients with cirrhosis, and to watch for any signs and symptoms as appropriate. The implication of this potential side effect poses difficult management strategies for such patients, and second-line alternatives such as chemotherapy may need to be considered.

PMID: 27836000 [PubMed - indexed for MEDLINE]

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Development and Validation of Algorithms to Identify Statin Intolerance in a US Administrative Database.

Value Health. 2016 Sep - Oct;19(6):852-860

Authors: Schulman KL, Lamerato LE, Dalal MR, Sung J, Jhaveri M, Koren A, Mallya UG, Foody JM

Abstract
OBJECTIVES: To develop and validate algorithms to define statin intolerance (SI) in an administrative database using electronic medical records (EMRs) as the reference comparison.
METHODS: One thousand adults with one or more qualifying changes in statin therapy and one or more previous diagnoses of hyperlipidemia, hypercholesterolemia, or mixed dyslipidemia were identified from the Henry Ford Health System administrative database. Data regarding statin utilization, comorbidities, and adverse effects were extracted from the administrative database and corresponding EMR. Patients were stratified by cardiovascular (CV) risk. SI was classified as absolute intolerance or titration intolerance on the basis of changes in statin utilization and/or the occurrence of adverse effects and laboratory testing for creatine kinase. Measures of concordance (Cohen's kappa [κ]) and accuracy (sensitivity, specificity, positive predictive value [PPV], and negative predictive value) were calculated for the administrative database algorithms.
RESULTS: Half of the sample population was white, 52.9% were women, mean age was 60.6 years, and 35.7% were at high CV risk. SI was identified in 11.5% and 14.0%, absolute intolerance in 2.2% and 3.1%, and titration intolerance in 9.7% and 11.8% of the patients in the EMR and the administrative database, respectively. The algorithm identifying any SI had substantial concordance (κ = 0.66) and good sensitivity (78.1%), but modest PPV (64.0%). The titration intolerance algorithm performed better (κ = 0.74; sensitivity 85.4%; PPV 70.1%) than the absolute intolerance algorithm (κ = 0.40; sensitivity 50%; PPV 35.5%) and performed best in the high CV-risk group (n = 353), with robust concordance (κ = 0.73) and good sensitivity (80.9%) and PPV (75.3%).
CONCLUSIONS: Conservative but comprehensive algorithms are available to identify SI in administrative databases for application in real-world research. These are the first validated algorithms for use in administrative databases available to decision makers.

PMID: 27712714 [PubMed - indexed for MEDLINE]

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Measuring High-Risk Patients' Preferences for Pharmacogenetic Testing to Reduce Severe Adverse Drug Reaction: A Discrete Choice Experiment.

Value Health. 2016 Sep - Oct;19(6):767-775

Authors: Dong D, Ozdemir S, Mong Bee Y, Toh SA, Bilger M, Finkelstein E

Abstract
OBJECTIVES: To investigate patient preferences and willingness to pay (WTP) for a genetic test that can reduce the risk of life-threatening adverse drug reactions (ADRs). We hypothesize that test features (risk of developing the adverse reaction with and without testing, test cost, and treatment cost) and the choice context (physician recommendation and the most common choice made by peer patients) will influence choices.
METHODS: A discrete choice experiment was conducted in which 189 patients at high risk for gout were asked to choose between treatment options that varied along key attributes. A latent class logit model was used to analyze the choice data and test the hypotheses.
RESULTS: We identified two classes of patients: the risk-averse class and the cost-conscious class. The WTP to reduce the risk of life-threatening ADRs from 1 out of 600 to 1 out of 1 million was SGD1215 in the risk-averse class. In contrast, in the cost-conscious class, the WTP was insensitive to the extent of risk reduction. Overall, the predicted take-up rate for the test is 65% at a price of SGD400. If the test was recommended by a physician or was chosen by most of the patients, the take-up rate for the test would increase by 8.5 and 1.5 percentage points, respectively.
CONCLUSIONS: There is a potentially large demand for genetic tests that could reduce the risk of life-threatening ADRs. Physician recommendations and providing information on the choices of others are powerful influences on demand, even more so than moderate price reductions.

PMID: 27712704 [PubMed - indexed for MEDLINE]

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Long-Acting Bronchodilator Initiation in COPD and the Risk of Adverse Cardiopulmonary Events: A Population-Based Comparative Safety Study.

Chest. 2017 Jan;151(1):60-67

Authors: Suissa S, Dell'Aniello S, Ernst P

Abstract
BACKGROUND: Long-acting bronchodilators, including long-acting beta2-agonists (LABA) and the anticholinergic tiotropium, are recommended as initial maintenance therapy in COPD. Studies to date have been limited in size and reported ambivalent results on the comparative risk of cardiovascular, cerebrovascular, and pulmonary adverse events between these two long-acting bronchodilators. Moreover, little information is available for the period when treatment is first initiated, a time when subjects may be especially at risk.
METHODS: We identified a cohort of new users of long-acting bronchodilators between 2002 and 2012, age 55 or older, from the United Kingdom's Clinical Practice Research Datalink. Patients initiating tiotropium were matched on high-dimensional propensity scores and prior inhaled corticosteroid use with patients initiating LABAs, and followed for 1 year for the occurrence of acute myocardial infarction, stroke, heart failure, arrhythmia, and pneumonia.
RESULTS: A total of 26,442 tiotropium initiators were matched to 26,442 LABA initiators, mainly single inhalers combined with inhaled corticosteroids. The hazard ratio of acute myocardial infarction associated with tiotropium initiation, relative to LABA initiation, was 1.10 (95% CI, 0.88-1.38), whereas for stroke it was 1.02 (95% CI, 0.78-1.34), for arrhythmia 0.81 (95% CI, 0.60-1.09), and heart failure 0.90 (95% CI, 0.79-1.02). The incidence of pneumonia was significantly less with tiotropium (hazard ratio, 0.81; 95% CI, 0.72-0.92).
CONCLUSION: COPD treatment initiation with tiotropium compared with LABA does not increase cardiovascular risk in the first year of treatment. The risk of pneumonia is higher with LABA, a likely effect of the inhaled corticosteroids present in many LABA inhalers used in real world clinical practice.

PMID: 27554300 [PubMed - indexed for MEDLINE]

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A clustered randomized trial to IMProve treatment with AntiCoagulanTs in patients with Atrial Fibrillation (IMPACT-AF): design and rationale.

Am Heart J. 2016 Jun;176:107-13

Authors: Rao MP, Ciobanu AO, Lopes RD, Fox KA, Xian Y, Pokorney SD, Al-Khalidi HR, Jiang J, Kamath DY, Berwanger O, Xavier D, Bahit CM, Tajer C, Vinereanu D, Huo Y, Granger CB

Abstract
Atrial fibrillation (AF) is common, increasing as the population ages, and a major cause of embolic stroke. While oral anticoagulation (OAC) is highly effective at preventing stroke in patients with AF, it continues to be underused in eligible patients worldwide. The objective of this prospective, cluster randomized controlled trial (IMPACT-AF; ClinicalTrials.gov #NCT02082548) is to determine whether a comprehensive customized intervention will increase the rate and persistence of use of OAC in patients with AF. IMPACT-AF will be conducted in approximately 50 centers in 5 low- to middle-income countries. Before randomization, sites within countries will be paired to match in size, practice type and baseline rate of OAC use. Site pairs will be randomized to intervention versus control. In total, 40 to 70 patients with AF and at least 2 CHA2DS2-VASc risk factors will be enrolled at each site using a consecutive enrollment strategy, with the goal of capturing actual practice patterns. We aim for patients with a new diagnosis of AF to comprise at least 30% of the study cohort. Assuming an average baseline OAC use of 60% and a post-intervention use of 70% with a post-control rate of 60%, there will be roughly 94-98% power with 25 clusters per group (intracluster correlation coefficient of 0.02). While this trial focuses on improving treatment use and reducing preventable strokes, we also aim to better understand the reasons for OAC underuse. This will improve the intervention with the goal of creating educational recommendations to improve care for patients with AF.

PMID: 27264227 [PubMed - indexed for MEDLINE]

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Protocol for analyses of adverse event data from randomized controlled trials of statin therapy.

Am Heart J. 2016 Jun;176:63-9

Authors: Cholesterol Treatment Trialists' (CTT) Collaboration

Abstract
The Cholesterol Treatment Trialists' (CTT) Collaboration was originally established to conduct individual participant data meta-analyses of major vascular events, cause-specific mortality, and site-specific cancers in large, long-term, randomized trials of statin therapy (and other cholesterol-modifying treatments). The results of the trials of statin therapy and their associated meta-analyses have shown that statins significantly reduce the risk of major vascular events without any increase in the risk of nonvascular causes of death or of site-specific cancer, but do produce small increases in the incidence of myopathy, diabetes, and, probably, hemorrhagic stroke. The CTT Collaboration has not previously sought data on other outcomes, and so a comprehensive meta-analysis of all adverse events recorded in each of the eligible trials has not been conducted. This protocol prospectively describes plans to extend the CTT meta-analysis data set so as to provide a more complete understanding of the nature and magnitude of any other effects of statin therapy.

PMID: 27264221 [PubMed - indexed for MEDLINE]

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Extended duration dual antiplatelet therapy in patients with myocardial infarction: A study-level meta-analysis of controlled randomized trials.

Am Heart J. 2016 Jun;176:36-43

Authors: Patti G, Cavallari I

Abstract
BACKGROUND: Whether dual antiplatelet therapy (DAPT) is beneficial beyond 1 year after myocardial infarction (MI) is not demonstrated; in particular, available studies may be individually underpowered for end points at low incidence, that is, major and fatal bleeding or mortality. We thus assessed the effectiveness and safety of prolonged DAPT after MI over the long term.
METHODS: We conducted a systematic search to identify randomized trials on the topic; 3 studies and 21,534 post-MI patients receiving placebo or aspirin plus P2Y12 inhibition for ≥2 years were included. Incidence of the following outcome measures was evaluated: major adverse cardiac events (MACE), major bleeding, fatal bleeding, and cardiovascular and noncardiovascular death.
RESULTS: Occurrence of MACE was lower in patients treated with prolonged DAPT: 6.3% vs 7.9% in those without prolonged DAPT (odds ratios 0.74, 95% CI 0.60-0.91, P = .005); in the former, there was also a significant 16% reduction in cardiovascular mortality. Increase in major bleeding with extended duration DAPT was not significant in the overall analysis (1.5% vs 1.0%; P = .10), but became significant in the analysis restricted to patients receiving ticagrelor or prasugrel as second antiplatelet agent (odds ratios 2.16, 95% CI 1.63-2.86); prolonged use of DAPT did not raise rates of fatal bleeding or noncardiovascular mortality.
CONCLUSION: Prolonged DAPT after MI reduces MACE and cardiovascular mortality over the long term; this was paralleled by higher risk of nonfatal major bleeding mainly with the newer, more potent P2Y12 antagonists. Tailoring duration of DAPT after MI on the comparative evaluation of both ischemic and bleeding risk is mandatory in this setting.

PMID: 27264218 [PubMed - indexed for MEDLINE]

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Evaluation of Anemia.

Obstet Gynecol Clin North Am. 2016 Jun;43(2):247-64

Authors: Kujovich JL

Abstract
Anemia is a common problem in primary care. Classification based on mean cell volume narrows the differential diagnosis and directs testing. A marked macrocytosis is characteristic of vitamin B12 and folate deficiencies, certain medications, and primary bone marrow disorders. The three most common causes of microcytic anemia are iron deficiency, thalassemia trait, and anemia of inflammation. Additional laboratory testing is required for diagnosis. Determination of the rate of development of anemia and examination of a blood smear may provide diagnostic clues to guide more specialized testing. Diagnosis of iron, vitamin B12, or folate deficiency mandates determination of the underlying cause.

PMID: 27212091 [PubMed - indexed for MEDLINE]

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Funding Opportunity PA-17-285 from the NIH Guide for Grants and Contracts. The purpose of this FOA is encourage applications that seek to examine processes of recovery and relapse in the treatment of Alcohol Use Disorders. Applications high in innovation and significance are highly encouraged that address the following potential topics: 1) Defining recovery; 2) Examining new and innovative methods to examine precipitants of relapse; 3) Understanding mechanisms of mutual help and recovery; 4) Evaluating recovery systems of care; and 5) Examining processes of extended treatment for AUD

Funding Opportunity PA-17-284 from the NIH Guide for Grants and Contracts. The purpose of this FOA is encourage applications that seek to examine processes of recovery and relapse in the treatment of Alcohol Use Disorders. Applications high in innovation and significance are highly encouraged that address the following potential topics: 1) defining recovery; 2) Examining new and innovative methods to examine precipitants of relapse; 3) Understanding mechanisms of mutual help and recovery; 4) Evaluating recovery systems of care; and 5) Examining processes of extended treatment for AUD

Notice NOT-HG-17-005 from the NIH Guide for Grants and Contracts