Citations

AbstractObjectiveElevations in uric acid (UA) and the associated hyperuricaemia are commonly observed secondary to treatment with thiazide diuretics. We sought to identify novel single nucleotide polymorphisms (SNPs) associated with hydrochlorothiazide (HCTZ)‐induced elevations in UA and hyperuricaemia.MethodsA genome‐wide association study of HCTZ‐induced changes in UA was performed in Caucasian and African American participants from the pharmacogenomic evaluation of antihypertensive responses (PEAR) study who were treated with HCTZ monotherapy. Suggestive SNPs were replicated in Caucasians and African Americans from the PEAR study who were treated with HCTZ add‐on therapy. Replicated regions were followed up through expression and pathway analysis.ResultsFive unique gene regions were identified in African Americans (LUC7L2, ANKRD17/COX18, FTO, PADI4 and PARD3B), and one region was identified in Caucasians (GRIN3A). Increases in UA of up to 1.8 mg dL−1 were observed following HCTZ therapy in individuals homozygous for risk alleles, with heterozygotes displaying an intermediate phenotype. Several risk alleles were also associated with an increased risk of HCTZ‐induced clinical hyperuricaemia. A composite risk score, constructed in African Americans using the ‘top’ SNP from each gene region, was strongly associated with HCTZ‐induced UA elevations (P = 1.79 × 10−7) and explained 11% of the variability in UA response. Expression studies in RNA from whole blood revealed significant differences in expression of FTO by rs4784333 genotype. Pathway analysis showed putative connections between many of the genes identified through common microRNAs.ConclusionSeveral novel gene regions were associated with HCTZ‐induced UA elevations in African Americans (LUC7L2, COX18/ANKRD17, FTO, PADI4 and PARD3B), and one region was associated with these elevations in Caucasians (GRIN3A).

BackgroundPostmenopausal hormone therapy (HT) increases the risk of venous thrombosis and ischemic stroke.ObjectivesWe postulated that HT might increase the risk of ischemic stroke by promoting venous clots that travel to the brain through a right to left shunt (RLS).MethodsA total of 2,389 records were studied. After eliminating the premenopausal patients, and those with TIAs and non‐ischemic strokes, the medical records of 1846 postmenopausal women hospitalized at four institutions for ischemic stroke were reviewed to identify those who had undergone an adequate study to assess for RLS. The proportion of women with a shunt in users and non‐users of HT was compared in stroke patients and in a reference population consisting of postmenopausal women undergoing elective cardiac catheterization.ResultsThere were 363 (20%) records that had complete data and were included in the analysis. A shunt was more prevalent in patients with a cryptogenic stroke than in patients with a stroke of known cause (55/88 (63%) vs. 53/275 (19%), P < 0.001). In patients with a stroke of known cause, the frequency of a shunt was similar to that in reference women 31/136 (23%), and the proportion of women with a shunt was similar in non‐users and current users of HT (14% vs. 20%, P = 0.40). However, among patients with a cryptogenic stroke, the prevalence of a shunt was 1.5 times higher in current users than non‐users of HT (82% vs. 56%, P = 0.04).ConclusionsApproximately 23% of older women have a RLS. HT in these women may increase the risk of ischemic stroke by promoting paradoxical embolism. © 2014 Wiley Periodicals, Inc.

The non‐invasive evaluation of prosthetic valve function is challenging. The effects of flow rate, valvular geometry, leaflet motion, and pressure recovery all impact the Doppler assessment of prosthetic performance. Differentiating prosthesis obstruction from pressure recovery in patients who are found to have high Doppler velocities across an aortic valve prosthesis is critical in order to direct appropriate management. In this manuscript, we present two cases of patients with aortic valve prosthesis with high Doppler velocities and review the pathophysiology and evaluation of prosthesis function. © 2014 Wiley Periodicals, Inc.

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases including polycythemia vera (PV), essential thrombocythemia (ET), and primary(idiopathic) myelofibrosis (PMF). In this systematic review, we provide a comprehensive report on the incidence and prevalence of MPNs across the globe. Electronic databases (PubMed, EMBASE, MEDLINE, and Web of Science) were searched from their inception to August 2012 for articles reporting MPN incidence or prevalence rates. A random effects meta‐analysis was undertaken to produce combined incidence rates for PV, ET, and PMF. Both heterogeneity and small study bias were assessed. Thirty‐four studies were included. Reported annual incidence rates ranged from 0.01 to 2.61, 0.21 to 2.27, and 0.22 to 0.99 per 100,000 for PV, ET, and PMF, respectively. The combined annual incidence rates for PV, ET, and PMF were 0.84, 1.03, and 0.47 per 100,000. There was high heterogeneity across disease entities (I2 97.1–99.8%) and evidence of publication bias for ET and PMF (Egger test, P = 0.007 and P ≤ 0.001, respectively).The pooled incidence reflects the rarity of MPNs. The calculated pooled incidence rates do not reflect MPN incidence across the globe due to the high unexplained heterogeneity. Improved, widespread registration of MPNs would provide better information for global comparison of the incidence and prevalence of MPNs. Am. J. Hematol. 89:581–587, 2014. © 2014 Wiley Periodicals, Inc.

Background It is generally felt that patient education and patient knowledge regarding triptan use for acute migraine management are important for successful and safe treatment. It is unclear how knowledgeable triptan users are regarding their triptan, how much education occurs when triptans are prescribed, and the impact patient education has on actual patient knowledge regarding triptan use. Objective The primary objective was to compare triptan users' self‐perceived knowledge and actual knowledge about triptans in patients who report having received triptan education vs patients who report not having received triptan education. Methods This was a multicenter prospective observational study of 207 migraine patients who were using triptans for abortive therapy and who were being evaluated as new patients at academic headache specialty clinics in the U nited S tates. Patients completed standardized questionnaires regarding their self‐perceived knowledge about triptans, their actual knowledge regarding triptans, and the perceived education about the triptan that they had received at the time of prescription. Results Although greater than 80% of the subjects reported receiving education about when to take the triptan and the number of doses they could take for headache, only 71.5% reported receiving education about triptan side effects, 64% for the number of triptan doses they could take each week/month, 64% for taking other medications with the triptan, and 49% for medical contraindications to triptan use. Compared with subjects who did not recall receiving education about when to take their triptan, subjects who recalled such education had a statistically significant greater actual knowledge for taking the triptan immediately after a headache begins (91% vs 77%, P = .049; confidence interval [ CI ]: 0.00–0.33), treating when pain is mild (75% vs 50%, P = .009; CI : 0.04–0.45), understanding that they do not need to fail treatment with over‐the‐counter medications before taking a triptan (74% vs 42%, P = .001; CI : 0.11–0.51), and recognizing that coronary artery disease is a contraindication to triptan use (40% vs 19%, P = .001; CI : 0.09–0.34). Conclusion This study provides evidence that patients who recall having received education at the time of triptan prescribing have greater knowledge regarding optimal triptan use. Triptan users who recalled having received this education had greater recognition of the importance of taking the triptan immediately at the onset of a headache, treating when pain is mild, not needing to fail treatment with over‐the‐counter medications before taking a triptan, and understanding that coronary artery disease is a contraindication to triptan use.

AbstractBackground & AimsSmall duct primary sclerosing cholangitis (PSC) is phenotypically a mild version of large duct PSC, but it is unknown whether these phenotypes share aetiology. We aimed to characterize their relationship by investigating genetic associations in the human leucocyte antigen (HLA) complex, which represent the strongest genetic risk factors in large duct PSC.MethodsFour classical HLA loci (HLA‐A, HLA‐B, HLA‐C and HLA‐DRB1) were genotyped in 87 small duct PSC patients, 485 large duct PSC patients and 1117 controls across three geographical regions.ResultsHLA‐DRB1*13:01 (OR = 2.0, 95% CI 1.2–3.4, P = 0.01) and HLA‐B*08 (OR = 1.6, 95% CI 1.1–2.4, P = 0.02) were significantly associated with small duct PSC compared with healthy controls. Based on the observed frequency of HLA‐B*08 in small duct PSC, the strongest risk factor in large duct PSC, an estimated 32% (95% CI 4–65%) of this population can be hypothesized to represent early stages or mild variants of large duct PSC. This subgroup may be constituted by small duct PSC patients with inflammatory bowel disease (IBD), which greatly resembled large duct PSC in its HLA association. In contrast, small duct PSC without IBD was only associated with HLA‐DRB1*13:01(P = 0.03) and was otherwise distinctly dissimilar from large duct PSC.ConclusionsSmall duct PSC with IBD resembles large duct PSC in its HLA association and may represent early stages or mild variants of large duct disease. Different HLA associations in small duct PSC without IBD could indicate that this subgroup is a different entity. HLA‐DRB1*13:01 may represent a specific risk factor for inflammatory bile duct disease.

AbstractAlthough coding variants in THAP1 have been causally associated with primary dystonia, the contribution of noncoding variants remains uncertain. Herein, we examine a previously identified Intron 1 variant (c.71+9C>A, rs200209986). Among 1672 subjects with mainly adult‐onset primary dystonia, 12 harbored the variant in contrast to 1/1574 controls (P < 0.01). Dystonia classification included cervical dystonia (N = 3), laryngeal dystonia (adductor subtype, N = 3), jaw‐opening oromandibular dystonia (N = 1), blepharospasm (N = 2), and unclassified (N = 3). Age of dystonia onset ranged from 25 to 69 years (mean = 54 years). In comparison to controls with no identified THAP1 sequence variants, the c.71+9C>A variant was associated with an elevated ratio of Isoform 1 (NM_018105) to Isoform 2 (NM_199003) in leukocytes. In silico and minigene analyses indicated that c.71+9C>A alters THAP1 splicing. Lymphoblastoid cells harboring the c.71+9C>A variant showed extensive apoptosis with relatively fewer cells in the G2 phase of the cell cycle. Differentially expressed genes from lymphoblastoid cells revealed that the c.71+9C>A variant exerts effects on DNA synthesis, cell growth and proliferation, cell survival, and cytotoxicity. In aggregate, these data indicate that THAP1 c.71+9C>A is a risk factor for adult‐onset primary dystonia.

Background Optimizing patient satisfaction with their medical care and maximizing patient adherence with treatment plans requires an understanding of patient preferences regarding education and their role in decision making when treatments are prescribed. Objective To assess the congruence between patient expectations and actual practice regarding education and decision making at the time a triptan is prescribed. Methods This multicenter cross‐sectional survey was performed by headache fellow members of the A merican H eadache S ociety H eadache F ellows R esearch C onsortium at their respective tertiary care headache clinics. Migraine patients who were new patients to the headache clinic and who were current triptan users (use within prior 3 months and for ≥1 year) or past triptan users (no use within 6 months; prior use within 2 years) completed questionnaires that assessed the education they received and their role in decision making at the time a triptan was first prescribed as well as their desire for education and participation in decision making when a triptan is prescribed. Results Consistent with patient preference, most participants received the majority of their education about the triptan from the prescriber's office (70.2%). In descending rank order, participants most desired to be informed about how to decide if a triptan should be taken, when during the course of migraine a triptan should be taken, possible side effects, cost, and how to obtain refills. Regarding side effects, most participants preferred to receive education about the most common side effects of a triptan rather than addressing all possible side effects. Regarding triptan dosing, participants desired to be informed in descending order of importance about taking other medications with triptans, how many doses can be taken for each migraine, how many doses can be taken each week/month, what to do if the triptan does not work, and the triptan mechanism of action. The vast majority of participants (92%) preferred that the decision to prescribe a triptan be a joint decision between the patient and the provider. In actual practice, participants were not as involved in decision making as they would like to be, with patients reporting that the prescriber was the sole decision maker 55.1% of the time. Participants had confidence in their providers (87.7%) and generally felt they did a good job educating them about the triptan (71.1%). Conclusions Based on this study, it is clear that patients prefer the shared model approach to medical decision making in regards to the prescription of triptans. The majority of patients received education that was generally consistent with their desires. Patients preferred that the prescribing provider be the primary source of information. The most desired educational topics included when/if a triptan should be taken, the number of times a triptan can be taken for a single migraine, co‐administration with other acute medications, and the most common side effects. Focusing on these topics should enhance patient satisfaction and may improve compliance.