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The choice of oral anticoagulant (OAC) for patients with atrial fibrillation (AF) may be influenced by individual clinical features or by patterns of risk factors and comorbidities. We reviewed analyses of subgroups of patients from trials of vitamin K antagonists vs. non-vitamin K oral anticoagulants (NOACs) for stroke prevention in AF with the aim to identify patient groups who might benefit from a particular OAC more than from another. In addition, we discuss the timing of initiation of anticoagulation. In the second of a two-part review, we discuss the use of NOAC for stroke prevention in the following subgroups of patients with AF: (vii) secondary stroke prevention in patients after stroke or transient ischaemic attack (TIA), (viii) patients with acute stroke requiring thrombolysis or thrombectomy, (ix) those initiating or restarting OAC treatment after stroke or TIA, (x) those with renal impairment on dialysis, (xi) the elderly, (xii) those at high risk of gastrointestinal bleeding, and (xiii) those with hypertension. In addition, we discuss adherence and compliance. Finally, we present a summary of treatment suggestions. In specific subgroups of patients with AF, evidence supports the use of particular NOACs and/or particular doses of anticoagulant. The appropriate choice of treatment for these subgroups will help to promote optimal clinical outcomes., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Patients with atrial fibrillation (AF) have a high risk of stroke and mortality, which can be considerably reduced by oral anticoagulants (OAC). Recently, four non-vitamin-K oral anticoagulants (NOACs) were compared with warfarin in large randomized trials for the prevention of stroke and systemic embolism. Today's clinician is faced with the difficult task of selecting a suitable OAC for a patient with a particular clinical profile or a particular pattern of risk factors and concomitant diseases. We reviewed analyses of subgroups of patients from trials of vitamin K antagonists vs. NOACs for stroke prevention in AF with the aim to identify patient groups who might benefit from a particular OAC more than from another. In the first of a two-part review, we discuss the choice of NOAC for stroke prevention in the following subgroups of patients with AF: (i) stable coronary artery disease or peripheral artery disease, including percutaneous coronary intervention with stenting and triple therapy; (ii) cardioversion, ablation and anti-arrhythmic drug therapy; (iii) mechanical valves and rheumatic valve disease, (iv) patients with time in therapeutic range of >70% on warfarin; (v) patients with a single stroke risk factor (CHA2DS2VASc score of 1 in males, 2 in females); and (vi) patients with a single first episode of paroxysmal AF. Although there are no major differences in terms of efficacy and safety between the NOACs for some clinical scenarios, in others we are able to suggest that particular drugs and/or doses be prioritized for anticoagulation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Context: GH insensitivity (GHI) is a condition characterized by pronounced IGF-I deficiency and severe short stature. We previously identified a novel compound heterozygous GH receptor (GHR) mutation, GHR:p.R229H/c.899dupC, in a patient presenting with GHI. The heterozygous p.R229H (prepeptide) variant was previously associated with GHI despite a lack of adequate functional studies. The novel heterozygous GHR:c.899dupC variant affects the critical JAK2-binding Box 1 region of the GHR intracellular domain; the duplication predicted a frameshift and early protein termination., Objective: The individual and synergistic effect(s) of the p.R229H and c.899dupC mutations on GHR function(s) were evaluated in reconstitution studies., Results: The recombinant human GHR (hGHR):p.R229H variant was readily expressed, and unexpectedly, GH-induced signal transducer and activator of transcription 5b (STAT5b) phosphorylation was comparable to that induced by wild-type hGHR. The truncated, immunodetected hGHR:c.899dupC variant, in contrast, was unresponsive to GH. To mimic a compound heterozygous state, the two variants were coexpressed, and strikingly, the presence of the hGHR:c.899dupC effectively abolished the GH-induced STAT5b activities that were observed with hGHR:p.R229H alone. Furthermore, hGHR:c.899dupC dose-dependently reduced the GH-induced STAT5b activities associated with hGHR:p.R229H. This dominant negative effect was also observed when hGHR:c.899dupC was coexpressed with wild-type hGHR., Conclusion: The p.R229H variant, contrary to an earlier report, appeared to function like wild-type GHR and, therefore, is unlikely to cause GHI. The c.899dupC variant is a novel dominant negative mutation that disrupted normal GHR signaling and is the cause for the GHI phenotype of the reported patient.

Background: Pouchitis is a frequent complication after ileal pouch-anal anastamosis (IPAA) for ulcerative colitis (UC). The aim of this study was to determine whether genetic polymorphisms in the innate immune receptors toll-like receptor (TLR)4 and caspase activation and recruitment domain family member 15 (CARD15) genes are associated with pouchitis., Methods: From a retrospectively ascertained cohort of patients with UC 5 to 12 years after IPAA (n = 101), subjects were classified into 3 groups: no pouchitis (n = 52); 1 to 2 episodes per year (n = 11), and more than 2 episodes per year (n = 38). Single nucleotide polymorphisms in the tlr4 gene (D299G, T399I) were determined by a real-time polymerase chain reaction-based fluorogenic probe technique; and card15 polymorphisms (L1007fsinsC, R702W, G908R) were determined by pyrosequencing., Results: Pouchitis affected 49% (49/101) of the study population. No correlation between pouchitis and the presence of TLR4 polymorphisms was found. The percentage of patients who harbored CARD15 mutations was significantly higher in patients with pouchitis than in patients without pouchitis (18% versus 8%; P < 0.05); 24% of pouchitis patients with more than 2 episodes per year harbored CARD15 mutations (P < 0.01 compared with the no pouchitis group). The CARD15 insertion mutation L1007fsinsC was present in 14% of patients with pouchitis and in 0% without pouchitis (P < 0.05). All patients who carried L1007fsinsC developed more than 2 episodes per year., Conclusions: CARD15 polymorphisms are seen in greater frequency in patients with pouchitis after IPAA for UC. These findings, if borne out in prospective analyses, suggest that CARD15 mutations, particularly L1007fsinsC, may predispose to the development of pouchitis after IPAA for UC.

Congenital lipoid adrenal hyperplasia (lipoid CAH), the most severe form of CAH, is caused by mutations in the steroidogenic acute regulatory protein (StAR). Lipoid CAH is common among the Japanese, Korean, and Palestinian Arab populations, but is rare elsewhere. We describe six patients with lipoid CAH: four Japanese, one Palestinian, and one Guatemalan Native American. All had classical clinical presentations of normal female external genitalia in both genetic sexes, with severe glucocorticoid and mineralocorticoid deficiency presenting in the first month of life. Quite atypically, one patient had small adrenal glands shown by computed tomographic scanning. The StAR genes were characterized in all six patients. Three of the Japanese patients were compound heterozygotes for the common Japanese mutation Q258X in association with three different novel frameshift mutations; the fourth Japanese patient was homozygous for the mutation R182L, which is common among Palestinian patients but has not been described previously in a Japanese patient. Our Palestinian and Native American patients were each homozygous for novel frameshift mutations. Thus we have found five new frameshift mutations, but no new amino acid replacement (missense) mutations. This would be consistent with the view that only a small number of residues in the StAR protein are crucial for biological activity. The tomographic finding of small adrenals in a patient with genetically proven lipoid CAH due to a StAR mutation suggests a substantially broader spectrum of clinical findings in this disease than has been appreciated previously.