Introduction of DOACs in routine practice was associated with improved rates of overall OAC use for AF, but significant gaps remain. In addition, there is significant practice-level variation in OAC and DOAC use.

Cow's milk is a common cause of food allergy in children. Children usually outgrow cow's milk allergy by the age of 3-5 years, but some will have persistent symptoms beyond childhood. We performed a systematic review of randomized controlled trials (RCTs) and observational studies to assess the evidence supporting the use of oral immunotherapy in IgE-mediated cow's milk allergy to inform the World Allergy Organization guidelines. Of 1034 screened articles published until May 2011, five RCTs and five observational studies fulfilled a priori specified inclusion criteria. RCTs including 218 patients showed that oral immunotherapy, compared to elimination diet alone, increased the likelihood of achieving full tolerance of cow's milk [relative risk: 10.0 (95% CI: 4.1-24.2)]. Adverse effects of immunotherapy include frequent local symptoms (16% of doses), mild laryngospasm [relative risk: 12.9 (1.7-98.6)], mild asthma [rate ratio: 3.8 (2.9-5.0)], reactions requiring oral glucocorticosteroids [relative risk: 11.3 (2.7-46.5)] or intramuscular epinephrine injection [rate ratio 5.8 (1.6-21.9)]. Results of observational studies were consistent with those of RCTs. Despite the availability of RCTs, the overall low quality of evidence leaves important uncertainty about anticipated effects of immunotherapy due to very serious imprecision of the estimates of effects and the likelihood of publication bias for some of the critical outcomes. A potentially large benefit of oral immunotherapy in patients with cow's milk allergy may be counterbalanced by frequent and sometimes serious adverse effects. Additional, larger RCTs measuring all patient-important outcomes are still needed.

Genetic mutation and pharmacological inhibition of Bruton's tyrosine kinase (Btk) both have been shown to prevent the development of collagen-induced arthritis (CIA) in mice, providing a rationale for the development of Btk inhibitors for treating rheumatoid arthritis (RA). In the present study, we characterized a novel Btk inhibitor, 6-cyclopro-, in vitro and in rodent models of immune hypersensitivity and arthritis. We demonstrated that RN486 not only potently and selectively inhibited the Btk enzyme, but also displayed functional activities in human cell-based assays in multiple cell types, blocking Fc receptor cross-linking-induced degranulation in mast cells (IC 50 ϭ 2.9 nM), Fc␥ receptor engagement-mediated tumor necrosis factor ␣ production in monocytes (IC 50 ϭ 7.0 nM), and B cell antigen receptor-induced expression of an activation marker, CD69, in B cells in whole blood (IC 50 ϭ 21.0 nM). RN486 displayed similar functional activities in rodent models, effectively preventing type I and type III hypersensitivity responses. More importantly, RN486 produced robust anti-inflammatory and boneprotective effects in mouse CIA and rat adjuvant-induced arthritis (AIA) models. In the AIA model, RN486 inhibited both joint and systemic inflammation either alone or in combination with methotrexate, reducing both paw swelling and inflammatory markers in the blood. Together, our findings not only demonstrate that Btk plays an essential and conserved role in regulating immunoreceptor-mediated immune responses in both humans and rodents, but also provide evidence and mechanistic insights to support the development of selective Btk inhibitors as small-molecule disease-modifying drugs for RA and potentially other autoimmune diseases.

Saccharomyces cerevisiae cell division ends with destruction of a septum deposited during cytokinesis; this must occur only after the structure's construction is complete. Genes involved in septum destruction are induced by the transcription factor Ace2, which is activated by the kinase Cbk1, an Ndr/LATS-related protein that functions in a system related to metazoan hippo pathways. Phosphorylation of a conserved hydrophobic motif (HM) site regulates Cbk1; at peak levels in late mitosis we found that approximately 3% of Cbk1 carries this modification. HM site phosphorylation prior to mitotic exit occurs in response to activation of the FEAR (Cdc fourteen early anaphase release) pathway. However, HM site phosphorylation is not sufficient for Cbk1 to act on Ace2: the kinase is also negatively regulated prior to cytokinesis, likely by cyclin-dependent kinase (CDK) phosphorylation. Cbk1 cannot phosphorylate Ace2 until after mitotic exit network (MEN)-initiated release of the phosphatase Cdc14. Treatment of Cbk1 with Cdc14 in vitro does not increase its intrinsic enzymatic activity, but Cdc14 is required for Cbk1 function in vivo. Thus, we propose that Cdc14 coordinates cell separation with mitotic exit via FEAR-initiated phosphorylation of the Cbk1 HM site and MEN-activated reversal of mitotic CDK phosphorylations that block both Cbk1 and Ace2 function.