Autoantibody production and immune complex deposition within the kidney promote renal disease in patients with lupus nephritis. Thus, therapeutics that inhibit these pathways may be efficacious in ...the treatment of systemic lupus erythematosus. Bruton's tyrosine kinase (BTK) is a critical signaling component of both BCR and FcR signaling. We sought to assess the efficacy of inhibiting BTK in the development of lupus-like disease, and in this article describe (R)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-2,4-difluorophenoxyphenyl)-1H-pyrazole-4-carboxamide (PF-06250112), a novel highly selective and potent BTK inhibitor. We demonstrate in vitro that PF-06250112 inhibits both BCR-mediated signaling and proliferation, as well as FcR-mediated activation. To assess the therapeutic impact of BTK inhibition, we treated aged NZBxW_F1 mice with PF-06250112 and demonstrate that PF-06250112 significantly limits the spontaneous accumulation of splenic germinal center B cells and plasma cells. Correspondingly, anti-dsDNA and autoantibody levels were reduced in a dose-dependent manner. Moreover, administration of PF-06250112 prevented the development of proteinuria and improved glomerular pathology scores in all treatment groups. Strikingly, this therapeutic effect could occur with only a modest reduction observed in anti-dsDNA titers, implying a critical role for BTK signaling in disease pathogenesis beyond inhibition of autoantibody production. We subsequently demonstrate that PF-06250112 prevents proteinuria in an FcR-dependent, Ab-mediated model of glomerulonephritis. Importantly, these results highlight that BTK inhibition potently limits the development of glomerulonephritis by impacting both cell- and effector molecule-mediated pathways. These data provide support for evaluating the efficacy of BTK inhibition in systemic lupus erythematosus patients.
Accessing timely acute medical care is a challenge for older adults. This article describes an innovative healthcare model that uses high‐intensity telemedicine services to provide rapid acute care ...for older adults without requiring them to leave their senior living community (SLC) residences. This program, based in a primary care geriatrics practice that cares for SLC residents, is designed to offer acute care through telemedicine for complaints that are felt to need attention before the next available outpatient visit but not to require emergency department (ED) resources. This option gives residents access to care in their residence. Measures used to evaluate the program include successful completion of telemedicine visits, satisfaction of residents and caregivers with telemedicine care, and site of care that would have been recommended had telemedicine been unavailable. During the first 2 years of the program's operation, 281 of 301 requested telemedicine visits were completed successfully. Twelve residents were sent to an ED for care after the telemedicine visit. Ninety‐four percent of residents reported being satisfied or very satisfied with telemedicine care. Had telemedicine not been available, residents would have been sent to an ED (48.1%) or urgent care center (27.0%) or been scheduled for an outpatient visit (24.4%). The project demonstrated that high‐intensity telemedicine services for acute illnesses are feasible and acceptable and can provide definitive care without requiring ED or urgent care use. Continuation of the program will require evaluation demonstrating equal or better resident‐level outcomes and the development of sustainable business models.
Objectives
Studies have found that participation in emergency department research associate (EDRA) programs is associated with medical school acceptance. However, little is known about the ...association between EDRA program participation and other academic and professional outcomes. We sought to characterize the academic and professional outcomes of EDRA program participants and their perception of program influence on academic and professional outcomes.
Methods
We conducted a cross‐sectional study of University of Rochester EDRA program participants who graduated from the program May 2010 to May 2017. EDRAs were sent a secure, deidentified, survey. Standard descriptive statistics were used to characterize participant demographics and outcomes. National acceptance rates were referenced from sources.
Results
A total of 56 graduates completed the survey (64% response rate). Forty (71%) identified as female, 12 (21%) identified as Asian, one (2%) identified as Black or African American, and three (5%) identified as Hispanic or Latino. Acceptance rates to MD programs, DO programs, PhD programs, and master’s programs were 88% (22/25), 92% (12/13), 100% (2/2), and 100% (9/9), respectively. Rates were significantly higher compared to national rates (all p < 0.001). Eighty‐three percent (30/36 responses) and 74% (37/50) spoke about the EDRA program during postgraduate program and job interviews, respectively, and 78% (35/45 responses) included the EDRA program in their personal statements. Twenty‐five percent (14/55) changed their career goals after participating in the EDRA program, of which 36% (5/14) left medicine and 21% (3/14) were undecided and chose to become a physician.
Conclusions
An EDRA program can help develop and support a career in medicine and science. EDRA graduates used their experiences directly in their postgraduate program applications and job interviews. Acceptance rates of EDRA program graduates to postgraduate programs were higher than national averages. An EDRA program can help clarify career goals after program participation.
British Columbia's 8-1-1 telephone service connects callers with nurses for health care advice. As of Nov. 16, 2020, callers advised by a registered nurse to obtain in-person medical care can be ...subsequently referred to virtual physicians. We sought to determine health system use and outcomes of 8-1-1 callers urgently triaged by a nurse and subsequently assessed by a virtual physician.
We identified callers referred to a virtual physician between Nov. 16, 2020, and Apr. 30, 2021. After assessment, virtual physicians assigned callers to 1 of 5 triage dispositions (i.e., go to emergency department ED now, see primary care provider within 24 hours, schedule an appointment with a health care provider, try home treatment, other). We linked relevant administrative databases to ascertain subsequent health care use and outcomes.
We identified 5937 encounters with virtual physicians involving 5886 8-1-1 callers. Virtual physicians advised 1546 callers (26.0%) to go to the ED immediately, of whom 971 (62.8%) had 1 or more ED visits within 24 hours. Virtual physicians advised 556 (9.4%) callers to seek primary care within 24 hours, of whom 132 (23.7%) had primary care billings within 24 hours. Virtual physicians advised 1773 (29.9%) callers to schedule an appointment with a health care provider, of whom 812 (45.8%) had primary care billings within 7 days. Virtual physicians advised 1834 (30.9%) callers to try a home treatment, of whom 892 (48.6%) had no health system encounters over the next 7 days. Eight (0.1%) callers died within 7 days of assessment with a virtual physician, 5 of whom were advised to go to the ED immediately. Fifty-four (2.9%) callers with a "try home treatment" disposition were admitted to hospital within 7 days of a virtual physician assessment, and no callers who were advised home treatment died.
This Canadian study evaluated health service use and outcomes arising from the addition of virtual physicians to a provincial health information telephone service. Our findings suggest that supplementation of this service with an assessment from a virtual physician safely reduces the overall proportion of callers advised to seek urgent in-person visits.
Interleukin (IL)-13 has recently been shown to play important and unique roles in asthma, parasite immunity, and tumor recurrence. At least two distinct receptor components, IL-4 receptor (R)alpha ...and IL-13Ralpha1, mediate the diverse actions of IL-13. We have recently described an additional high affinity receptor for IL-13, IL-13Ralpha2, whose function in IL-13 signaling is unknown. To better appreciate the functional importance of IL-13Ralpha2, mice deficient in IL-13Ralpha2 were generated by gene targeting. Serum immunoglobulin E levels were increased in IL-13Ralpha2-/- mice despite the fact that serum IL-13 was absent and immune interferon gamma production increased compared with wild-type mice. IL-13Ralpha2-deficient mice display increased bone marrow macrophage progenitor frequency and decreased tissue macrophage nitric oxide and IL-12 production in response to lipopolysaccharide. These results are consistent with a phenotype of enhanced IL-13 responsiveness and demonstrate a role for endogenous IL-13 and IL-13Ralpha2 in regulating immune responses in wild-type mice.
Toll-Like Receptor (TLR) and IL-1 signaling is mediated by the adaptor protein MyD88 through IRAK4 activation. TLR and IL-1 family ligands activate NFkB through this pathway and stimulate ...proliferation and cell survival, as well as induce cytokine and chemokine production that can amplify tumor cell survival. The gain-of-function L265P mutation in MyD88 occurs in ∼30% of patients with activated B-cell like diffuse large B-cell lymphoma (ABC-DLBCL) and ∼90% of Waldenström's macroglobulinemia. Therefore, inhibition of IRAK4 may be therapeutically relevant in hematologic malignancies containing MyD88 mutations. Recent clinical results with kinase inhibitors strongly support a role for signaling through the B-cell receptor (BCR) pathway in the progression of hematological malignancies including ABC-DLBCL. We were interested to understand the potential utility of selective IRAK4 inhibitors in combination with inhibition of the BCR signaling networks. We have reported previously the identification and characterization of potent and selective IRAK4 inhibitors that are effective in blocking inflammatory signaling in immune cells and demonstrate efficacy in vivo in models of autoimmune disease. ND-2158, a potent (Ki of 1.2 nM) and highly selective IRAK4 inhibitor has been shown to be effective in reducing the proliferation of ABC-DLBCL cell lines. ND-2158 does not decrease cell viability for other cell lines that lack the MyD88 mutation including a germinal center-like DLBCL cell line, BJAB, suggesting that the anti-proliferative effects in ABC-DLBCL cells relate in part to the activating MyD88 mutation. Complete cross-over dose-response proliferation studies of the ABC-DLBCL cell line, OCI-LY10, were conducted using ND-2158 in combination with blockade of key BCR signaling network nodes, using inhibitors of either Btk (ibrutinib), PI3Kdelta (GS-1101), or Syk (P505-15). Isobologram analysis using the Chou-Talalay method revealed that ND-2158 was able to synergistically block cell proliferation in combination with ibrutinib, P505-15, or GS-1101. Interestingly, we find that blockade of SYK, PI3Kdelta, or BTK signaling enhances the potency of ND-2158 in ABC-DLBCL cells. The IC50 values observed in this context are comparable to the potency of ND-2158 when used as a single agent to inhibit inflammatory signaling in immune cells that are not dependent on BCR signaling. The cell proliferation blockade IC50for ND-2158 shifted from an average value of ∼7 μM to 0.19, 0.05, or 0.15 μM, when combined with the IC50 concentrations of the inhibitors of BTK, PI3Kdelta or SYK kinases, respectively. These results suggest that inhibition of both BCR signaling pathways that are amplified in ABC-DLBCL, and IRAK4 signaling activated through MyD88 mutations, are required for a more complete blockade of ABC-DLBCL proliferation. Moreover, we explored ND-2158 combination with lenalidomide, known to be synergistic with BCR and NFkB pathway inhibitors. In contrast to combinations with BCR signaling inhibition, studies with lenalidomide failed to demonstrate an additive or synergistic activity when combined with IRAK4 inhibition in ABC-DLBCL cell lines. Therefore, we conclude that IRAK4 activation, as well as aberrant BCR signaling, are likely to contribute to the proliferative capacity of ABC-DLBCL. We propose that combinatorial therapeutic approaches, including inhibition of IRAK4, may provide benefit for patients with ABC-DLBCL.
Chaudhary:Nimbus Discovery Inc.: Employment. Off Label Use: Exploratory inhibitor of IRAK4 for research purposes. Wood:Nimbus Discovery Inc.: Employment. Romero:Nimbus Discovery Inc.: Consultancy, Equity Ownership. Robinson:Schrodinger Inc. Consultant to Nimbus Discovery Inc.: Consultancy. Greenwood:Schrodinger Inc. Consultant to Nimbus Discovery Inc.: Consultancy. Shelley:Schrodinger Inc. Consultant to Nimbus Discovery Inc.: Consultancy. Morin:Nimbus Discovery Inc.: Consultancy. Kapeller:Nimbus Discovery Inc.: Employment. Westlin:Nimbus Discovery Inc.: Employment, Equity Ownership.
There is a significant body of literature on Value Added Tax (VAT) but a relatively small portion studies its impact on international trade. One of the original impetuses for the implementation of ...VAT in Europe was the trade neutral principle. The VAT system was designed to neither encourage nor discourage trade flows. Studies have primarily focused on the VAT design but the actual implementation and mechanics of VAT has been largely overlooked. This paper analyzes the mechanics of VAT system in the EU and its role in intra-EU trade. It finds the actual implementation of VAT specifically through differences in rates, exemptions, varied administrative procedures and poorly functioning rebate system diverts trade flows and in some instances a barrier to trade.
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